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Immune checkpoint inhibitor (ICI)‐associated myocarditis is a rare, potentially life‐threatening complication of immunotherapy. We report a case of a 60‐year‐old female with a history of colorectal cancer treated with nivolumab immunotherapy who presented with new cardiomyopathy complicated by cardiogenic shock and ventricular arrhythmias. Treatment of ICI‐associated myocarditis requires aggressive immunosuppression and supportive therapy. In this case, the patient required advanced mechanical circulatory support as a bridge to recovery. This case highlights the complexity of diagnosis, haemodynamic management, and treatment of fulminant ICI myocarditis.

Purpose of review Cardiovascular calcification, a common feature of atherosclerotic lesions, has long been known to associate with cardiovascular risk. The roles of lipoproteins in atherosclerosis are also established, and lipid-modifying therapies have shown capacity for plaque regression. However, the association of lipid-modifying therapies with calcification is more complex, and currently no medical therapies have been found to reverse or attenuate calcification in patients. In this review, we summarize recent developments in our understanding of the interplay between lipids and cardiovascular calcification, as well as new imaging modalities for assessing calcified atherosclerotic plaque vulnerability. Recent findings Recent clinical studies have highlighted the associations of lipoprotein subtypes, such as low-density and high-density lipoprotein particles, as well as lipoprotein (a) [Lp(a)], with coronary calcification and calcific aortic valve disease. Further, evidence continues to emerge for the utility of fused 18F-sodium fluoride positron-emission tomographic and computed tomographic (18F-NaF PET/CT) imaging in characterizing the microarchitecture and vulnerability of atherosclerotic plaque, in both humans and animal models. Summary The relationship between lipids and cardiovascular calcification is complex, and new imaging techniques, such as 18F-NaF PET/CT imaging, may allow for better identification of disease-modifying therapies and prediction of calcified plaque progression and stability to help guide clinical management.

Heart failure is a leading diagnosis for hospitalization with a high risk of readmission. Despite robust data and recommendations by professional societies, there is a well-documented gap in delivering guideline-directed medical therapy (GDMT) known to reduce hospitalizations and improve mortality for patients with heart failure with reduced ejection fraction (HFrEF). The Dashboard Activated Services and Telehealth for HF (DASH-HF) is a quality improvement initiative to evaluate the effectiveness of proactive population management clinics to optimize use and dosing of GDMT for patients with HFrEF relative to usual care. The study utilizes the existing Veterans Affairs Academic Detailing HF Dashboard to target actionable patients (n=300) with a low optimization potential score (OPS) (Table 1). The intervention clinics utilize multidisciplinary providers (e.g., physicians, pharmacists) to perform chart review and telemedicine visits to address opportunities to optimize GDMT. The primary outcome of the study is the OPS 6 months after the end of the intervention, defined by active prescriptions and prescribed doses for each class of GDMT. Secondary outcomes include differences in hospitalizations and mortality and measures of health service efficiency such as patients contacted per clinic. The intervention duration was September to December 2021, and analysis is planned for June 2022. This is a unique study to systematically identify HFrEF patients with the largest gaps in GDMT and proactively engage with this group. We describe the study design for identifying target patients, logistics of the intervention, patient characteristics, and an overview of barriers faced during the intervention. The Coronavirus disease 2019 pandemic has led to a marked increase in telehealth services. If successful, this study may serve as a key pilot trial for more robust telehealth delivery, targeting patients at highest risk for HF-related hospitalizations and mortality.

Background: Endothelial-to-mesenchymal transition (EndMT), the process whereby endothelial cells (ECs) transition into multipotent stem cell-like cells, has been implicated in a variety of cardiovascular pathologies, including cardiovascular calcification. EndMT is a dynamic mechanical process that involves detachment of transitioning ECs from adjacent cells and active migration of these cells from the endothelium into the interstitium. While gene and protein expression profiles of ECs undergoing EndMT have been well characterized, less is known about the mechanical properties, or “mechanotype,” of ECs as they undergo EndMT. Methods/Results: Human aortic endothelial cells (HAEC) were treated with the inflammatory cytokine, tumor necrosis factor-α (TNF-α), to induce inflammatory EndMT. Real-time PCR analyses showed that TNF-α significantly reduced the expression of endothelial markers ( PECAM1, NOS3 ) by 24 hours and significantly increased the expression of mesenchymal markers ( COL1A1, COL3A1, FN1, CNN1 ) starting at 48 hours of treatment. Mechanotyping of EC was performed by evaluating cell deformability with the parallel microfiltration (PMF) technique. PMF is a novel method that determines relative deformability by filtering cells across a porous membrane. Results showed that TNF-α has a biphasic effect on EC deformability, increasing the deformability after 24 hours, while decreasing deformability after 48 hours of treatment. Deformability decreased further with 96 hours of TNF-α treatment. Transwell migration assays revealed that TNF-α increased migration of ECs through a porous membrane, whereas EC migration was not enhanced when assessed by a scratch wound assay. Conclusion: Our results demonstrate that ECs undergo dynamic changes in their mechanotype during inflammatory EndMT. A deeper understanding of the mechanisms governing these changes may help inform therapeutic targets for EndMT-associated disease processes.

Background Heart transplant selection committee meetings have transitioned from in-person to remote video meetings during the COVID-19 pandemic, but how this impacts committee members and patient outcomes is unknown. Objective The aim of this study is to determine the perceived impact of remote video transplant selection meetings on usability and patient care and to measure patient selection outcomes during the transition period from in-person to virtual meetings. Methods A 35-item anonymous survey was developed and distributed electronically to the heart transplant selection committee. We reviewed medical records to compare the outcomes of patients presented at in-person meetings (January-March 2020) to those presented during video meetings (March-June 2020). Results Among 83 committee members queried, 50 were regular attendees. Of the 50 regular attendees, 24 (48%) were physicians and 26 (52%) were nonphysicians, including nurses, social workers, and coordinators; 46 responses were received, 23 (50%) from physicians and 23 (50%) from nonphysicians, with 41 responses fully completed. Overall, respondents were satisfied with the videoconference format and felt that video meetings did not impact patient care and were an acceptable alternative to in-person meetings. However, 54% (22/41) preferred in-person meetings, with 71% (15/21) of nonphysicians preferring in-person meetings compared to only 35% (7/20) of physicians (P=.02). Of the 46 new patient evaluations presented, there was a statistically nonsignificant trend toward fewer patients initially declined at video meetings compared with in-person meetings (6/24, 25% compared to 10/22, 45%; P=.32). Conclusions The transition from in-person to video heart transplant selection committee meetings was well-received and did not appear to affect committee members’ perceived ability to deliver patient care. Patient selection outcomes were similar between meeting modalities.

Coronavirus disease 2019 (COVID-19) is a global pandemic. In the USA, the burden of mortality and morbidity has fallen on minority populations. The understanding of the impact of this pandemic has been limited in Asian-Americans and Pacific Islanders (AAPIs), though disaggregated data suggest disproportionately high mortality rates. AAPIs are at high risk for COVID-19 transmission, in part due to their over-representation in the essential workforce, but also due to cultural factors, such as intergenerational residency, and other social determinants of health, including poverty and lack of health insurance. Some AAPI subgroups also report a high comorbidity burden, which may increase their susceptibility to more severe COVID-19 infection. Furthermore, AAPIs have encountered rising xenophobia and racism across the country, and we fear such discrimination only serves to exacerbate these rapidly emerging disparities in this community. We recommend interventions including disaggregation of mortality and morbidity data, investment in community-based healthcare, advocacy against discrimination and the use of non-inflammatory language, and a continued emphasis on underlying comorbidities, to ensure the protection of vulnerable communities and the navigation of this current crisis.

Background : Coronavirus disease 2019 (COVID-19) data from race/ethnic subgroups remain limited, potentially masking subgroup-level heterogeneity. We evaluated differences in outcomes in Asian American/Pacific Islander (AAPI) and Hispanic/Latino subgroups compared with non-Hispanic White patients hospitalized with COVID-19. Methods : In the American Heart Association COVID-19 registry including 105 US hospitals, mortality and major adverse cardiovascular events in adults age ≥18 years hospitalized with COVID-19 between March-November 2020 were evaluated. Race/ethnicity groups included AAPI overall and subgroups (Chinese, Asian Indian, Vietnamese, and Pacific Islander), Hispanic/Latino overall and subgroups (Mexican, Puerto Rican), compared with non-Hispanic White (NHW). Results : Among 13,511 patients, 7% were identified as AAPI (of whom 17% were identified as Chinese, 9% Asian Indian, 8% Pacific Islander, and 7% Vietnamese); 35% as Hispanic (of whom 15% were identified as Mexican and 1% Puerto Rican); and 59% as NHW. Mean [SD] age at hospitalization was lower in Asian Indian (60.4 [17.4] years), Pacific Islander (49.4 [16.7] years), and Mexican patients (57.4 [16.9] years), compared with NHW patients (66.9 [17.3] years, p

PURPOSE OF THE REVIEW: Commercial wearable biosensors are commonly used among athletes and highly active individuals, although their value in sports cardiology is not well established. In this review, we discuss the evidence for the current applications of wearables and provide our outlook for promising future directions of this emerging field. RECENT FINDINGS: The integration of routine assessment of physiological parameters, activity data, and features such as electrocardiogram recording has generated excitement over a role for wearables to help diagnose and monitor cardiovascular disease. Presently, however, there are significant challenges limiting their routine clinical use. While studies suggest that wearable-derived data may help guide training, evidence for the use of wearables in guiding exercise regimens for individuals with cardiovascular disease is lacking. Further, there is a paucity of data to demonstrate its efficacy in detecting exercise-related arrhythmias or conditions associated with sudden cardiac death. Further technological developments may lead to a greater potential for wearables to aid in sports cardiology practice. SUMMARY: The ability to collect vast amounts of physiological information can help athletes personalize training regimens. However, interpretation of these data and separating the signal from the noise are paramount, especially when used in a clinical setting. While there are currently no standardized approaches for the use of wearable-derived data in sports cardiology, we outline three domains in which they could guide the care of athletes in the future: (1) optimizing athletic performance (2) guiding exercise in athletes with known cardiovascular disease, and (3) screening for cardiovascular disease.

BackgroundDespite the association of physical activity with improved cardiovascular outcomes and the association of high coronary artery calcification (CAC) scores with poor prognosis, elite endurance athletes have increased CAC. Yet, they nevertheless have better cardiovascular survival. We hypothesized that exercise may transform vascular calcium deposits to a more stable morphology.MethodsTo test this, hyperlipidemic mice (Apoe-/-) with baseline aortic calcification were separated into 2 groups (n = 9/group) with control mice allowed to move ad-lib while the exercise group underwent a progressive treadmill regimen for 9 weeks. All mice underwent blood collections and in vivo 18F-NaF μPET/μCT imaging both at the start and end of the exercise regimen. At euthanasia, aortic root specimens were obtained for histomorphometry.ResultsResults showed that, while aortic calcification progressed similarly in both groups based on µCT, the fold change in 18F-NaF density was significantly less in the exercise group. Histomorphometric analysis of the aortic root calcium deposits showed that the exercised mice had a lower mineral surface area index than the control group. The exercise regimen also raised serum PTH levels twofold.ConclusionThese findings suggest that weeks-long progressive exercise alters the microarchitecture of atherosclerotic calcium deposits by reducing mineral surface growth, potentially favoring plaque stability.

BackgroundGaps in the receipt and dosing of guideline-directed medical therapy (GDMT) persist for patients with heart failure with reduced ejection fraction (HFrEF) [1]. In 2020, the Veterans Affairs (VA) developed a heart failure (HF) specific population dashboard to monitor care quality and performance on standard HFrEF performance measures [2].MethodsThe Dashboard Activated Services and Telehealth for HF (DASH-HF) study is a pragmatic randomized quality improvement study designed to evaluate the utility of proactive population management clinics using the VA's HF dashboard to optimize GDMT for patients with HFrEF. Panel management telemedicine clinics incorporated multidisciplinary clinicians to perform chart review and impromptu telephone encounters to evaluate current HFrEF management and opportunities to optimize GDMT. The study will evaluate the efficacy of proactive panel management to usual care at 6months as quantified by the GDMT optimization potential score. Secondary outcomes include hospitalizations, mortality, and clinician time per intervention. The study completed enrollment and randomization of 300 participants. The intervention was performed from September to December 2021.ConclusionDASH-HF will contribute to the literature by evaluating use of the existing VA dashboard to identify HF patients with the lowest adherence to GDMT and proactively target this group for the intervention.Registrationhttps://clinicaltrials.gov/. Unique identifier: NCT05001165.

Ventricular arrhythmias are challenging to manage in athletes with concern for an elevated risk of sudden cardiac death (SCD) during sports competition. Monomorphic ventricular arrhythmias (MMVA), while often benign in athletes with a structurally normal heart, are also associated with a unique subset of idiopathic and malignant substrates that must be clearly defined. A comprehensive evaluation for structural and/or electrical heart disease is required in order to exclude cardiac conditions that increase risk of SCD with exercise, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Unique issues for physicians who manage this population include navigating athletes through the decision of whether they can safely continue their chosen sport. In the absence of structural heart disease, therapies such as radiofrequency catheter ablation are very effective for certain arrhythmias and may allow for return to competitive sports participation. In this comprehensive review, we summarise the recommendations for evaluating and managing athletes with MMVA.

Author(s): Dixit, Neal M; Shah, Shivani; Ziaeian, Boback; Fonarow, Gregg C; Hsu, Jeffrey J | Abstract: Heart failure remains a huge societal concern despite medical advancement, with an annual direct cost of over $30 billion. While guideline-directed medical therapy (GDMT) is proven to reduce morbidity and mortality, many eligible patients with heart failure with reduced ejection fraction (HFrEF) are not receiving one or more of the recommended medications, often due to suboptimal initiation and titration in the outpatient setting. Hospitalization serves as a key point to initiate and titrate GDMT. Four evidence-based therapies have clinical benefit within 30 days of initiation and form a crucial foundation for HFrEF therapy: renin-angiotensin-aldosterone system inhibitors with or without a neprilysin inhibitor, β-blockers, mineralocorticoid-receptor-antagonists, and sodium-glucose cotransporter-2 inhibitors. The authors present a practical guide for the implementation of these four pillars of GDMT during a hospitalization for acute heart failure.

Background The COVID-19 pandemic has introduced numerous changes to clinical and administrative practices in heart transplantation. One change is the transition of transplant selection committee meetings from in-person to remote video conference in order to maintain social distancing requirements. The impact of this transition on committee members and patient care is unknown. Methods A 35-item anonymous survey, adapted from the validated Telehealth Usability Questionnaire, was developed and distributed electronically to the UCLA heart transplant selection committee. Quantitative and qualitative descriptive analyses were performed. Results Of 83 committee members queried, 46 (55%) responded. 50% were non-physician members and 50% were physician members, including 48% cardiologists, 13% anesthesiologists, and 9% surgeons. Over a 6 week period, there was a 5% increase in the average number of attendees from in-person to video meetings. Respondents were satisfied with the ease of use, interface quality, and interaction quality of the video conference system, except for the ability to see meeting attendees. Overall, respondents were satisfied with video meetings, agreeing that they could contribute effectively and achieve their goals over video. However, if given the choice, 54% still preferred the in-person format. Respondents did not feel that video meetings impacted patient care, such as ability to clarify clinical questions, create management plans, and determine and/or update transplant listing status. Multitasking, technology integration, and location convenience were the predominant positive aspects of video meetings, while communication was the main negative, including inability to see attendees, audio interruptions and barriers to communication flow. Communication and clinical decision-making were the predominant positive aspects of in-person meetings (Figure). Conclusions The transition from in-person to remote video conference heart transplantation selection committee meetings during the COVID-19 era has been well-received and does not appear to affect committee members’ perception of their ability to deliver patient care. Future, longer-term studies are needed to evaluate the impact of video meetings on transplant-related outcomes.

The infectious disease Coronavirus Disease 2019 (COVID‐19) was declared a pandemic by the World Health Organization in March 2020. The impact of COVID‐19 on solid organ transplantations, including heart transplantation, is currently unclear. Many transplant programs have been forced to swiftly re‐evaluate and adapt their practices, leading to a marked decrease in transplants performed. This trend has been due to various factors, including increased donor COVID‐19 screening scrutiny and recipient waiting list management in anticipation of COVID‐19 critical care surge capacity planning. In the face of these unknown variables, determining when and how to proceed with transplantation in our population of patients with end‐stage cardiomyopathies is challenging. Here, we describe our center’s experience with orthotopic heart transplantation (OHT) in one of the country’s pandemic epicenters, where we performed eight OHTs in the first two months after community spread began in late February 2020.

The COVID-19 pandemic has brought into sharp focus the need to harness and leverage our digital infrastructure for remote patient monitoring. As current viral tests and vaccines are slow to emerge, we see a need for more robust disease detection and monitoring of individual and population health, which could be aided by wearable sensors. While the utility of this technology has been used to correlate physiological metrics to daily living and human performance, the translation of such technology toward predicting the incidence of COVID-19 remains a necessity. When used in conjunction with predictive platforms, users of wearable devices could be alerted when changes in their metrics match those associated with COVID-19. Anonymous data localized to regions such as neighborhoods or zip codes could provide public health officials and researchers a valuable tool to track and mitigate the spread of the virus, particularly during a second wave. Identifiable data, for example remote monitoring of cohorts (family, businesses, and facilities) associated with individuals diagnosed with COVID-19, can provide valuable data such as acceleration of transmission and symptom onset. This manuscript describes clinically relevant physiological metrics which can be measured from commercial devices today and highlights their role in tracking the health, stability, and recovery of COVID-19+ individuals and front-line workers. Our goal disseminating from this paper is to initiate a call to action among front-line workers and engineers toward developing digital health platforms for monitoring and managing this pandemic.

Currently, there is a limited ability to interactively study developmental cardiac mechanics and physiology. We therefore combined light-sheet fluorescence microscopy (LSFM) with virtual reality (VR) to provide a hybrid platform for 3D architecture and time-dependent cardiac contractile function characterization. By taking advantage of the rapid acquisition, high axial resolution, low phototoxicity, and high fidelity in 3D and 4D (3D spatial + 1D time or spectra), this VR-LSFM hybrid methodology enables interactive visualization and quantification otherwise not available by conventional methods, such as routine optical microscopes. We hereby demonstrate multiscale applicability of VR-LSFM to (a) interrogate skin fibroblasts interacting with a hyaluronic acid–based hydrogel, (b) navigate through the endocardial trabecular network during zebrafish development, and (c) localize gene therapy-mediated potassium channel expression in adult murine hearts. We further combined our batch intensity normalized segmentation algorithm with deformable image registration to interface a VR environment with imaging computation for the analysis of cardiac contraction. Thus, the VR-LSFM hybrid platform demonstrates an efficient and robust framework for creating a user-directed microenvironment in which we uncovered developmental cardiac mechanics and physiology with high spatiotemporal resolution.A user-directed perspective for studying cardiac mechanics, physiology, and developmental biology at single-cell resolution.

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is rapidly infecting people worldwide, resulting in the infectious disease coronavirus disease 19 (COVID‐19) that has been declared a pandemic. Much remains unknown about COVID‐19, including its effects on solid organ transplant (SOT) recipients. Given their immunosuppressed state, SOT recipients are presumed to be at high risk of complications with viral infections such as SARS‐CoV‐2. Limited case reports in single SOT recipients, however, have not suggested a particularly severe course in this population. In this report, we present a dual‐organ (heart/kidney) transplant recipient who was found to have COVID‐19 and, despite the presence of a number of risk factors for poor outcomes, had a relatively mild clinical course.

The advent of 4-dimensional (4D) light-sheet fluorescence microscopy (LSFM) has provided an entry point for rapid image acquisition to uncover real-time cardiovascular structure and function with high axial resolution and minimal photo-bleaching/-toxicity. We hereby review the fundamental principles of our LSFM system to investigate cardiovascular morphogenesis and regeneration after injury. LSFM enables us to reveal the micro-circulation of blood cells in the zebrafish embryo and assess cardiac ventricular remodeling in response to chemotherapy-induced injury using an automated segmentation approach. Next, we review two distinct mechanisms underlying zebrafish vascular regeneration following tail amputation. We elucidate the role of endothelial Notch signaling to restore vascular regeneration after exposure to the redox active ultrafine particles (UFP) in air pollutants. By manipulating the blood viscosity and subsequently, endothelial wall shear stress, we demonstrate the mechanism whereby hemodynamic shear forces impart both mechanical and metabolic effects to modulate vascular regeneration. Overall, the implementation of 4D LSFM allows for the elucidation of mechanisms governing cardiovascular injury and regeneration with high spatiotemporal resolution.

Rociletinib is a new third generation epidermal growth factor receptor tyrosine kinase inhibitor (TKI) treatment for non-small cell lung cancer. Known side effects include hyperglycemia and QT prolongation. We describe the first case of rociletinib associated macroscopic pseudo-T wave alternans with

Understanding of vitamin D physiology is important because about half of the population is being diagnosed with deficiency and treated with supplements. Clinical guidelines were developed based on observational studies showing an association between low serum levels and increased cardiovascular risk. However, new randomized controlled trials have failed to confirm any cardiovascular benefit from supplementation in the general population. A major concern is that excess vitamin D is known to cause calcific vasculopathy and valvulopathy in animal models. For decades, administration of vitamin D has been used in rodents as a reliable experimental model of vascular calcification. Technically, vitamin D is a misnomer. It is not a true vitamin because it can be synthesized endogenously through ultraviolet exposure of the skin. It is a steroid hormone that comes in 3 forms that are sequential metabolites produced by hydroxylases. As a fat-soluble hormone, the vitamin D-hormone metabolites must have special mechanisms for delivery in the aqueous bloodstream. Importantly, endogenously synthesized forms are carried by a binding protein, whereas dietary forms are carried within lipoprotein particles. This may result in distinct biodistributions for sunlight-derived versus supplement-derived vitamin D hormones. Because the cardiovascular effects of vitamin D hormones are not straightforward, both toxic and beneficial effects may result from current recommendations.

AimsRedox active ultrafine particles (UFP, d

Heart failure (HF) with borderline ejection fraction was first defined in 2013 in the American College of Cardiology/American Heart Association guidelines as the presence of the typical symptoms of HF and a left ventricular ejection fraction (LVEF) of 41% to 49%. In 2016, the European Society of Cardiology specified HF with mid-range ejection fraction (HFmrEF) as LVEF of 40% to 49%. This range of LVEF is less well studied compared with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). Although there are effective, guideline-directed medical therapies for patients with HFrEF, no therapies thus far show measurable benefit in HFpEF. Patients with HFmrEF have a clinical profile and prognosis that are closer to those of patients with HFpEF than those of HFrEF, with certain distinctions. Whether these patients represent a unique and dynamic HF group that may benefit from targeted therapies known to be beneficial in patients with HFrEF, such as neurohormonal blockade, requires further study. This review summarizes what is known about the clinical epidemiology, pathophysiology, and prognosis for patients with HFmrEF and how these features compare with the more well-studied HF groups. Although recommended treatments currently focus on aggressive management of comorbidities, we summarize the studies that identify a potential signal for beneficial therapies. Future studies are needed to not only better characterize the HFmrEF population but to also determine effective management strategies to reduce the high cardiovascular morbidity and mortality burden on this phenotype of patients with HF.

Despite the association of physical activity with improved cardiovascular outcomes and the association of high coronary artery calcification (CAC) scores with poor prognosis, elite endurance athletes have increased CAC. Yet, they nevertheless have better cardiovascular survival. We hypothesized that exercise may transform vascular calcium deposits to a more stable morphology. To test this, hyperlipidemic mice (Apoe(−/−)) with baseline aortic calcification were separated into 2 groups (n = 9/group) with control mice allowed to move ad-lib while the exercise group underwent a progressive treadmill regimen for 9 weeks. All mice underwent blood collections and in vivo (18)F-NaF μPET/μCT imaging both at the start and end of the exercise regimen. At euthanasia, aortic root specimens were obtained for histomorphometry. Results showed that, while aortic calcification progressed similarly in both groups based on μCT, the fold change in (18)F-NaF density was significantly less in the exercise group. Histomorphometric analysis of the aortic root calcium deposits showed that the exercised mice had a lower mineral surface area index than the control group. The exercise regimen also raised serum PTH levels two-fold. These findings suggest that weeks-long progressive exercise alters the microarchitecture of atherosclerotic calcium deposits by reducing mineral surface growth, potentially favoring plaque stability.

Biomechanical forces and endothelial-mesenchymal transition (EndoMT) are known to mediate valvulogenesis. However, the relative contributions of myocardial contractile and hemodynamic shear forces remain poorly understood. We integrated 4D light-sheet imaging of transgenic zebrafish models with moving-domain computational fluid dynamics to determine effects of changes in contractile forces and fluid wall shear stress (WSS) on ventriculobulbar (VB) valve development. Augmentation of myocardial contractility with isoproterenol increased both WSS and Notch1b activity in the developing outflow tract (OFT) and resulted in VB valve hyperplasia. Increasing WSS in the OFT, achieved by increasing blood viscosity through EPO mRNA injection, also resulted in VB valve hyperplasia. Conversely, decreasing myocardial contractility by Tnnt2a morpholino oligonucleotide (MO) administration, 2,3-butanedione monoxime treatment, or Plcγ1 inhibition completely blocked VB valve formation, which could not be rescued by increasing WSS or activating Notch. Decreasing WSS in the OFT, achieved by slowing heart rate with metoprolol or reducing viscosity with Gata1a MO, did not affect VB valve formation. Immunofluorescent staining with the mesenchymal marker, DM-GRASP, revealed that biomechanical force–mediated Notch1b activity is implicated in EndoMT to modulate valve morphology. Altogether, increases in WSS result in Notch1b- and EndoMT-mediated VB valve hyperplasia, whereas decreases in contractility result in reduced Notch1b activity, absence of EndoMT, and VB valve underdevelopment. Thus, we provide developmental mechanotransduction mechanisms underlying Notch1b-mediated EndoMT in the OFT.

Post-Acute COVID-19 Syndrome (PACS) is defined by persistent symptoms >3–4 weeks after onset of COVID-19. The mechanism of these persistent symptoms is distinct from acute COVID-19 although not completely understood despite the high incidence of PACS. Cardiovascular symptoms such as chest pain and palpitations commonly occur in PACS, but the underlying cause of symptoms is infrequently known. While autopsy studies have shown that the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) rarely causes direct myocardial injury, several syndromes such as myocarditis, pericarditis, and Postural Orthostatic Tachycardia Syndrome have been implicated in PACS. Additionally, patients hospitalized with acute COVID-19 who display biomarker evidence of myocardial injury may have underlying coronary artery disease revealed by the physiological stress of SARS-CoV-2 infection and may benefit from medical optimization. We review what is known about PACS and the cardiovascular system and propose a framework for evaluation and management of related symptoms.

As immunotherapy use in various malignancies expands, immune checkpoint inhibitor (ICI) myocarditis is a rare but potentially fatal complication requiring a high degree of clinical suspicion for early diagnosis and treatment. A 60 year-old female with colon cancer status post 3 months of nivolumab

The ability to image tissue morphogenesis in real-time and in 3-dimensions (3-D) remains an optical challenge. The advent of light-sheet fluorescence microscopy (LSFM) has advanced developmental biology and tissue regeneration research. In this review, we introduce a LSFM system in which the illumination lens reshapes a thin light-sheet to rapidly scan across a sample of interest while the detection lens orthogonally collects the imaging data. This multiscale strategy provides deep-tissue penetration, high-spatiotemporal resolution, and minimal photobleaching and phototoxicity, allowing in vivo visualization of a variety of tissues and processes, ranging from developing hearts in live zebrafish embryos to ex vivo interrogation of the microarchitecture of optically cleared neonatal hearts. Here, we highlight multiple applications of LSFM and discuss several studies that have allowed better characterization of developmental and pathological processes in multiple models and tissues. These findings demonstrate the capacity of multiscale light-sheet imaging to uncover cardiovascular developmental and regenerative phenomena.

The hemodynamic forces experienced by the heart influence cardiac development, especially trabeculation, which forms a network of branching outgrowths from the myocardium. Genetic program defects in the Notch signaling cascade are involved in ventricular defects such as Left Ventricular Non-Compaction Cardiomyopathy or Hypoplastic Left Heart Syndrome. Using this protocol, it can be determined that shear stress driven trabeculation and Notch signaling are related to one another. Using Light-sheet Fluorescence Microscopy, visualization of the developing zebrafish heart was possible. In this manuscript, it was assessed whether hemodynamic forces modulate the initiation of trabeculation via Notch signaling and thus, influence contractile function occurs. For qualitative and quantitative shear stress analysis, 4-D (3-D+time) images were acquired during zebrafish cardiac morphogenesis, and integrated light-sheet fluorescence microscopy with 4-D synchronization captured the ventricular motion. Blood viscosity was reduced via gata1a-morpholino oligonucleotides (MO) micro-injection to decrease shear stress, thereby, down-regulating Notch signaling and attenuating trabeculation. Co-injection of Nrg1 mRNA with gata1a MO rescued Notch-related genes to restore trabeculation. To confirm shear stress driven Notch signaling influences trabeculation, cardiomyocyte contraction was further arrested via tnnt2a-MO to reduce hemodynamic forces, thereby, down-regulating Notch target genes to develop a non-trabeculated myocardium. Finally, corroboration of the expression patterns of shear stress-responsive Notch genes was conducted by subjecting endothelial cells to pulsatile flow. Thus, the 4-D light-sheet microscopy uncovered hemodynamic forces underlying Notch signaling and trabeculation with clinical relevance to non-compaction cardiomyopathy.

Hemodynamic shear force has been implicated as modulating Notch signaling-mediated cardiac trabeculation. Whether the spatiotemporal variations in wall shear stress (WSS) coordinate the initiation of trabeculation to influence ventricular contractile function remains unknown. Using light-sheet fluorescent microscopy, we reconstructed the 4D moving domain and applied computational fluid dynamics to quantify 4D WSS along the trabecular ridges and in the groves. In WT zebrafish, pulsatile shear stress developed along the trabecular ridges, with prominent endocardial Notch activity at 3 days after fertilization (dpf), and oscillatory shear stress developed in the trabecular grooves, with epicardial Notch activity at 4 dpf. Genetic manipulations were performed to reduce hematopoiesis and inhibit atrial contraction to lower WSS in synchrony with attenuation of oscillatory shear index (OSI) during ventricular development. γ-Secretase inhibitor of Notch intracellular domain (NICD) abrogated endocardial and epicardial Notch activity. Rescue with NICD mRNA restored Notch activity sequentially from the endocardium to trabecular grooves, which was corroborated by observed Notch-mediated cardiomyocyte proliferations on WT zebrafish trabeculae. We also demonstrated in vitro that a high OSI value correlated with upregulated endothelial Notch-related mRNA expression. In silico computation of energy dissipation further supports the role of trabeculation to preserve ventricular structure and contractile function. Thus, spatiotemporal variations in WSS coordinate trabecular organization for ventricular contractile function.

Cardiac valve formation is a complex process affected by blood flow, but the mechanotransduction mechanisms underlying valvulogenesis remain incompletely understood. Using four-dimensional (4-D) light-sheet imaging, we evaluated the effects of pharmacological and genetic hemodynamic modulation on ventriculobulbar (VB) valve formation in the outflow tracts (OFT) of transgenic Tg(fli1a:GFP) zebrafish embryos. Treatment with isoproterenol increased heart rate and cardiac contractility, increased Notch1b activity in the OFT, and resulted in the development of hyperplastic VB valve leaflets. While metoprolol treatment reduced heart rate without affecting contractility, there were no significant differences in Notch1b expression in the OFT or valve morphology. Meanwhile, BDM treatment significantly reduced heart rate and contractility, reduced Notch1b expression in the OFT, and prevented the formation of normal VB valve leaflets. Similarly, no VB valve leaflets were seen in the cloche mutant or Tnnt2a MO-injected embryos. Additionally, increasing blood viscosity by micro-injection of embryos with EPO mRNA increased Notch1b activity in the OFT and led to hyperplastic VB valve leaflets, but decreasing blood viscosity by gata1a MO micro-injection did not have any significant effect. Further, activation of the Notch signaling pathway with micro-injection of NICD mRNA resulted in hyperplastic VB valve leaflets. By integrating advanced optics with zebrafish genetics at the interface of developmental cardiac mechanics, we provide mechanotransduction insights into cardiac valve development within the OFT.

Purpose of Review: Real-time 3-dimensional (3-D) imaging of cardiovascular injury and regeneration remains challenging. We introduced a multi-scale imaging strategy that uses light-sheet illumination to enable applications of cardiovascular injury and repair in models ranging from zebrafish to rodent hearts. Recent Findings: Light-sheet imaging enables rapid data acquisition with high spatiotemporal resolution and with minimal photo-bleaching or photo-toxicity. We demonstrated the capacity of this novel light-sheet approach for scanning a region of interest with specific fluorescence contrast, thereby providing axial and temporal resolution at the cellular level without stitching image columns or pivoting illumination beams during one-time imaging. This cutting-edge imaging technique allows for elucidating the differentiation of stem cells in cardiac regeneration, providing an entry point to discover novel micro-circulation phenomenon with clinical significance for injury and repair. Summary: These findings demonstrate the multi-scale applications of this novel light-sheet imaging strategy to advance research in cardiovascular development and regeneration.

Calcific aortic vasculopathy correlates with bone loss in osteoporosis in an age-independent manner. Prior work suggests that teriparatide, the bone anabolic treatment for postmenopausal osteoporosis, may inhibit the onset of aortic calcification. Whether teriparatide affects the progression of preexisting aortic calcification, widespread among this patient population, is unknown. Female apolipoprotein E-deficient mice were aged for over 1 yr to induce aortic calcification, treated for 4.5 wk with daily injections of control vehicle (PBS), 40 µg/kg teriparatide (PTH40), or 400 µg/kg teriparatide (PTH400), and assayed for aortic calcification by microcomputed tomography (microCT) before and after treatment. In a followup cohort, aged female apolipoprotein E-deficient mice were treated with PBS or PTH400 and assayed for aortic calcification by serial microCT and micropositron emission tomography. In both cohorts, aortic calcification detected by microCT progressed similarly in all groups. Mean aortic 18F-NaF incorporation, detected by serial micropositron emission tomography, increased in the PBS-treated group (+14 ± 5%). In contrast, 18F-NaF incorporation decreased in the PTH400-treated group (−33 ± 20%, P = 0.03). Quantitative histochemical analysis by Alizarin red staining revealed a lower mineral surface area index in the PTH400-treated group compared with the PBS-treated group ( P = 0.04). Furthermore, Masson trichrome staining showed a significant increase in collagen deposition in the left ventricular myocardium of mice that received PTH400 [2.1 ± 0.6% vs. control mice (0.5 ± 0.1%), P = 0.02]. In summary, although teriparatide may not affect the calcium mineral content of aortic calcification, it reduces 18F-NaF uptake in calcified lesions, suggesting the possibility that it may reduce mineral surface area with potential impact on plaque stability. NEW & NOTEWORTHY Parathyroid hormone regulates bone mineralization and may also affect vascular calcification, which is an important issue, given that its active fragment, teriparatide, is widely used for the treatment of osteoporosis. To determine whether teriparatide alters vascular calcification, we imaged aortic calcification in mice treated with teriparatide and control mice. Although teriparatide did not affect the calcium content of cardiovascular deposits, it reduced their fluoride tracer uptake.