Research Funding

Background: Cardiac rehabilitation (CR) is a comprehensive secondary prevention program involving exercise training, behavioral activation, and psychosocial support following cardiac events such as myocardial infarction, coronary revascularization, valve replacement. Randomized clinical trials (RCT) have demonstrated lower mortality and greater physical, mental, and social functioning in patients who participate in CR vs. usual care. However, the long-term mortality benefit of CR is directly proportional to the number of sessions completed, and less than half of Veterans who enroll in CR complete the recommended number of sessions. Significance: Home-based CR (HBCR) is an alternative to traditional CR programs that has comparable efficacy in improving morbidity/mortality and increases access to critical services. Improving participation in home-based CR has been identified as a major priority by the National Director of Cardiology. We propose to test a novel and easily scalable interve

ABSTRACT Nearly 63 million people (20% of the US population) are eligible for VA benefits and services because they are veterans, family members or survivors of veterans. Cardiovascular diseases (CVD) contribute to significant morbidity and mortality of the military veterans and civilians (CDC/National Center for Health Statistics). I have been associated with VA and non-VA funded clinician-scientists and basic researchers for the past 25 years. I am also a VA funded investigator. The overall focus of my research as a VA funded scientist is to investigate the causal role of inflammation, inflammatory cytokines and chemokines, and inhibitors of inflammation in CVD. Since inflammation is a critical component in the pathogenesis of CVD, and CVD are the major contributing factors for morbidity and mortality within both military veteran and civilian populations of both sexes, my studies are highly relevant to the VA mission. Since hypertension, diabetes, obesity, and smoking predispose vet

Project Summary Functional mitral regurgitation (FMR) portends a bleak prognosis and is a common consequence of ischemic and non-ischemic cardiomyopathy (ICM, NICM), where adverse annular and left ventricular (LV) remodeling and/or infarction alters mitral valve (MV) function. Prior studies demonstrate significant increases in mortality risk as severity of FMR increases; mortality rates range from 15-40% at 1 year. Furthermore, as the prevalence of heart failure (HF) is rising, FMR is projected to double from over 2 million patients in 2000 to over 4 million patients in the United States by 2030. Defining FMR severity, optimal timing of intervention, and most appropriate method for intervention remain controversial. Recently, MITRA-FR and COAPT trials demonstrated contrasting survival benefit with percutaneous MV repair, demonstrating the importance and need for more optimal selection criteria. Currently, the patient selection criteria for Mitraclip therapy are solely based on MV anat

Project Summary Valvular heart disease is an important health problem afflicting over 2.5% of the US population and catheter- based therapies to address it have advanced significantly in recent years. While surgical repair remains the gold standard, the reduced risk of catheter-based interventions has provided the ability to intervene earlier in the disease process and in patients too sick for surgery while avoiding the risks of cardiopulmonary bypass. A significant limitation of these procedures, however, is that they do not provide the capability to remove native tissue and previously implanted devices to tailor the anatomy to receive a new prosthetic device. For example, transcatheter valves rely on displacing the diseased valve leaflets rather than removing them. In transcatheter aortic valve replacement, the displaced leaflets can obstruct blood flow to the coronary arteries and prevent access for subsequent coronary interventions. In transcatheter mitral valve replacement, the na

ABSTRACT: Approximately 5-10% of older adults have aortic stenosis (AS) with anticipated doubling by 2050; with no available medical therapy to slow progression, treatment is limited to aortic valve replacement (AVR). While AVR has historically been reserved for symptomatic severe AS, cardiac remodeling and irreversible injury occur before the onset of symptoms and before AS is "severe" and contribute to death and persistent heart failure (HF) symptoms/rehospitalization in up to 40% of patients 1 year after AVR, suggesting that AVR before onset of irreversible changes to the heart is likely to improve post-AVR outcomes. Fortunately, randomized strategy trials are underway to test the benefit of earlier less invasive transcatheter AVR (TAVR) before symptoms and severe AS. However, earlier TAVR isn't a panacea; beyond inherent procedural risks, this will also lead to more repeat procedures (with risks/costs) when prosthetic valves degenerate. Echocardiography and standard biomarkers (e.g

PROJECT SUMMARY A broad range of diseases, from hypertension to structural heart diseases like aortic stenosis or coarctation of the aorta, cause pressure overload stress on the heart. In response, the heart undergoes hypertrophy (called pressure overload hypertrophy or POH) which can promote adaptation or cause heart failure. Understanding the mechanism underlying these opposite clinical outcomes would create new therapeutic opportunities. The unstressed heart relies mainly on fatty acids for fuel but alters energy sources depending on availability. POH causes the heart to increase its reliance on glucose for energy, but, unfortunately, this metabolic inflexibility impacts hypertrophic growth and ventricular dysfunction. Therefore, improving the balance of sources used for fuel generation during POH could promote adaptation but therapies targeting this approach have not been realized partially because the mechanisms underlying these metabolic changes are incompletely known. Our prelim

SUMMARY Bioprosthetic heart valves (BHV), made from glutaraldehyde-fixed xenografts, are widely used for surgical (SAVR) and transcatheter valve interventions (TAVR), but suffer from limited durability due to Structural Valve Degeneration (SVD). Advances in BHV device engineering and delivery have created the possibility to provide state-of-the-art care to heart valve disease patients that were once deemed inoperable due to their risk score and advanced co-morbidities. However, the same class of devices is offered to all patients, irrespectively of their co-morbidities and susceptibility to structural valve degeneration. Metabolic syndrome (MetS) is a common comorbidity in patients who require BHV and is a known risk factor for cardiovascular diseases. Our published and preliminary results show the enhanced susceptibility of bio-implantable materials to oxidation, glycation, pro- calcific proteins, and crosslinkers in patients with Metabolic Syndrome or rodent model of MetS, using Zuck

Aortic stenosis (AS) is a valve condition that affects over 12.6 million adults and causes an estimated 102,700 deaths each year. Many patients with AS do not know about the diagnosis because it is difficult to diagnose with a stethoscope. It is estimated that there are over 560,000 undiagnosed cases of AS in the United States alone. When patients with symptomatic AS are not treated, 50% will die in 2 years. We have developed a method to automate the diagnosis of AS from cardiac ultrasound imaging using machine learning. This represents a new way to diagnose AS. In this proposal we will improve these networks to reliably identify severe AS patients that should be referred for evaluation. Additionally, we will train the networks to work with portable handheld ultrasound devices and we will study how to implement this tool in primary care offices to screen high risk patients. By developing and validating innovative machine learning (ML) methods for diagnosing AS we will establish tools t

ABSTRACT Aortic stenosis is one of the most common and serious heart valve disease problems, in which the aortic valve opening is narrowed and the left ventricle is under greater load to pump sufficient blood to the body. Transcatheter aortic valve replacement (TAVR) is a minimally invasive and now common approach for treating this disease. However, the long-term durability of transcatheter bioprosthetic valves has become a major concern due to bioprosthetic structural valve degeneration (SVD), a well-known complication post-TVAR and the main cause of impaired valve durability. SVD is a multifactorial process presented as leaflet calcification of the prosthetic valve, leading to valve dysfunction (stenosis and/or wear and tear). To address the SVD and early valve failure, we have identified a new tissue material based on the pulmonary visceral pleura (PVP) that promises to be a superior candidate for the bioprosthetic valve. The bioprosthetic valves for the current TAVR are typically m

PROJECT SUMMARY Our long-term goal is to specify how patient-specific blood cell activities become altered in transcatheter aortic valve replacement (TAVR) in order to optimize the management of patients with aortic valve diseases. The objective of this application is to determine how patient-specific hematological, physiological and procedural factors promote platelet-driven procoagulant and inflammatory complications in TAVR. Our central hypothesis is that patient-specific biochemical and blood flow features in TAVR support the activation of platelet signaling responses, which promote procoagulant platelet generation and responses underlying transcatheter heart valve (THV) complications and degeneration. This hypothesis is rooted in our preliminary data that: 1) activated platelets adhere to THVs in vivo in a manner related to subclinical leaflet thrombosis (SLT); 2) GPVI-mediated platelet procoagulant signaling responses and fibrin formation are upregulated in TAVR patients; 3) pati

Abstract Diseases affecting the heart valves are among the most common type of cardiovascular medical condition affecting 2.5% of the population in the United States. The aortic valve is the most often affected and encompasses both congenital and acquired forms. Congenital aortic valve disease is the result of a malformed valve and represents the most common type of congenital heart defect when including bicuspid aortic valve (BAV), which has a prevalence of 1-2% in the population. At birth, diseased aortic valves are often myxomatous with bicuspid valve morphology and display congenital aortic valve stenosis (AVS). If untreated, congenital AVS results in progressive left ventricular hypertrophy and ultimately heart failure. Severe congenital AVS is treated with surgical or catheter-based valve intervention or replacement. Accordingly, there is a critical need for pharmacologic therapies for AVS that will obviate the need for surgical intervention. We were the first to discover that p

SUMMARY: Pulmonary Hypertension (PH) is a severe and life-threatening disease that increases mortality rates by 7-fold. Pulmonary Arterial Hypertension (PAH, WHO Group 1) is the most severe subtype, with a median survival of just three years. PAH must be distinguished from another subtype called Pulmonary Venous Hypertension (PVH, WHO Group 2) because PAH treatments can harm PVH patients. Unfortunately, the current diagnostic and prognostic process for PAH is slow, taking 2-4 years after symptom onset, and relies on a series of costly, inconclusive, noninvasive tests ending with invasive catheterization for conclusive diagnosis. Delays and invasive diagnostics worsen patient suffering and jeopardize the chances of early effective treatment. Thus, there is an urgent need for a streamlined, accurate non-invasive tool for PAH diagnosis, classification, and prognosis. Our project aims to develop a '4D Right-Heart Virtual Catheter (vCath)' capable of providing a comprehensive hemodynamic an

PROJECT SUMMARY Coarctation of the aorta (CoA), a severe congenital narrowing of the aorta, is one of the most common forms of congenital heart defects with a reported prevalence of approximately 4 per 10,000 live births. It is the second most costly form of congenital heart disease with pediatric costs in excess of $300M annually, the majority of which incur shortly after birth. After birth, catastrophic deficits to blood flow can occur and post-natal surgical correction is required to restore normal blood flow to the brain and body. The current method of prenatal diagnosis relies on fetal echocardiography. Fetal echocardiography is hampered by many difficulties visualizing the fetal aortic arch during later gestations, and as a result, and to avoid a missed diagnosis, there is a high false positive rate of fetal echocardiography for CoA, approaching 50%. The consequence of a prenatal diagnosis of CoA is intensive third trimester and perinatal care, change in delivery location, and im

Abstract Motion effects (including respiratory motion, body motion, cardiac motion) and associated mismatched attenuation correction substantially degrade the cardiac PET image quality and quantitative accuracy. Although a number of motion correction methods have been implemented on clinical scanners, they 1) are largely respiratory motion corrections requiring external motion tracking hardware; and 2) does not take into account motion-induced PET-CT mismatch in attenuation correction. The correction of motion for 82Rb cardiac dynamic PET imaging is particularly challenging, as the rapid tracer kinetics of 82Rb leads to substantial tracer distribution change in the dynamic frame images over time. 82Rb’s ultra-short half-life of only 75 seconds also poses additional significant challenges of image noise. In this R01, we propose to develop a series of motion correction methods with aligned PET-CT for both static and dynamic cardiac applications. All the new developments proposed here are

Valvular heart disease represents a major public health problem worldwide. The incidence of valvular heart disease increases with age, and it is estimated that about 15% of the population above the age of 75 years suffer from some form of significant valvular disorder. Mitral regurgitation (MR) is the most frequent form of valvular heart diseases, where it is estimated that moderate and severe MR occurs at a frequency of 1.7% as adjusted to the US adult population, and up to 5% of the population in Europe have significant mitral valve disease. The natural history of chronic MR is characterized by a compensated hemodynamic state in its early phases, followed by a gradual progressive left ventricular (LV) remodeling and eccentric hypertrophy resulting in heart failure. MR patients with depressed systolic function can present a difficult management dilemma; corrective valve surgery is not recommended, and medical therapy is ineffective in preventing LV dysfunction. It should perhaps be no

PROJECT SUMMURY/ABSTRACT Valvular heart disease (VHD) is the third-most common cause of heart problems in the United States, with mitral valve disease as the second-most common VHD after aortic stenosis. Mitral valve disease can cause many complications if left untreated and is more common in younger patients, in whom bioprosthetic heart valves (BHVs) are prone to faster degeneration. An ultimate solution for younger patients with long life expectancy is a living tissue valve, although exploratory studies for tissue-engineered heart valve (TEHVs) have yet to satisfy the regulatory requirements for clinical use. In preclinical studies, current TEHVs have been unable to adjust their composition to withstand the hemodynamic loads to which they would be exposed, and their leaflets were found to shrink due to their degradable scaffolds, which led to poor leaflet coaptation, followed by progressive regurgitation and valvular insufficiency. The native mitral valve is bileaflet, with a saddle-

SUMMARY Despite legislation and federal initiatives, such as the Pediatric Device Consortia Grants Program, intended to facilitate pediatric medical device development, innovation for pediatric cardiac patients continues to lag behind the advances made for adult devices, making children requiring reconstructive heart surgery an underserved population. All implantable biomaterials (glutaraldehyde bovine pericardium, xenograft valves and conduits, cryopreserved allografts, autologous pericardium, and collagen bioscaffolds) as well as some artificial polymers are subjected to structural degeneration driven by calcification (via passive calcium deposition and absorption of calcium-binding proteins) and – as discovered by our group – by glyco-oxidation, which via permanent incorporation of glycated protein and cross-links formation, alters the architecture and mechanical proprieties of biomaterials. This resubmitted application has two overarching goals: to understand the mechanisms of acce

SUMMARY Left ventricular (LV) pressure overload caused by conditions such as chronic hypertension or aortic stenosis is a significant risk factor for the development of heart failure. A decline in microbial diversity caused by certain antibiotics also increases the risk of heart failure, suggesting that the gut harbors cardioprotective microbes. However, our current knowledge of which microbes are cardioprotective and which have deleterious cardiac effects is inadequate, not allowing us to leverage gut microbial manipulation with antibiotics to treat or mitigate heart failure. microRNA-204-5p (miR-204) is a noncoding RNA well-expressed in mouse and human hearts. We recently reported that the miR-204 inhibits mouse myocardial hypertrophy induced by experimental pressure overload, and its expression in many tissues, including the heart, is sensitive to changes in the gut microbiome. Our preliminary data show that glycopeptide antibiotic vancomycin alters the mouse gut microbial landscape

PROJECT ABSTRACT Calcific aortic stenosis (CAS) is the most prevalent heart valve disorder affecting up to 50% of adolescents with congenital valve disease and over 25% of those over age 75, following life-long exposure to risk factors. Independent of age, outcomes are poor following the onset of aortic stenotic (AS) symptoms, unless outflow obstruction is relieved. CAS is progressive and manifests as cusp thickening with osteogenic-like remodeling, calcium deposition in regions of high mechanical demand and narrowing of the valve opening. Despite this, the mechanisms underlying these phenotypes and their contributions to the severity of AS pathogenesis are not well defined, but biomechanical stress was implicated. This is best illustrated in congenital bicuspid aortic valve (BAV) disease, causing structural narrowing of the aortic valve (AoV) opening and increased biomechanical stress over the cusp surface. In more than half of BAV patients, CAS develops at least 10-15 years earlier t

Among older adults, heart valve disease is common and often requires treatment with valve repair or replacement. What used to require open heart surgery can now be done with less invasive transcatheter heart valve interventions (THVIs), allowing for less morbidity and quicker recovery. However, despite the safety and procedural success of THVIs, over one-half of patients are dead, have poor quality of life (QoL), and/or are hospitalized 1 year after a THVI. Cardiac rehabilitation (CR) effectively mitigates these poor outcomes in patients with cardiovascular disease, including those undergoing heart valve procedures. However, among Medicare beneficiaries, only 25% of those undergoing a THVI participate in center-based CR (CBCR), which highlights a significant unmet clinical need. To address this need, our long-term goal is to develop a home- based CR (HBCR) program that extends the benefits of CR to more individuals after THVIs. Our over-arching hypothesis is that a HBCR mobile health i

Summary About 2.5% of the US population has a valvular heart disease. While neglected for a long time, problems related to the tricuspid valve affect more than 70 million people worldwide. Among these, more than 1.6 million are in the US. The yearly incidence is about 200,000 with a 1-year mortality rate of 36.1%. The most common problem is tricuspid valve regurgitation. The majority of tricuspid regurgitation cases are treated surgically via prosthetic ring annuloplasty in open surgery. However, open surgery approaches introduce risks of perioperative complications and require long recovery times. A large percentage of the population with tricuspid regurgitation cannot receive surgical treatment because of the high-risk profile. Few patients undergo isolated tricuspid valve surgery because the challenging anatomy of the tricuspid valve and lack of clinical experience has hindered progress in this area. Therefore, there is a clinical need for novel approaches that would allow tricuspid

PROJECT SUMMARY Ovarian cancer is the most lethal gynecologic malignancy and ranks as the fifth leading cause of cancer-related mortality among women in the United States. Standard treatment consists of cytoreductive surgery followed by chemotherapy with carboplatin and paclitaxel. However, recurrence occurs in approximately 70% of patients within 18 to 24 months, primarily due to the development of platinum resistance. The prognosis for platinum- resistant ovarian cancer remains dismal, necessitating the development of alternative therapeutic approaches. Doxorubicin (DOX), a broad-spectrum anthracycline, is extensively utilized in oncology, including the treatment of ovarian cancer. Despite its efficacy, the clinical application of DOX is restricted by dose-limiting toxicities, particularly myocardial toxicity that can progress to chronic heart failure, as well as the emergence of multidrug resistance upon repeated administration. To mitigate these limitations, liposomal doxorubicin

ABSTRACT Supravalvular aortic stenosis (SVAS) is characterized by focal narrowing of the aorta that increases the risk for sudden cardiac death. SVAS is caused by mutations in the elastin gene that lead to decreased elastin amounts and there are currently no pharmaceutical treatments. The mechanisms by which elastin insufficiency cause SVAS are not well understood. Elastin is a critical mechanical component of the aorta and contributes to the passive stiffness (or modulus) that determines how much the aorta will deform (or strain) under applied hemodynamic stresses. Strain on smooth muscle cells (SMCs) within the aortic wall affects differentiation, proliferation, and migration. Cellular transmembrane channels, including Piezo1/2, are mechanosensitive molecules that transduce mechanical changes (such as strain) into biological effects (such as differentiation). Activation of Piezo channels leads to increases in intracellular calcium that can stimulate nuclear translocation of YAP/TAZ,

SUMMARY Tetralogy of Fallot (TOF) is a critical congenital heart malformation that typically requires intervention soon after birth and affects about 1,660 newborns per year in the US. In TOF, blood flow through the pulmonary artery is reduced or blocked (due to pulmonary stenosis or atresia), while blood flow through the aorta is increased. Prenatally, TOF-induced abnormal blood flow progressively leads to pathological cardiac valve tissue remodeling. The semilunar (aortic and pulmonary) valve leaflets and the great arteries (the aorta and pulmonary artery) are particularly susceptible to abnormal blood flow. This is because fetal stages are a critical time when extracellular matrix components that dictate valve integrity and function, such as collagen and elastin, deposit and organize within valve tissues, and smooth muscle cells are differentiating and organizing in supporting arteries. However, how semilunar valves and great arteries remodel in response to TOF-induced abnormal hemo

(PLEASE KEEP IN WORD, DO NOT PDF) This project responds directly to PAR-21-038; the PI changes direction from valvular heart disease to study acute kidney injury (AKI). Indeed, the PI is a new faculty member in the Division of Nephrology, Department of Medicine. The PI will apply her previous expertise in platelet structure to examine a new therapeutic approach to deliver mitochondria to injured kidneys and therefore stop the progression of AKI to end-stage renal disease. The PI is working closely with Dr. Daehn, an expert in kidney disease and mitochondrial function. In addition, she will be collaborating with Dr. Brestoff, an expert in mitochondria transplantation, to validate the proposed experimental approach. AKI is a critical health condition characterized by a sudden decline in kidney function. It occurs in approximately 20%-30% of hospitalized patients. In the US, AKI is leading to high morbidity and mortality. Although AKI encompasses various etiologies, tubular injury is an e

PROJECT SUMMARY/ABSTRACT Advanced heart diseases lead to a reduced blood supply from the heart and consequently fatigue and deficits in performing physical activity. In the proposed research, we will assess the lack of physiological reserve in older adults with advanced heart disease, focusing on motor and cardiac function, to develop a novel, objective, quick, and accurate frailty score. We designed this approach to enhance candidate selection of older adults going through invasive therapies for advanced heart diseases. Although our approach is generic, to reduce between- subject variability we focus on transcatheter aortic valve replacement (TAVR) for older adult with aortic stenosis. Therapeutic options continue to grow for TAVR; however, it can be difficult to identify candidates with frailty level that prohibit them from tolerating the stress from aggressive therapy and those with potential reversible frailty. It is thus critically important to introduce meaningful routine objecti

Project Summary/Abstract Approximately 12.4% of patients >75 years of age have aortic stenosis (AS) and 3.4% have severe AS. Transcatheter aortic valve replacement (TAVR) has emerged as a safe and effective therapeutic option for patients with symptomatic severe AS. More than 50,000 TAVRs are now performed annually across >500 hospitals in the United States (US). Despite stringent patient selection criteria and standardized procedural techniques, there remains significant hospital variation in outcomes, including mortality, morbidity, and readmissions, following TAVR in the US. However, the reasons underlying hospital variation in TAVR outcomes remain poorly understood. Identifying organizational practices and processes of care associated with better outcomes is critical to improve the overall outcomes of patients undergoing TAVR. The overarching objective of this proposal is to perform a mixed methods study using a positive deviance approach to understand determinants of hospital vari

PROJECT SUMMARY ABSTRACT Rheumatic heart disease (RHD) remains a high prevalence condition in low-and-middle-income countries, currently affecting at least 40 million people, many of whom suffer premature death. Most patients with RHD present late, missing the opportunity to benefit from secondary antibiotic prophylaxis. Screening echocardiography in RHD endemic settings identifies many children with early, latent RHD, but until recently the effectiveness of prophylaxis to protect children with latent RHD was not known. The GOAL Trial (conducted in Uganda by this investigative team) found that children with latent RHD who receive prophylaxis with intramuscular penicillin are less likely to progress at two-years (0.8% penicillin vs. 8.3% no penicillin, p<0.001). However, despite these results, scale-up of echocardiographic screening and early initiation of prophylaxis with intramuscular (IM) penicillin for RHD has a myriad of challenges. Among the most critical are substantial patient (

Project Summary Myxomatous valve disease (MVD) is among the most common types of cardiac valve disease and carries significant morbidity and mortality, leading to regurgitation and valve prolapse. While most of the research efforts at understanding MVD pathogenesis have focused on mouse models of syndromic MVD, the majority of MVD patients lack known syndromic mutations and present later in life, suggesting that MVD is more often acquired and likely influenced by environmental factors. We have recently demonstrated that hemodynamic shear forces direct cardiac valve development through transcription factors KLF2 and KLF4, but the role of hemodynamic forces and KLF2/4 in regulating mature valve homeostasis remains unexplored. Preliminary studies indicate that genetic inducible loss of KLF2/4 from valve endothelial cells (VEC) results in a phenotype highly concordant with human MVD. Importantly, similar MVD pathology results from transplanted hearts with loss of blood flow across the mitr

Project Summary: YoungHeartValve (YHV), Inc. is commercializing the Rejuvenate™ Heart Valve, a balloon-expandable, stented, transcatheter aortic heart valve (TAVR) with hyaluronan-impregnated polymeric, flexible leaflets that will obviate the need for chronic anti-coagulation and prevent calcification while simultaneously rivaling the longevity of surgically placed mechanical valves. Unique and novel Dynamic Sealing Technology (DST) that activates once implanted will form fit the valve to provide for a more complete and reliable annular seal, rivaling that of sutured-in-place surgical valves. Further, YHV’s “no tissue / no farm” manufacturing automation and supply chain will significantly reduce the cost and complexity of today’s pericardial based TAVR systems, thereby opening up possibilities for this life-saving technology to truly be adopted worldwide. Aim 1 will verify Valve 2.0 design meets all ISO Standards and begin manufacturing for scale up. Aim 2 will complete acute and chron