Miami Heart Research Institute
Florida Heart Research Foundation
Current Research
F&A POLICY:
Miami Heart Research Institute & Florida Heart Research Foundation's policy on F&A Costs (Facilities and Administrative Costs), formerly known as indirect costs and overhead, is that MHRI & FHRF do not reimburse administrative expenses of any kind for awarded grants or projects. This has always been the policy of Miami Heart Research Institute, Florida Heart Research Foundation and its Board, as well as part of every grant agreement we enter into.
Miami Heart Research Institute and Florida Heart Research Foundation request that every grant be exclusively used to support an approved grant or project and pay for direct expenses of said approved grant or project. No portion of the funds awarded for the approved grant or project will be used to pay indirect overhead expenses.
2023-2024 NEW & CONTINUED RESEARCH RECIPIENTS/PROJECTS:
- Joshua Hutcheson, PhD (Principal Investigator) & Prem Chapagain, PhD, Jin He, PhD & Francisco Fernandez-Lima, PhD (Co-Investigators), Florida International University, research study entitled: "A Nanoanalytical Approach to Unraveling Differences Between Physiological and Pathological Mineralization". Calcification, the buildup of calcium mineral, commonly occurs in two places: during natural bone formation and in diseased blood vessels. Calcification of major vessels that distribute blood from the heart to the body, known as arteries, serves as a predictor of future heart problems and even death. Bone-like mineral buildup can cause heart attacks and make arteries stiff, putting more strain on the heart. Interestingly, the more mineral found in arteries, the less in bones, and vice versa—a phenomenon known as the "calcification paradox." Accordingly, individuals with weaker bones tend to have more mineral in their arteries. However, we still do not fully understand how minerals form in each tissue. The study focuses on nano-sized structures called calcifying extracellular vesicles (EVs), which play a role in mineral formation. By comparing how these EVs form and function in bone cells versus artery cells, the study seeks to uncover differences in their makeup and behavior that can provide new insight into the origins of the calcification paradox. Ultimately, this research could lead to better understanding of mineral formation in both tissues and potentially influence future treatments for conditions like osteoporosis and cardiovascular disease.
- Florida Heart Research Foundation Cardiovascular Summer Research Internship Program at FIU: The annual Summer Research Internship program at FIU pairs motivated high school students and incoming FIU students with cardiovascular researchers, offering these students an immersive experience in innovation during their summer break. This program also encourages matriculation into undergraduate research following their summer experience. Through generous support from the Florida Heart Research Foundation, we have expanded the FIU MARC U*STAR program. MARC U*STAR is an NIH-funded training program for undergraduate students. Students within MARC U*STAR are paired with faculty mentors and complete two-year long research projects that prepare them for graduate school. The Florida Heart Research Foundation funding will specifically support MARC U*STAR affiliate students performing cardiovascular research with FIU faculty. Following this intensive training in cardiovascular research from high school through their undergraduate careers, students emerge well-poised to make substantial impacts in cardiovascular research and medicine in academic graduate programs, medical training, and/or industry.
- Florida Heart Research Foundation Cardiovascular Doctoral Student Grant Program at FSU:
- Sediqua Bufford, PhD Candidate, Florida State University, research study entitled: "Transriptomics Signature of African-American vs Caucasian Human Heart Tissue: the first step to the understanding of cardiovascular health disparities". The overall goal is to utilize translational research to discover and target potential genes that can be used as a biomarker to advance clinical therapies to close the gap of reported mortalities due to cardiovascular disease. With a keen understanding of the urgency and significance of addressing health disparities within this population, we are ecstatic about the potential opportunity to collaborate while utilizing cutting-edge research initiatives that aim to unravel the complexities of cardiovascular health disparities. We will investigate if there is a correlation in genetic profiles based on sex and race. In Aim 1 we will study the transcriptomic profiling of the human heart evaluating the potential for different gene expression signatures in heart tissue obtained from African-American vs Caucasian individuals, including potential sex differences as well. Aim 2 involves studying physiology and disease at the cellular level using human inducible pluripotent stem cells derived cardiomyocytes (hiPSC-CMs). These hiPSC-CMs experiments will include samples from multiple individuals, i.e., African-American males and females, and Caucasian males and females. The first step will be to determine if the contractile profile of hiPSC-CMs differ based on race and sex. Subsequently, we will leverage the data obtained in Aim 1 to identify genes that may be associated with distinct contractile behaviors within our variable groups. The benefits of using hiPSC-CMs to investigate human heart disease is a comprehension of disease mechanisms, more specific drug development, and the advancement of precision medicine with the ability to identify distinct characteristics among different population groups. The goal of this project is to generate fundamental data intended for the development of more targeted treatments designed for a population currently suffering from significantly elevated mortality rates.
- Paula Nieto Morals, PhD Candidate, Florida State University, research study entitled: "Investigating the role of TNNC1 in Pediatric Dilated Cardiomyopathy". Dilated cardiomyopathy (DCM) is the most common cardiomyopathy in children, with nearly 40% of symptomatic cases resulting in heart transplantation or death within two years. Pediatric dilated cardiomyopathy (PDCM) involves the enlargement and weakening of the heart muscle, leading to impaired systolic function and heart failure. While the disease's severity is well known, its molecular genetics are complex and poorly understood. Most pediatric cardiomyopathies are idiopathic or familial, involving mutations in over 30 genes. Recently, rare variants in TNNC1, which encodes cardiac troponin C (cTnC), have been linked to PDCM, although the underlying mechanisms are not well studied. This study aims to investigate the role of TNNC1 in PDCM using a new knock-in mouse model and human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs). Additionally, the study will assess the therapeutic potential of a novel myotropic drug to modulate contractility. Preliminary data from the mouse model show a DCM phenotype at four weeks of age assessed by echocardiography, with increased heart size and left ventricular dimensions confirmed by histopathology. Since cTnC is a major cytosolic calcium buffer, further research will examine if calcium regulation of the myofilament and intracellular calcium handling are altered in these mice and hiPSC-CMs. Understanding how rare genetic variants affect myocardial processes offers insights into the structural and functional roles of heart proteins. This study aims to uncover conserved pathogenic pathways, validate the mouse model's translational relevance, and identify potential therapeutic targets for precision medicine in PDCM.
- Joerg Herrmann, MD, Mayo Clinic, Rochester, research study entitled: "TACTIC - TrAstuzumab Cardiomyopathy Therapeutic Intervention with Carvedilol Trial". Breast cancer patients undergoing trastuzumab treatment are at risk of heart function decline or heart failure symptoms, but it is unknown if, when, and for how long cardiovascular protective strategies, e.g. with a beta-blocker, could help. This study randomly assigns those taking curative-intent trastuzumab to the beta-blocker carvedilol—either when significant heart function decline or subtle early signs of heart injury (either by elevation of a cardiac blood biomarker, i.e. cardiac troponin, or by an abnormal heart ultrasound marker, i.e. global longitudinal strain) are noted, or preventatively before beginning trastuzumab therapy. This study will further randomly assign those patients on carvedilol in these three groups to either discontinue at the end of trastuzumab therapy or to continue for another year, providing much needed clinical trial data on what the best strategy (“tactic”) for those at risk of cardiotoxicity with trastuzumab therapy is.
- Joerg Herrmann, MD, Mayo Clinic, research study entitled: “CAncer Survivor CArdiomyopathy DEtection (CASCADE)”. Currently, there are over 15 million cancer survivors in the United States, and this number is projected to exceed 20 million within the next five years-- most of whom will be long-term survivors (5+ years). Many of these individuals are at a high lifetime risk of developing heart disease due to their exposure to anthracycline-based chemotherapy during cancer treatment. The most efficient and cost-effective way to monitor, predict and prevent the development of heart failure in these cancer survivors is not known. While echocardiography has been the standard approach, serial studies are costly and require logistics, time and effort, kindling interest in identifying less expensive cardiac surveillance strategies that can be implemented over long periods of time to a large population at risk. The current application’s objective is to assess and optimize the diagnostic performance of novel artificial intelligence (AI) electrocardiography (ECG) and an established blood marker for heart disease (NT-pro-BNP) for the detection of an abnormal heart function in cancer survivors and to compare and combine these two tests to define the most optimal strategy. These studies will inform cardiac surveillance efforts for clinical practice and the planning of a randomized clinical trial to address the clinical impact of optimal cardiac surveillance.
- Nanette Bishopric, MD, Georgetown University, research study entitled: “Restoration of Heart Function by Targeting Remodeling Pathways in the Ischemic and Stressed Heart”. The heart is able to pump because it is made up of specialized muscle cells (=cardiac myocytes) that beat spontaneously and respond to the body’s constantly changing demands for blood supply. These cells are very long-lived. Over a lifetime of continuous beating, they adapt dynamically to changes in body size, hormonal state, and activity, and successfully meet a variety of acute challenges, ranging from mental stress to tennis matches to marathons. Many common chronic diseases, such as high blood pressure and diabetes, also cause persistent and ongoing stress that can lead to damaged function and heart failure. Despite recent success in treatment and prevention of heart attacks, cardiovascular disease continues to be the #1 cause of death in the US, as it has been since the middle of the last century. The reason is the increasing frequency of heart failure – particularly the kind known as Heart Failure with Preserved Ejection Fraction (HFpEF). More than 3 million people in the United States are living with this kind of heart failure. Heart attacks weaken the ability of the heart to pump. In contrast, HFpEF prevents the heart from relaxing. This means that it takes higher pressure to fill it with blood for the next beat. The abnormal pressure is felt in all the filling systems of the heart, especially the lungs. This in turn leads to shortness of breath, reduced exercise capacity, and a high risk of atrial fibrillation. Recognized only recently as a disorder, the incidence of HFpEF is increasing rapidly along with its major known causes: obesity, physical inactivity, diabetes, high blood pressure, and old age. Aging is also a powerful risk factor for cancer, thus cancer treatments are frequently given in the setting of HFpEF, increasing the risk of heart failure. There is no known cure and no specific treatment for HFpEF, although symptoms can be relieved with daily medication. It is increasing apparent that inflammation is an important feature of many of these conditions, and a likely common factor in their harmful cardiac effects. Groundbreaking research in our laboratory, along with others, has now begun to shine light on exactly what goes wrong at the molecular and cellular level in HFpEF, leading the way to more effective targeting and reversal of this debilitating and eventually fatal condition. In this ongoing project, we are working to understand the causal relationship between chronic stress and HFpEF. We hypothesize that inflammation is one component of a maladaptive molecular response involving that impairs the ability of the heart muscle to relax. With the multi-year support of the Miami Heart Research Institute, we have been able reveal a network of biochemical pathways in the stressed heart cell and have designed and tested novel structurally-designed molecules to reverse the process of HFpEF. In the current year of funding, we will continue to explore the role of molecular pathways common to inflammation, cancer chemotherapy and aging through the use of genetically modified cells and animal models. We will specifically explore the roles of RAGE, a receptor for inflammatory signals, and p300, a key regulator of the heart’s response to damage in the context of toxins such as cancer chemotherapy. Our ultimate goal is to prevent HFpEF-related morbidity and mortality, as well as to reverse it.
- Jose R. Lopez, MD, Mount Sinai Medical Center, research study entitled: “Cardioprotection in Diabetic Cardiomyopathy via upregulation of ATP-sensitive K+ channels”. Diabetes is a major public health problem that represents a huge health concern for Americans and the global population. Studies estimate that the number of people living with diabetes today ranges from 415 million to 425 million, and currently, 1.5 million deaths are attributed to diabetes worldwide every year. There are two main types of diabetes, type 1 (T1D) and the more common type 2 (T2D) diabetes. Both T1D and T2D patients develop heart failure even in the absence of other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease. Nearly 80% of the deaths related to diabetes are attributed to cardiac complications. Although drugs and insulin have been successfully used to treat high blood glucose levels in diabetic patients. Despite maintaining adequate blood glucose levels in diabetic patients, the latter has not been enough to prevent cardiac complications. Plant-based dietary nutrients referred to as nutraceuticals have been the basis for innovative strategies to promote health and prevent or slow the progression of chronic diseases. The term nutraceutical is defined as a food or portion of food, that has a medical or health benefits, including the prevention and treatment of chronic disease. Citrus fruits such as oranges, mandarins, grapefruit are notably rich in flavonoids, and citrus flavonoids have been demonstrated to protect against diabetic complications. Among them, naringin found mainly in grapefruits and oranges has been reported to be helpful for the treatment of obesity, hypertension, cardiovascular diseases, and blood glucose levels in diabetic patients. However, no studies have been carried to determine if naringin, in addition to helping to maintain normal blood sugar levels, can protect diabetic patients from developing heart failure. In two experimental mouse models of diabetes, we have previously found that their heart cells have elevated intracellular calcium concentrations, elevated production of free radicals, a decrease in cell viability, reduced glucose transport into the cells, and low expression of ATP sensitive potassium channels. This project will explore whether or not naringin provides cardioprotection in diabetic models, and whether or not this protection is elicited via the expression of the ATP sensitive potassium channels. Our preliminary work suggests that naringin represents a novel therapeutic approach and an exciting and promising new direction for treating diabetic patients. We hope that this new therapy can eventually prevent or modify the progression of diabetic heart failure.
- Nirat Beohar, MD, Principal Investigator & Steve Xydas, MD, Angelo LaPietra MD, George Gonzalez, MD, Co-Investigators, Mount Sinai Medical Center, research study entitled: "A Cerebral Embolic Protection during High-Risk Cardiac Surgery: A Feasibility study of the Sentinel Cerebral Embolic Filter Device to Reduce Neurologic Complications”. Stroke and cognitive dysfunction are related complications after cardiac surgery. Despite technical improvements the rates of stroke (as high as 4%) and neurocognitive decline (as high as 50-70%) after cardiac surgery have remained mostly unchanged over the years. The Sentinel CEP filter (Boston Scientific, Minneapolis, MN), remains the only currently FDA approved device indicated for reduction of clotting debris in trans-catheter aortic valve replacement (TAVR) procedures. There are currently no data studying the use of this device in cardiac surgery. The importance of reducing adverse neurological events after cardiac surgery and the indication from TAVR data that the CEP may be effective, suggest that a randomized trial of CEP with the Sentinel device should be done to guide future surgical therapy and Guidelines. Our proposed 30-patient feasibility study aims to: 1. Evaluate the practicality of placing and removing the CEP in the operating room using a mobile X-ray (C-arm); 2. Assess the ability to scientifically characterize debris collected in the CEP filter; 3. Determine the frequency of embolic debris collection in the CEP device; and to 4. Investigate the possibility of conducting pre-operative and post-operative (30 days after surgery) neurological evaluations.
- Florida Heart Research Foundation Cardiovascular Doctoral Student Grant Program at FIU:
- Daniel Chaparro, PhD Candidate, Florida International University, research study entitled: "Valvular Heterogeneity in Bicuspid Aortic Valve Disease and Post Developmental Remodeling". Bicuspid aortic valve (BAV) disease is the most common congenital defect in humans where a person is born with two instead of three leaflets within the aortic valve (AoV). People born with this defect are at a much higher risk of developing early onset aortic valve disease (AVD) necessitating valvular replacement intervention sooner and more frequently. While investigating a common genetically modified mouse model of BAV, we noticed a pattern between melanocytic pigmentation on the tissue and the presence of this congenital defect. Now, we are actively investigating if melanocytic pigment production itself plays a role in BAV malformations and AVD progression by using some genetically modified mouse models of varying pigmentation levels.
- Perony Nogueira, PhD Candidate, Florida International University, research study entitled: "Developmental origin of elastin producing cells and mechanism underlying elastogenesis in the murine aortic valve".
Our group has recently demonstrated that the presence of pigment in the heart aortic valve is related to the arrangement of elastic fibers responsible for the mechanical behavior of the valve. My project aims to determine the origin and characteristics of the cells that make pigment in the valve. I have found that the pigment cells derive from at least two precursor populations. I have also found that in addition to the cells known to produce elastin in other tissues, namely fibroblasts and endothelial cells, pigment cells in the valve can make elastin.
- Abeer Al Barghouthi, PhD Candidate, Florida International University, research study entitled: “The Role of 3D Multiscale Biophysical Cues on the Maturation Advancement of Induced Pluripotent Stem Cell-Derived Cardiomyocytes”. Heart disease continues to exert a significant global burden, contributing to millions of fatalities every year. To date, there are no clinical solutions that regenerate tissue damaged by a heart attack. A promising avenue to address this dire need involves induced pluripotent stem cell-derived cardiomyocytes (iCMs), engineered heart cells with potential to repair the damaged tissue. However, iCMs in their current state do not fully resemble or behave like the native heart cells. They lack advanced structural organization and functional maturity. Native heart cells, cardiomyocytes (CMs) thrive in a complex 3D setting within the body, specifically the extracellular matrix (ECM). They interact with various biophysical cues from the surrounding environment at multiple scales. We seek to unravel the mechanisms by which these 3D-ECM inspired biophysical cues influence the development of iCMs. We will investigate the individual and collective roles of these cues on the maturation of iCMs at multiple length scales. This work will uncover some of the passive mechanical regulators of heart muscle maturation and enable us to use those mechanical cues in biomanufacturing mature engineered heart tissues.
- Yih-Mei Lin, PhD Candidate, Florida International University, research study entitled: "Development of Physiological Cardiac Patch for Diminishing Adverse Events of Ischemic Heart Injury”. Myocardial infarction (MI) continues to be a leading cause of morbidity and mortality worldwide. With the development of ischemic injury, the myocardium goes through a series of stages from acute inflammation, proliferation and repair, to scar tissue maturation and ventricular remodeling. These events not only cause the death of cardiomyocytes but also gradually break down the extracellular matrix and eventually form fibrotic scar tissue. Without proper treatment, this will result in the obstruction of blood flow and dysfunction of heart. One of the current cardiovascular approaches to treat MI is developing functional induced pluripotent stem cells differentiated cardiomyocytes (iPSC-CMs) derived cardiac patch; however, it has been challenging to overcome clinical requirement such as immune response. An enhanced engineered cardiac patch with improved functionality and immunosuppression property would be an urgent need to delay or reduce myocardial scar burden. The use of mechanical stimulation is in attempt to recapitulate the mechanical environment in the heart that is necessary for proper cardiac development. In fact, physiologically-oscillatory flow conditioning has been observed to facilitate de novo tissue deposition. In addition, mechanical stimulation has the potential to produce optimum cardioprotective cargo of exosomes. However, oscillatory flow stimulation has not related to the formation of cardiac tissue patch and the effects of exosomes released from iPSC-CMs on the patch remain unclear. Therefore, this study aims to address the role of physiologically-oscillatory flow in facilitating iPSC-CMs derived cardiac patch development and the potential application of iPSC-CMs-derived exosomes to the patch. The efforts of this study could offer a new strategy to enhance the production of cardiac patch with functional recovery property and minimal translational challenges.
- Manuel Perez-Nevarez, PhD Candidate, Florida International University, research study entitled: "Flow-Induced Conditioning of Stem Cells for the Production of Cardioprotective Exosomes”. Stem cell therapy has previously been investigated as an option for the treatment of infarcted cardiac tissues. However, recent findings suggest that the beneficial effects of stem cells are the localized secretion of bioactive factors that act to recapitulate the therapeutic effects of the parent stem cells. A subset of these secreted factors (exosomes) contain growth factors and proteins, that may potentially be used as therapeutic agents to promote the healing of injured heart tissue. Mesenchymal stem cells (MSC) are able to respond and adapt to forces sensed from their external microenvironment. It has been shown that physical cues produced by fluid-induced shear forces significantly modulate MSC function and increase the production of both proteins and secreted exosomes. In addition, pulsatile flow regimens have been shown to induce preferential MSC gene expression and phenotype. However, the relationship between the specific flow parameters of the conditioning regimen and the production of cardioprotective exosomes is not fully understood. There is a need for the development of a process that can produce exosomes with optimal secretory contents for use in cardiac applications. The proposed study will provide insights on the flow-conditioning parameters that upregulate the production of cardioprotective exosomes as well as their effects on in-vitro models of cardiac ischemia. Determination of an efficacious preconditioning regimen could lead to the identification of a drug delivery strategy for cardiac wound healing applications.
2022-2023 NEW & CONTINUED RESEARCH RECIPIENTS/PROJECTS:
- LaPrincess Brewer, MD, Mayo Clinic Rochester, research, education and prevention grant for "FAITH! Emergency Preparedness Initiative: First Aid CPR and AED Training Among African-American Churches": The recent cardiac events of Damar Hamlin and Bronny James highlighted in the media shine a spotlight on a vital issue: the importance of cardiopulmonary resuscitation (CPR) training and readily available automated external defibrillators (AEDs). Thanks to both, and the quick actions of bystanders, these young men are on their way to recovery. Their survival stories are event more compelling considering the significant survival disparities for African-Americans in out-of-hospital cardiac arrest situations. The New England Journal of Medicine recently published a study which found that despite the significantly increased chances of survival with immediate CPR, Black and Hispanic individuals receive these life-saving efforts from bystanders far less often than their White counterparts. This was true not only in predominantly White neighborhoods, but also in public locations and predominantly Black or Hispanic neighborhoods. These findings demonstrate the critical need for CPR training and access to AEDs in these disproportionately impacted communities. The FAITH! (Fostering African-American Improvement in Total Health!) Program, led by Mayo Clinic cardiologist, Dr. LaPrincess Brewer, partners with local African-American churches to increase awareness and prevention of cardiovascular disease (DVD) through multi-component healthy lifestyle interventions. The program's primary goal is to promote health and wellness in a culturally relevant, faith-based manner to address ongoing health disparities in African-Americans. Given the staggering disparities related to bystander CPR and cardiac arrest survival, along with the disproportionate incidence of cardiovascular risk factors in African-Americans, we aim to increase knowledge and preparedness to handle life-threatening CVD emergencies by offering CPR training and equipping partnering churches with on-site AEDs.
- LaPrincess Brewer, MD, Mayo Clinic Rochester, research, education and prevention grant for "FAITH! Hypertension App Mobile Health Initiative to Improve Hypertension Control and Cardiovascular Health Among African-Americans": The FAITH! (Fostering African American Improvement in Total Health!) Program, led by Mayo Clinic cardiologist, Dr. LaPrincess Brewer, has previously leveraged community-academic partnerships in Minnesota to co-design a smartphone-based mobile app (FAITH! HTN App) with patients and clinicians to promote hypertension self-management with culturally tailored resources. The app was integrated into a 2021 pilot collaboration with a federally qualified health center (FQHC) In Minneapolis, MN to support a Centers for Disease Control and Prevention (CDC) initiative for cardiovascular disease prevention/management in disproportionately impacted communities. This project involves an integrated care model (ICM) and the mobile health intervention to improve hypertension self-management in under resourced, high-risk African-American patients while simultaneously addressing adverse social determinants of health (SDOH). The app provides culturally relevant education tools to promote patient self-empowerment for hypertension control. The ICM includes weekly check-ins between patients and Community Health Workers (CHWs) to assess blood pressure control and screen for SDOH acting as barriers to care. Patients are referred to community resources for unmet needs. The CHW reports and app allow for meaningful clinical data transfer to enhance the patient-clinician relationship and hypertension care plans. The successful 2021 pilot study resulted in improved blood pressure among African-American patients with uncontrolled hypertension. There was a clinically meaningful 6-point reduction in systolic BP, from baseline to immediate post-intervention (N=7). Additionally, the FAITH! HTN App increased participant knowledge of cardiovascular topics including HTN, as there were statistically significant increases in self-assessment quiz scores on education modules. Positive behavioral changes related to HTN self-care were also observed. In follow-up focus groups and surveys, patients notes that the intervention fostered healthy lifestyle changes and overall accountability for hypertension self-management including and beyond medication adherence. Patients perceived the FAITH! HTN App as engaging, informative, and found the peer support through the sharing board particularly useful. We are currently moving forward with a larger-scale trial in collaboration with another FQHC, Neighborhood Health Source, which will include 100 total participants randomized to either an intervention group (using the app) or control group (standard of care).
- Nanette Bishopric, MD, Georgetown University, research study entitled: “Restoration of Heart Function by Targeting Remodeling Pathways in the Ischemic and Stressed Heart”. The heart is very resilient, and heart muscle cells (the cell type that beats) are very long-lived. Over a lifetime of continuous beating, they adapt dynamically to changes in body size, hormonal state, and activity, and successfully meet a variety of acute challenges, ranging from febrile illnesses to tennis matches to marathons. However, certain common chronic diseases, such as high blood pressure and diabetes, cause persistent and ongoing stress that can lead to damaged function and heart failure. Despite recent success in treatment and prevention of heart attacks, cardiovascular disease continues to be the #1 cause of death in the US, as it has been since the middle of the last century. The reason is the increasing frequency of heart failure – particularly the kind known as Heart Failure with Preserved Ejection Fraction (HFpEF). More than 3 million people in the United States are living with this kind of heart failure. Heart attacks weaken the ability of the heart to pump. In contrast, HFpEF prevents the heart from relaxing. This means that it takes higher pressure to fill it with blood for the next beat. The abnormal pressure is felt in all the filling systems of the heart, especially the lungs. This in turn leads to shortness of breath, reduced exercise capacity, and a high risk of atrial fibrillation. Recognized only recently as a disorder, the incidence of HFpEF is increasing rapidaly along with its major known causes: obesity, physical inactivity, diabetes, high blood pressure, and old age. There is no known cure and no specific treatment for HFpEF, although symptoms can be relieved with daily medication. Groundbreaking research in our laboratory, along with others, has now begun to shine light on exactly what goes wrong at the molecular and cellular level in HFpEF, leading the way to more effective targeting and reversal of this debilitating and eventually fatal condition. In this ongoing project, we are working to understand the causal relationship between chronic stress and HFpEF. Our working hypothesis is that certain kinds of chronic diseases (e.g. diabetes, hypertension, and obesity) trigger a maladaptive molecular response involving that impairs the ability of the heart muscle to relax. With the multi-year support of the Miami Heart Research Institute, we have been able reveal a network of biochemical pathways in the stressed heart cell that lead to HFpEF. We have designed and tested novel structurally-designed molecules that have shown promise in reversing HFpEF by acting on processes within the heart muscle itself. Our aim in the current year of funding is to continue these efforts, but also to look at novel stress factors common to inflammation, cancer chemotherapy and aging, to see how these factors adversely impact the heart’s genetic response pathways. In Aim 1, we will explore the role of RAGE, a cell surface receptor that mediates some of the harmful effects of diabetes and aging, as an indirect source of damage to the heart. In Aim 2, we will use the cancer chemotherapy agent doxorubicin (Adriamycin) to model the effects of acute oxidative stress on the heart. These new models will help us to understand how to combat the stress signals that lead to heart damage, and ultimately to prevent HFpEF-related morbidity and mortality, as well as to reverse it.
- Joshua Hutcheson, PhD & Alexander Agoulnik, PhD, Florida International University, research study entitled: "A Novel Small Molecule Therapy for Late-Stage Atherosclerosis". Despite great progress in understanding the factors that contribute to heart disease and the development of effective cholesterol-lowering medications like statins, heart disease remains the leading cause of death worldwide. One major culprit in heart disease is the buildup of plaques in our arteries. These plaques form when arteries become inflamed and accumulate fatty substances like cholesterol. Atherosclerosis occurs when these plaques cause the vessels to narrow. If the vessels within the heart become too narrow, blood flow is restricted, and the heart muscle does not receive adequate oxygen needed for function. If the plaques rupture, blood flow can immediately stop, causing major heart attacks that lead to sudden death. Current guidelines recommend strategies like taking cholesterol-lowering drugs and making lifestyle changes like losing weight and quitting smoking to reduce our risk of heart disease. These strategies have immediate benefits but can often take years for a person’s risk to return to a normal baseline. This lingering risk is likely due to plaques that do not go away completely, even with medication and lifestyle changes. These methods mainly help prevent new plaques from forming or getting worse, but they do not quickly get rid of the ones that are already present. Recently, studies have sought to reduce this lingering risk by targeting the inflammation that contributes to plaque formation. Strategies have included a treatment that uses antibodies to lower inflammation in the body. The results from clinical trials have been promising, with fewer heart problems in people who received this treatment. However, there are some downsides to this approach, like the need for frequent antibody injections. In our study, we want to see if a more appropriate kind of medication, a small molecule, can help reverse these plaques when combined with statins and lifestyle changes. This small molecule targets a specific receptor in the body that has been shown to be safe in large clinical trials. So far, our data shows that this molecule can prevent and even reverse a late-stage complication of plaque build-up called vascular calcification. Interestingly, just making lifestyle changes doesn't seem to have the same effect on this late-stage complication. The small molecule used in our study may be able to reprogram the cells involved in inflammation such that they help clear away existing plaque. Our ongoing research in the current year of funding seeks to further explore how to reverse existing plaque and to identify which compounds are the most effective in concert with lifestyle and cholesterol-lowering treatments. The long-term goal is to develop a treatment that people can take to reverse plaques and reduce their risk of heart problems.
- Joshua Hutcheson, PhD (Principal Investigator) & Prem Chapagain, PhD, Jin He, PhD & Francisco Fernandez-Lima, PhD (Co-Investigators), Florida International University, research study entitled: "A Nanoanalytical Approach to Unraveling Differences Between Physiological and Pathological Mineralization". Calcification, the deposition of calcium mineral, occurs prominently in two tissues: physiological bone formation and in the diseased artery wall. Vascular calcification in the arteries is the most significant predictor of future cardiovascular disease and mortality. Bone-like mineral formation can cause plaque rupture, leading to sudden heart attacks and strokes, and stiffens blood vessels, increasing stress on the heart. Interestingly, the amount of mineral in bone and vascular tissues tend to inversely correlate—a phenomenon known as the “calcification paradox.” Increased vascular calcification is observed in patients with lower bone mineral density. Development of treatments that can restore appropriate mineral balance is hindered by an incomplete understanding of the mineral formation process in each tissue. Though many bone-like mechanisms are observed during vascular calcification, our data indicate that fundamental differences in the calcification processes of bone and vascular cells may underlie the calcification paradox. This interdisciplinary study will use novel material characterization and molecular biology approaches to analyze the earliest possible mechanisms in mineralization and provide new insight into the fundamental differences between bone and vascular calcification.
- Sharan Ramaswamy, PhD, Florida International University, research entitled "Additional In Vitro Assessments of Decellularized and Dehydrated Augmented Elastin Heart Valve to Confirm its Functionality, Durability and Cellular Responses". Heart valve replacements with the capacity to regenerate are conceptually very appealing in the treatment of critical valve diseases in the young, because of their potential to grow with the child. Our studies to-date with support from the Florida Heart Research Foundation have successfully enabled the deposition of allogeneic, elastin in the extracellular matrix (ECM) by stem cells which are subsequently decellularized but retaining the elastin content. This valve-relevant elastin is known to trigger cellular chemotaxis, which would thereby facilitate accelerated valve regeneration after implantation. However, prior to further in vivo assessment, our immediate goals are first to perform the following in vitro testing: (i) confirm the augmented elastin valve’s ability to hydrodynamically function well in the acute term in the mitral valve location using a pulse duplicator system and confirm its durability for an equivalent of 3 months using a valve durability tester, which is the time frame in which we anticipate full valve regeneration, based on our existing results, (ii) assess the ability of valvular cells to be able to secrete ECM on the augmented elastin valve after 2 weeks of culture, (iii) perform a preliminary examination of the immune response, via 2 weeks of co-culture of immune cells with valvular cells on the augmented elastin valve. Our previous findings have demonstrated that a raw bio-scaffold remains relatively undegraded up to 3-months post-implantation, in the mitral valve location in a juvenile non-human primate model. Thus, confirmation of an acceptable hydrodynamic functionality and 3 months-equivalent durability of the augmented elastin valve, as well as a favorable response by valvular cells and immune cells to the augmented elastin valve, will thereby establish that it can permit full valve regeneration in vivo. Completion of these project goals will subsequently permit us to assess if the fully decellularized, augmented elastin valve can support somatic growth. In summary, these three project goals are major steps towards our translation efforts to in vivo assessment and subsequent clinical trials, where currently, critical congenital valve diseases in young children have a very poor prognosis for survival. To quote Dr. Ramaswamy, "I consider it my life's mission to be able to effectively resolve critical congenital heart valve defects in children who are born with this dreadful condition, for which there is no current treatment option."
- Florida Heart Research Foundation Cardiovascular Doctoral Student Grant Program at FIU:
- Daniel Chaparro, PhD Candidate, Florida International University, research study entitled: "Aortic Valve Leaflet Innervation in Tissue Mechanics and Disease Progression". Surprisingly, there are neurons within the aortic valve. However, their role in aortic valve function and disease remain unknown. The aortic valve ensures that blood flows in one direction from the heart to the rest of the body. A well-defined structure gives the aortic valve the unique mechanical properties required to open and close as the heart beats. Disruption of this structure during aortic valve disease (AVD) leads to heart failure. The tissue, specifically the aortic valve leaflets (AVLs), is maintained by a complex mixture of cells. Currently there is no treatment for AVD and to develop new therapeutic options we first need to understand how neurons, and other cells, within the tissue work to maintain aortic valve structure and function. Neurons reside on the side of the AVL that experiences the most mechanical stress during the cardiac cycle. AVL neurons decrease in abundance with age at a rate that mirrors the onset of AVD in human patients. These cells also associate with formation of the AVL structure during development in our experimental models. We hypothesize that AVL neurons can sense the mechanical environment within AVLs and play a role in controlling valve mechanics and that neural dysfunction leads to AVD progression. In this project we explore the role of aortic valve neurons in function and disease. The outcomes of these studies could lead to new therapeutic targets for AVD, a major cause of heart disease.
- Perony Nogueira, PhD Candidate, Florida International University, research study entitled: "Developmental origin of elastin producing cells and mechanism underlying elastogenesis in the murine aortic valve". In the United States alone, there were more than 27,000 deaths related to valvular heart disease in 2017 according to the CDC and these numbers are increasing over time. The aortic valve plays an important role in heart physiology by preventing the backflow of blood from the body to the left ventricle of the heart. One of the important components of the aortic valve that ensures its proper function is elastin. We have recently shown that the cells that produce elastin in the aortic valve share characteristics with pigment cells, melanocytes, and smooth muscle cells. We have also found that aortic valves that have no pigment are almost completely devoid of elastin fibers. The main goal of this study is to determine the developmental origin of the elastin producing cells and how pigment synthesis is associated with the process of elastin production in the aortic valve. We will use genetically modified mice to establish if the precursor population that gives rise to melanocytes in the skin is also responsible for the generation of the elastin producing cells in the aortic valve. We will immune label elastin and perform electron microscopy to investigate how its production and secretion is affected in the aortic valve of hypopigmented mice. Finally, we will attempt to rescue the lack of elastin fibers in the aortic valve of these mice by bypassing the need for the rate limiting enzyme in pigment production. This study will contribute to a better understanding of AoV development and elastin related pathology affording us with potential novel approaches for treating valvular disease.
- Mohammad Shaver, PhD Candidate, Florida International University, research study entitled: "The Role of Mechanical Stimulation in the Biogenesis of Vascular Calcifying Extracellular Vesicles". Heart disease is a leading cause of death in developed countries, especially in the United States. One of the main indicators of high risk for heart disease is the presence of vascular calcification, which occurs when bone-like minerals form in the walls of arteries. This calcification process often starts when small particles called calcifying extracellular vesicles (EVs) are released from vascular smooth muscle cells (VSMCs) in response to abnormal conditions. The formation of calcifying EVs requires a specific protein called caveolin-1 (CAV1). This protein is located in the membrane of VSMCs and helps sense and respond to changes in the mechanical environment within the tissue. Hypertension is a leading risk factor for the development of heart disease in general and calcification in particular. However, the effects of mechanical stimulation and the formation and release of calcifying EVs from VSMCs is not yet fully understood. Therefore, the aim of this research study is to investigate how mechanical stretch affects the movement of CAV1 within VSMCs and the associated formation and calcification of EVs. By examining the impact of the mechanical environment on EV formation and calcification, this study hopes to uncover new insights into the role of factors that cause vascular calcification. The outcomes of this study could potentially lead to the discovery of therapeutic approaches to regulate the trafficking of CAV1 and treat vascular calcification more effectively.
- Jose A Adams, MD, Mount Sinai Medical Center, research study entitled: "Whole Body Periodic Acceleration (pGz) in Heart Failure". Heart failure (HF) is a devastating problem which occurs in more than 50 per 1000 individuals greater than 65 years of age. The lifetime risk of heart failure from ages 45 through 95 years is 20-45%. The symptoms of HF are varied but include; shortness of breath, easy fatigue, intolerance to exercise, fluid retention, and congestion of the lungs. The causes of HF include; scarring of the heart due to previous heart attack, uncontrolled diabetes and hypertension, genetics and other still unknown causes. Death from HF remains at approximately 50% within 5 years of diagnosis. Additionally, HF accounts for over 1 million hospitalizations annually. Furthermore, the total cost of HF in the US exceeds $30 billion annually, making HF a significant public health problem and economic burden. Whole Body Periodic Acceleration (pGz) is the back and forth motion of the body in a head to foot direction utilizing a bed like platform. The motion is similar to “a mother pushing a baby carriage back and forth”. The pGz motion induces pulsations to the body in the in all blood vessels, liberating beneficial substances from the cells which line these vessels. Previous grant support from the Miami Heart Research Institute/Florida Heart Research Foundation have allowed our laboratory to show that pGz improves the function of the heart after cardiac arrest. Additionally, pGz performed before (pre-conditioning) cardiac arrest or a heart attack, improved recovery, and heart function when compared with no treatment. This project investigates the use of pGz in models of the most common causes of HF. The study will determine whether or not pGz will improve heart function after established HF and will seek to determine if such improvements in heart function are related to the effects of pGz on heart scarring, excess inflammation, and other biochemical pathways. The findings of this study when applied to populations with HF could have a tremendous impact in reducing death, improving quality of life, and reducing healthcare costs in those affected by HF.
- Gervasio A. Lamas, MD/Christos Mihos, DO, Mount Sinai Medical Center, research study entitled: “Effects of Exercise and FITness on Left Ventricular Torsion and Wall MechanIcs STudy (FIT-TWIST)”. Exercise capacity is one of the most important markers of cardiovascular health. Cardiac ultrasound imaging (i.e. “Echocardiography”) is the primary method used by cardiologists to evaluate heart function. Yet for many years, cardiologists could not, by looking at an echo, tell whether the patient was fit, or a “couch potato”. The standard metric to express cardiac function, the ejection fraction (EF), or the percentage of blood ejected with each heartbeat (normal is 55% to 65%), simply does not reflect exercise capacity. Evidence suggests that the cardiovascular benefits of fitness are strongly influenced by the health of cardiac mechanics, which are measured using an advanced echocardiographic technique called 2D speckle-tracking echocardiography. This method has the capability of quantifying subtle aspects of cardiac motion and “fitness” based on the way the heart moves – shortening and twisting when it contracts, or “pumps”, and reversing its motion to relax. This study of cardiac mechanics in health and ischemic heart disease, will enroll 150 healthy subjects and assess the effects of different forms of exercise on cardiac mechanics in FIT-TWIST/Health. We hypothesize that the cardiac mechanics of normal subjects will change in a favorable way and guide ultimate selection of the most beneficial form of cardiovascular exercise. In FIT-TWIST/MI, we will assess 50 patients who have had a “heart attack” (myocardial infarction, MI), an insult to cardiac structure that leads to major disruption of cardiac mechanics. In these patients, we will study the effects of a standard cardiac rehabilitation program, a program of 36 sessions of graded exercise over a 12-week period. We hypothesize that cardiac rehabilitation restores some degree of normality to cardiac mechanics, thus explaining the extreme benefit on post-MI survival of cardiac rehab participation.
- Gervasio A. Lamas, MD, Mount Sinai Medical Center, research study entitled: "Trial to Assess Chelation Therapy 3a (TACT3a)". Diabetes triples the risk for fatty deposits in arteries, including in the heart, brain, and legs. We will use the most severe manifestation of arterial blockages, critical limb-threatening leg and foot artery blockage, as a marker of extreme risk for patients with diabetes. TACT3A will test a novel therapy, chelation, to try and reduce risk in these very ill patients. Chelation is a process by which a medication “sticks” to various toxins in the blood, usually toxic metals, like lead and cadmium, acquired from the environment, and allows them to be harmlessly excreted. Edetate disodium is a repurposed old drug, a chelator with high affinity for lead and cadmium, 2 common toxic metals that are toxic to coronary and other arteries. We will enroll 50 patients at Mount Sinai with diabetes and severe blockages of the leg arteries and try to prevent major amputation, coronary revasculari-zation, stroke, MI, or death (all-cause) during an average 1.25 years of follow-up. Patients will be randomly assigned to chelation or placebo. Treatment will consist of 40 active or placebo infusions over 30 weeks. This study, if successful, will be presented to FDA as part of the rapidly growing evidence that environmentally acquired metal pollutants are a reversible risk factor for cardiovascular disease and that chelation is a safe and effective therapeutic intervention in patients with extremely high risk of cardiovascular events.
- Demilade Adedinsewo, MD, Mayo Clinic Jacksonville, research study entitled: "Evaluating ElectroCardioGram based Artificial Intelligence predictions across device types (ECG-AI)". Utilizing artificial intelligence to analyze the 12-lead electrocardiogram (ECG), a first line diagnostic test for detection of heart disease, has enhanced the ECGs ability to accurately predict multiple cardiac disorders. The use of artificial intelligence in this context currently exceeds human-level interpretation of the ECG test. Despite its remarkable performance, there are significant challenges with scaling this technology and making it accessible to all for cardiovascular care. This is often due to differences in ECG data configuration, formats, and storage practices across health care institutions within the United States. The overall goal of this study is to develop and establish a process for extraction and integration of digital ECG signals from multiple devices, thus making novel artificial intelligence algorithms more accessible so patients can benefit equitably from this technology, facilitate data sharing/transfer, and support dataset curation for development of newer prediction algorithms.
- Brian Shapiro, MD/Bryan Taylor, PhD, Mayo Clinic Jacksonville, research study entitled: “Exercise Training to Improve Pulmonary Haemodynamic and Right Ventricular Function in Heart Failure Patients with Pulmonary Hypertension”. A common and very dangerous consequence of heart failure is disease of the blood vessels that supply the lungs, which results in a large increase in lung blood pressure; this is known as pulmonary hypertension. Pulmonary hypertension is actually a group of conditions. It may be caused by disease of the lung arteries themselves (“Group 1”), occur due to heart disease (“Group 2”) or lung disease (“Group 3”), or as a consequence of previous blockage of the lung blood vessels (“Group 4”). However, heart failure is one of the leading causes of pulmonary hypertension worldwide. Compared to heart failure patients without pulmonary hypertension, those with pulmonary hypertension have worse symptoms, are more limited in their ability to exercise and perform routine daily tasks, have to be hospitalized more regularly, suffer greater heart damage, are more likely to need a heart transplant, and are at a much greater risk of premature death. Worryingly, drugs typically used to treat pulmonary hypertension do not typically work, and may even worsen symptoms, in heart failure patients. As such, there is a real and urgent medical need to identify alternative safe and effect treatments for pulmonary hypertension due to heart failure. We know that improved physical activity through exercise training benefits patients with heart disease. There is clear evidence that moderate intensity exercise (e.g., brisk walking) can improve heart, blood vessel, and muscle function as well as overall health and well-being in heart failure patients. Preliminary work from our laboratory suggests that such exercise training is safe in heart failure patients with pulmonary hypertension. However, whether exercise therapy improves short-term clinical outcomes and overall physiological function in heart failure patients with pulmonary hypertension has yet to be addressed. The main aim of this project is to examine the safety and impact of supervised exercise training on short-term clinical outcomes (including disease severity and health-related quality-of-life), exercise capacity, and heart and lung blood vessel function in heart failure patients with pulmonary hypertension. Completion of this project will provide a critical first-step towards understanding the potential clinical and therapeutic benefit of exercise training in heart failure patients with pulmonary hypertension. Overall, our findings will have the potential to positively influence the therapeutic options available for the treatment of heart failure patients with pulmonary hypertension, and may help drive the acceptance of exercise training delivered by local, generic heart and lung rehabilitation services as a standard of care for patients with any form of pulmonary hypertension.
- Joerg Herrmann, MD, Mayo Clinic, Rochester, research study entitled: "TACTIC - TrAstuzumab Cardiomyopathy Therapeutic Intervention with Carvedilol Trial". Breast cancer patients undergoing trastuzumab treatment are at risk of heart function decline or heart failure symptoms, but it is unknown if, when, and for how long cardiovascular protective strategies, e.g. with a beta-blocker, could help. This study randomly assigns those taking curative-intent trastuzumab to the beta-blocker carvedilol—either when significant heart function decline or subtle early signs of heart injury (either by elevation of a cardiac blood biomarker, i.e. cardiac troponin, or by an abnormal heart ultrasound marker, i.e. global longitudinal strain) are noted, or preventatively before beginning trastuzumab therapy. This study will further randomly assign those patients on carvedilol in these three groups to either discontinue at the end of trastuzumab therapy or to continue for another year, providing much needed clinical trial data on what the best strategy (“tactic”) for those at risk of cardiotoxicity with trastuzumab therapy is.
- Joerg Herrmann, MD, Mayo Clinic, research study entitled: “CAncer Survivor CArdiomyopathy DEtection (CASCADE)”. Currently, there are over 15 million cancer survivors in the United States, and this number is projected to exceed 20 million within the next five years-- most of whom will be long-term survivors (5+ years). Many of these individuals are at a high lifetime risk of developing heart disease due to their exposure to anthracycline-based chemotherapy during cancer treatment. The most efficient and cost-effective way to monitor, predict and prevent the development of heart failure in these cancer survivors is not known. While echocardiography has been the standard approach, serial studies are costly and require logistics, time and effort, kindling interest in identifying less expensive cardiac surveillance strategies that can be implemented over long periods of time to a large population at risk. The current application’s objective is to assess and optimize the diagnostic performance of novel artificial intelligence (AI) electrocardiography (ECG) and an established blood marker for heart disease (NT-pro-BNP) for the detection of an abnormal heart function in cancer survivors and to compare and combine these two tests to define the most optimal strategy. These studies will inform cardiac surveillance efforts for clinical practice and the planning of a randomized clinical trial to address the clinical impact of optimal cardiac surveillance.
- Claudia Rodrigues, PhD, Florida Atlantic University, research study entitled: "Molecular Mechanisms of Anthracycline-Induced Cardiovascular Toxicity". Cardiovascular disease is the most common complication that develops in pediatric patients receiving chemotherapy. The survival rate of children who receive cancer treatment has significantly increased throughout the years. However, survivors are at high risk of suffering from different types of chronic health conditions due to chemotherapy toxicity, including cardiovascular disease. Heart injury, after exposure to chemotherapy agents, follows a progressive course in a significant number of patients, leading to congestive heart failure at a young age. The Rodrigues laboratory is investigating mechanisms underlying the cardiovascular toxicity of anthracyclines, a group of chemotherapy drugs used in the treatment of different types of pediatric and adult cancers. The goal of these studies is to identify novel mechanisms that can be therapeutically targeted for prevention of heart injury and preservation of cardiac function. This proposal specifically focuses on the identification of signaling mechanisms released from our blood vessels that impact the function of the heart under normal and chemotherapy exposure conditions. Since their discovery over 50 years ago, the toxic effects of anthracyclines to the cardiovascular system remain a significant medical problem. This project is an important step toward the identification of novel protective strategies that could be used to prevent chemotherapy-induced cardiovascular disease.
- Lina Shehadeh, PhD, University of Miami, research study entitled: “Anti-Osteopontin Monoclonal Antibody Therapy in a Pig Model of Atherosclerosis”. Atherosclerosis is a chronic inflammatory disease of the arteries responsible for up to 50% of all deaths in westernized society. It is principally lipid-driven, initiated by the accumulation of low-density lipoprotein (LDL) cholesterol. Clearance of LDL cholesterol from the bloodstream is therefore the first line of therapy and can be achieved by uptake via the LDL receptor (LDLR) in the liver. Existing therapies like statins and anti-PCSK9 antibodies are potent in LDL cholesterol clearance via increase of LDLR in the liver. In this project funded by the Miami Heart Research Institute, the Shehadeh lab will investigate how anti-Osteopontin (OPN) antibodies can further increase LDL cholesterol clearance. Data from the lab suggest that anti-OPN antibodies can further elevate LDLR levels and increase LDL cholesterol clearance. Experiments are proposed to develop the antibodies and validate findings in a large animal (pig) model of atherosclerosis.
- Chunming Dong, MD, University of Miami, research study entitled: "The Use of CRISPR/CAS9 Technology to Prevent Acute and Chronic Rejection in Cardiac Allograft Transplantation". Clustered Regularly Interspaced Short Palindromic Repeats-Cas9 (CRISPR-Cas9) is a gene editing technique that has revolutionized genome engineering and allows for efficient gene knockdowns and knock-ins. Organ transplantation between species is known as xenotransplantation. With the advent of CRISPR-Cas9 technology, there is a rush for xenotransplantation using genetically modified pig organs in humans to tackle donor organ shortage. However, the first and only cardiac xenograft transplant recipient only survived for two months. The two gene-edited pig kidneys were transplanted into brain-dead humans with no apparent signs of kidney functions. Thus, although xenograft transplantation may eventually lead to the clinical use of animal organs that will overcome the shortage of human organs, multiple hurdles remain before animal organs can be made available in routine medical care. These include ethical dilemmas, uncertain clinical outcomes, availability and cost of the genetically modified organs, insurance coverage, as well as policy issues. On the other hand, allograft organ transplantation (AOTx) using organs from the same species (i.e., human donors) has proven to be a life-saving approach for patients with end-stage heart, lung, liver and kidney diseases5. This isn’t to say that AOTx recipients do not face challenges. They are at increased risk for acute rejection (AR) and chronic rejection (CR) manifested as progressive cardiac allograft vasculopathy in heart transplant recipients. As a result, patients have to be on prolonged and heightened immunosuppression necessary to prevent AR, which increases their susceptibility to the development of cancers and infections. The common denominator for all of these morbidities is alloimmunity and the use of immunosuppressants. Therefore, approaches that could decrease the immune response to the graft without the need for prolonged and heightened immunosuppression would be of substantial therapeutic value. Dr. Dong’s laboratory not only has mastered the CRISPR-Cas9 technology, but has designed a proprietary sgRNA to guide the CRISPR-Cas9 system to ablate the major molecule responsible for triggering alloimmune response, namely the major histocompatibility complex (MHC) class I. Furthermore, they have developed a novel dual sgRNA lentiviral vector (DSLV) containing sgRNAs for both MHC class I & II (MHC II is another molecule triggering alloimmune response). Using this advanced CRISPR-Cas9 gene editing system, they have efficiently ablated MHC I and II in endothelial cells (ECs) and livers (easier to transduce than the heart and used for proof-of-concept). Upon implantation into the allogeneic recipient mice, the genetically modified ECs and livers showed markedly suppressed alloimmune reaction and improved survival, similar to unmodified allografts treated with immunosuppression. Based on these solid and exciting data, we propose to study the effects of MHC silencing in acute and chronic rejection using ECs, smooth muscle cells and aortic transplants—an established model to mimic heart transplantation to study AR and cardiac allograft vasculopathy (a major limiting factor for the long-term survival of cardiac transplant patients). Our project also has the potential to develop the technology that will lead to the production of universal donor tissues/hearts that will not activate the immune system as vigorously through targeted ablation of MHC in the allograft hearts. It will reduce the need for high-level immunosuppression and, thus lessening the adverse consequences associated with immunosuppression. The Miami Transplant Institute is the largest transplant center in the nation. With the success of this project, we will be well positioned to test our strategy in unused human hearts to evaluate the feasibility in humans. This will revolutionize the allograft transplant medicine with the goal of creating off-the-shelf universal donor hearts and other organs.
THE 2021-2022 RESEARCH RECIPIENTS/PROJECTS ARE:
- Demilade Adedinsewo, MD, Mayo Clinic Jacksonville, research study entitled: "Screening for PEripartum Cardiomyopathies using Artificial Intelligence (SPEC-AI)". An estimated 700 women die each year in the United States from pregnancy related complications. Pregnancy related deaths is also on the rise with heart disease being the leading cause of death during pregnancy and in the 12-month period following the birth of a child (postpartum period). Cardiomyopathy (abnormal heart pump function) is one of the most common acquired heart conditions during pregnancy and the post-partum period, but its diagnosis can be challenging due to the similarity in symptoms seen with cardiomyopathy and normal pregnancy such as leg swelling and shortness of breath. There are also significant disparities in maternal outcomes, with higher rates of death among non-whites and women of lower socioeconomic status. A delay in the diagnosis of cardiomyopathy and initiation of appropriate care are believed to be important contributors to pregnancy related deaths. As such, early identification of cardiomyopathy during pregnancy and the postpartum period is essential. Unfortunately, screening for cardiomyopathy during pregnancy or postpartum is not routinely performed due to the associated costs and complexities surrounding obtaining an ultrasound of the heart (echocardiogram) and the required expertise to perform and interpret these tests. The overall goal of this study is to investigate the use of a simple, inexpensive, non-invasive test - an electrocardiogram (a test which records electrical activity of the heart) enhanced with artificial intelligence (AI-ECG) as a screening tool for cardiomyopathy during pregnancy and the post-partum period. The results from this study will provide additional information regarding the effectiveness of the AI-ECG as a screening tool as well as preliminary evidence to support a subsequent large-scale study to evaluate the impact of the AI-ECG on clinical outcomes in pregnant and postpartum women.
- Jose R. Lopez, MD, Mount Sinai Medical Center, research study entitled: “Cardioprotection in Diabetic Cardiomyopathy via upregulation of ATP-sensitive K+ channels”. Diabetes is a major public health problem that represents a huge health concern for Americans and the global population. Studies estimate that the number of people living with diabetes today ranges from 415 million to 425 million, and currently, 1.5 million deaths are attributed to diabetes worldwide every year. There are two main types of diabetes, type 1 (T1D) and the more common type 2 (T2D) diabetes. Both T1D and T2D patients develop heart failure even in the absence of other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease. Nearly 80% of the deaths related to diabetes are attributed to cardiac complications. Although drugs and insulin have been successfully used to treat high blood glucose levels in diabetic patients. Despite maintaining adequate blood glucose levels in diabetic patients, the latter has not been enough to prevent cardiac complications. Plant-based dietary nutrients referred to as nutraceuticals have been the basis for innovative strategies to promote health and prevent or slow the progression of chronic diseases. The term nutraceutical is defined as a food or portion of food, that has a medical or health benefits, including the prevention and treatment of chronic disease. Citrus fruits such as oranges, mandarins, grapefruit are notably rich in flavonoids, and citrus flavonoids have been demonstrated to protect against diabetic complications. Among them, naringin found mainly in grapefruits and oranges has been reported to be helpful for the treatment of obesity, hypertension, cardiovascular diseases, and blood glucose levels in diabetic patients. However, no studies have been carried to determine if naringin, in addition to helping to maintain normal blood sugar levels, can protect diabetic patients from developing heart failure. In two experimental mouse models of diabetes, we have previously found that their heart cells have elevated intracellular calcium concentrations, elevated production of free radicals, a decrease in cell viability, reduced glucose transport into the cells, and low expression of ATP sensitive potassium channels. This project will explore whether or not naringin provides cardioprotection in diabetic models, and whether or not this protection is elicited via the expression of the ATP sensitive potassium channels. Our preliminary work suggests that naringin represents a novel therapeutic approach and an exciting and promising new direction for treating diabetic patients. We hope that this new therapy can eventually prevent or modify the progression of diabetic heart failure.
- Nanette Bishopric, MD, Georgetown University, research study entitled: “Restoration of Heart Function by Targeting Remodeling Pathways in the Ischemic and Stressed Heart”. This project focuses on understanding how stress alters the biology of heart muscle, how it damages heart function and the heart’s ability to heal, and how the effects of stress can be reversed. Stresses like poor blood supply, high blood pressure, leaking or blocked heart valves, aging, diabetes and obesity can all lead the heart muscle cell to change in fundamental ways. These molecular responses within the cell often trigger cell death and replacement by scar tissue, weakening the pumping action of the heart. Other stress-induced changes can prevent the beating heart muscle cell from being able to relax effectively. Both weak contraction and poor relaxation can lead to heart failure and death. In the heart, inability to relax is the principal feature of Heart Failure with Preserved Ejection Fraction (HFpEF). More than 3 million people in the United States are living with HFpEF. It causes shortness of breath, reduces the ability to exercise, and triggers dangerous heart rhythms. There is no known cure for HFpEF. Instead, doctors rely on medicine, like diuretics (“water pills”), to help people deal with the symptoms of HFpEF. Obviously, there is a tremendous need for more effective treatments. The ultimate goal of our research is to find new treatments that attack the underlying process of HFpEF. Our laboratory, with the multi-year support of the Miami Heart Research Institute, has helped to reveal a network of chemical pathways in the stressed cell that lead to HFpEF. We have designed novel molecules using computer modelling and have shown that they can stop or reverse these pathways, and prevent heart failure. Our aims are to use these molecules to reverse mouse models of heart failure caused by coronary artery blockage, pressure overload and chemotherapy, and to use powerful new DNA technologies that allow us to “see” the the effects of these molecules on the genetic material in the nucleus. Specifically, we will see how genes are turned on and off, and how nuclear DNA moves around to achieve this. By gaining this fundamental understanding, we will have insight into how reversal of HFpEF can prevent heart failure deaths, determine the safety of this approach, and improve outcomes for patients suffering from HFpEF.
- Sharan Ramaswamy, PhD, Florida International University, research entitled: "Stem Cell-seeded bioscaffolds supporting somatic growth, function and remodeling in the treatment of critical congenital valve disease in the young". Heart valve replacements with the capacity to regenerate are conceptually very appealing in the treatment of critical valve diseases in the young, because of their potential to grow with the child. Our studies to-date with support from the Florida Heart Research Foundation have successfully enabled the deposition of allogeneic, heart valve-relevant extracellular matrix (ECM) onto the surfaces of a bio-scaffold. This valve-relevant ECM contains molecules that are known to trigger cellular chemotaxis, which would thereby facilitate accelerated valve regeneration after implantation. However, prior to further in vivo assessment, our immediate goals are first to: (i) stabilize the structural properties of our valve ECM-rich materials, (ii) confirm ECM-rich valve’s ability to hydrodynamically function well in the acute term in the mitral valve location using a pulse duplicator system and (iii) Assess its structural properties after being subjected to 3-months of fatigue using an accelerated wear tester. Our previous findings have demonstrated that the raw bio-scaffold remains relatively undegraded up to 3-months post-implantation, in the mitral valve location in a juvenile non-human primate model. Thus, preservation of structural properties post-fatigue testing in our ECM-rich valves will establish that it can permit valve regeneration in vivo without deterioration in its mechanical properties. Completion of these project goals will subsequently permit us to assess if our ECM-rich valves can support somatic growth. We will also actively work with our surgical collaborators (at Joe DiMaggio’s Children’s hospital, Hollywood, FL) during this project to ensure that the ECM-rich valve’s geometry and dimensions support suturing and implantation. In summary, the aforementioned three project goals are major steps towards our translation efforts to the clinic, where at the moment, treatment of critical congenital valve diseases in young children has a very poor prognosis for survival.
- Florida Heart Doctoral Student, Daniel Chaparro,
Florida International University, research study entitled: "Aortic Valve Leaflet Innervation in Tissue Mechanics and Disease Progression".
Surprisingly, there are neurons within the aortic valve. However, their role in aortic valve function and disease remain unknown. The aortic valve ensures that blood flows in one direction from the heart to the rest of the body. A well-defined structure gives the aortic valve the unique mechanical properties required to open and close as the heart beats. Disruption of this structure during aortic valve disease (AVD) leads to heart failure. The tissue, specifically the aortic valve leaflets (AVLs), is maintained by a complex mixture of cells. Currently there is no treatment for AVD and to develop new therapeutic options we first need to understand how neurons, and other cells, within the tissue work to maintain aortic valve structure and function. Neurons reside on the side of the AVL that experiences the most mechanical stress during the cardiac cycle. AVL neurons decrease in abundance with age at a rate that mirrors the onset of AVD in human patients. These cells also associate with formation of the AVL structure during development in our experimental models. We hypothesize that AVL neurons can sense the mechanical environment within AVLs and play a role in controlling valve mechanics and that neural dysfunction leads to AVD progression. In this project we explore the role of aortic valve neurons in function and disease. The outcomes of these studies could lead to new therapeutic targets for AVD, a major cause of heart disease.
- Joshua Hutcheson, PhD & Alexander Agoulnik, PhD, Florida International University, research study entitled: "A Novel Small Molecule Therapy for Late-Stage Atherosclerosis". Despite tremendous advances in the understanding of risk factors and the development of blockbuster lipid lowering drugs such as statins, cardiovascular disease remains the global leading cause of death. Atherosclerotic plaques—formed due to inflammation and the accumulation of lipids in the arterial wall—are a major contributor to cardiovascular morbidity. Rupture of atherosclerotic plaques leads to heart attacks and strokes. Lipid-lowering strategies and lifestyle interventions such as weight loss and smoking cessation often require years before a patient’s risk returns to baseline levels. The residual risk is likely attributable to plaques that remain even after statin treatment or lifestyle changes. While the interventions prevent or stabilize further atherosclerotic plaque development, they do not immediately reverse existing plaque. Recent strategies have targeted inflammation to reduce residual risk by promoting the reduction of existing plaque. Clinical trial results showed significantly fewer cardiovascular events in individuals who received an antibody therapy designed to reduce pro-inflammatory signaling. The therapy used, however, is limited by drawbacks, including the requirement that patients receive antibody injections every few months. In this study, we will test the ability of a first-in-class small molecule developed in collaboration with investigators from the National Center for Advancing Translational Sciences at the NIH to reverse atherosclerotic plaques when given in combination with statin treatment and lifestyle interventions in the preclinical models of atherosclerosis. The small molecule targets relaxin peptide receptor that has previously demonstrated clinical safety in large clinical trials. The outcomes of the study could lead to an orally available treatment that could reverse atherosclerosis and reduce residual cardiovascular risk.
- Jose A Adams, MD, Mount Sinai Medical Center, research study entitled: "Whole Body Periodic Acceleration (pGz) in Heart Failure". Heart failure (HF) is a devastating problem which occurs in more than 50 per 1000 individuals greater than 65 years of age. The lifetime risk of heart failure from ages 45 through 95 years is 20-45%. The symptoms of HF are varied but include; shortness of breath, easy fatigue, intolerance to exercise, fluid retention, and congestion of the lungs. The causes of HF include; scarring of the heart due to previous heart attack, uncontrolled diabetes and hypertension, genetics and other still unknown causes. Death from HF remains at approximately 50% within 5 years of diagnosis. Additionally, HF accounts for over 1 million hospitalizations annually. Furthermore, the total cost of HF in the US exceeds $30 billion annually, making HF a significant public health problem and economic burden. Whole Body Periodic Acceleration (pGz) is the back and forth motion of the body in a head to foot direction utilizing a bed like platform. The motion is similar to “a mother pushing a baby carriage back and forth”. The pGz motion induces pulsations to the body in the in all blood vessels, liberating beneficial substances from the cells which line these vessels. Previous grant support from the Miami Heart Research Institute/Florida Heart Research Foundation have allowed our laboratory to show that pGz improves the function of the heart after cardiac arrest. Additionally, pGz performed before (pre-conditioning) cardiac arrest or a heart attack, improved recovery, and heart function when compared with no treatment. This project investigates the use of pGz in models of the most common causes of HF. The study will determine whether or not pGz will improve heart function after established HF and will seek to determine if such improvements in heart function are related to the effects of pGz on heart scarring, excess inflammation, and other biochemical pathways. The findings of this study when applied to populations with HF could have a tremendous impact in reducing death, improving quality of life, and reducing healthcare costs in those affected by HF.
- Claudia Rodrigues, PhD, Florida Atlantic University, research study entitled: "Molecular Mechanisms of Anthracycline-Induced Cardiovascular Toxicity". Cardiovascular disease is the most common complication that develops in pediatric patients receiving chemotherapy. The Rodrigues laboratory is investigating mechanisms underlying cardiac toxicity of chemotherapy drugs used in the treatment of different types of pediatric cancer. The survival rate of children who receive cancer treatment significantly increased throughout the years. However, survivors are at high risk of suffering from different types of chronic health conditions due to chemotherapy toxicity. Heart injury, after exposure to chemotherapy agents, follow a progressive course in a significant number of patients, leading to congestive heart failure at a young age. Congestive heart failure is the leading cause of death among survivors after cancer recurrence and secondary malignancy. The goal of our studies is to identify early mechanisms involved in cardiac toxicity of a specific class of chemotherapy drugs known as anthracyclines. Since their discovery over 50 years ago, the toxic effects of anthracyclines to the cardiovascular system remain a significant medical problem. Therefore, there is an urgent need for development of novel cardiovascular protective strategies to prevent or at least attenuate toxicity. This study is an important step towards the identification of novel mechanisms of anthracycline-induced cardiac toxicity and development of novel cardioprotective strategies for therapeutic use.
- Demilade Adedinsewo, MD,
Mayo Clinic Jacksonville, research study entitled: "Screening for PEripartum Cardiomyopathies using Artificial Intelligence (SPEC-AI)".
An estimated 700 women die each year in the United States from pregnancy related complications. Pregnancy related deaths is also on the rise with heart disease being the leading cause of death during pregnancy and in the 12-month period following the birth of a child (postpartum period). Cardiomyopathy (abnormal heart pump function) is one of the most common acquired heart conditions during pregnancy and the post-partum period, but its diagnosis can be challenging due to the similarity in symptoms seen with cardiomyopathy and normal pregnancy such as leg swelling and shortness of breath. There are also significant disparities in maternal outcomes, with higher rates of death among non-whites and women of lower socioeconomic status. A delay in the diagnosis of cardiomyopathy and initiation of appropriate care are believed to be important contributors to pregnancy related deaths. As such, early identification of cardiomyopathy during pregnancy and the postpartum period is essential. Unfortunately, screening for cardiomyopathy during pregnancy or postpartum is not routinely performed due to the associated costs and complexities surrounding obtaining an ultrasound of the heart (echocardiogram) and the required expertise to perform and interpret these tests. The overall goal of this study is to investigate the use of a simple, inexpensive, non-invasive test - an electrocardiogram (a test which records electrical activity of the heart) enhanced with artificial intelligence (AI-ECG) as a screening tool for cardiomyopathy during pregnancy and the post-partum period. The results from this study will provide additional information regarding the effectiveness of the AI-ECG as a screening tool as well as preliminary evidence to support a subsequent large-scale study to evaluate the impact of the AI-ECG on clinical outcomes in pregnant and postpartum women
- Lina Shehadeh, PhD, University of Miami, research study entitled: “Anti-Osteopontin Monoclonal Antibody Therapy in a Pig Model of Atherosclerosis”. Atherosclerosis is a chronic inflammatory disease of the arteries responsible for up to 50% of all deaths in westernized society. It is principally lipid-driven, initiated by the accumulation of low-density lipoprotein (LDL) cholesterol. Clearance of LDL cholesterol from the bloodstream is therefore the first line of therapy and can be achieved by uptake via the LDL receptor (LDLR) in the liver. Existing therapies like statins and anti-PCSK9 antibodies are potent in LDL cholesterol clearance via increase of LDLR in the liver. In this project funded by the Miami Heart Research Institute, the Shehadeh lab will investigate how anti-Osteopontin (OPN) antibodies can further increase LDL cholesterol clearance. Data from the lab suggest that anti-OPN antibodies can further elevate LDLR levels and increase LDL cholesterol clearance. Experiments are proposed to develop the antibodies and validate findings in a large animal (pig) model of atherosclerosis.
- Gervasio A. Lamas, MD/Christos Mihos, DO, Mount Sinai Medical Center, research study entitled: “Effects of Exercise and FITness on Left Ventricular Torsion and Wall MechanIcs STudy (FIT-TWIST)”. Exercise capacity is one of the most important markers of cardiovascular health. Cardiac ultrasound imaging (i.e. “Echocardiography”) is the primary method used by cardiologists to evaluate heart function. Yet for many years, cardiologists could not, by looking at an echo, tell whether the patient was fit, or a “couch potato”. The standard metric to express cardiac function, the ejection fraction (EF), or the percentage of blood ejected with each heartbeat (normal is 55% to 65%), simply does not reflect exercise capacity. Evidence suggests that the cardiovascular benefits of fitness are strongly influenced by the health of cardiac mechanics, which are measured using an advanced echocardiographic technique called 2D speckle-tracking echocardiography. This method has the capability of quantifying subtle aspects of cardiac motion and “fitness” based on the way the heart moves – shortening and twisting when it contracts, or “pumps”, and reversing its motion to relax. This study of cardiac mechanics in health and ischemic heart disease, will enroll 150 healthy subjects and assess the effects of different forms of exercise on cardiac mechanics in FIT-TWIST/Health. We hypothesize that the cardiac mechanics of normal subjects will change in a favorable way and guide ultimate selection of the most beneficial form of cardiovascular exercise. In FIT-TWIST/MI, we will assess 50 patients who have had a “heart attack” (myocardial infarction, MI), an insult to cardiac structure that leads to major disruption of cardiac mechanics. In these patients, we will study the effects of a standard cardiac rehabilitation program, a program of 36 sessions of graded exercise over a 12-week period. We hypothesize that cardiac rehabilitation restores some degree of normality to cardiac mechanics, thus explaining the extreme benefit on post-MI survival of cardiac rehab participation.
THE 2020 SUPPLEMENTAL RESEARCH RECIPIENTS/PROJECTS ARE:
- Joerg Herrmann, MD, Mayo Clinic, research study entitled: “CAncer Survivor CArdiomyopathy DEtection (CASCADE)”. Currently, there are over 15 million cancer survivors in the United States, and this number is projected to exceed 20 million within the next five years-- most of whom will be long-term survivors (5+ years). Many of these individuals are at a high lifetime risk of developing heart disease due to their exposure to anthracycline-based chemotherapy during cancer treatment. The most efficient and cost-effective way to monitor, predict and prevent the development of heart failure in these cancer survivors is not known. While echocardiography has been the standard approach, serial studies are costly and require logistics, time and effort, kindling interest in identifying less expensive cardiac surveillance strategies that can be implemented over long periods of time to a large population at risk. The current application’s objective is to assess and optimize the diagnostic performance of novel artificial intelligence (AI) electrocardiography (ECG) and an established blood marker for heart disease (NT-pro-BNP) for the detection of an abnormal heart function in cancer survivors and to compare and combine these two tests to define the most optimal strategy. These studies will inform cardiac surveillance efforts for clinical practice and the planning of a randomized clinical trial to address the clinical impact of optimal cardiac surveillance.
- Lina Shehadeh, PhD, University of Miami, research study entitled: “Anti-Osteopontin Monoclonal Antibody Therapy in a Pig Model of Atherosclerosis”. Atherosclerosis is a chronic inflammatory disease of the arteries responsible for up to 50% of all deaths in westernized society. It is principally lipid-driven, initiated by the accumulation of low-density lipoprotein (LDL) cholesterol. Clearance of LDL cholesterol from the bloodstream is therefore the first line of therapy and can be achieved by uptake via the LDL receptor (LDLR) in the liver. Existing therapies like statins and anti-PCSK9 antibodies are potent in LDL cholesterol clearance via increase of LDLR in the liver. In this project funded by the Miami Heart Research Institute, the Shehadeh lab will investigate how anti-Osteopontin (OPN) antibodies can further increase LDL cholesterol clearance. Data from the lab suggest that anti-OPN antibodies can further elevate LDLR levels and increase LDL cholesterol clearance. Experiments are proposed to develop the antibodies and validate findings in a large animal (pig) model of atherosclerosis.
- Gervasio A. Lamas, MD/Christos Mihos, DO, Mount Sinai Medical Center, research study entitled: “Effects of Exercise and FITness on Left Ventricular Torsion and Wall MechanIcs STudy (FIT-TWIST)”. Exercise capacity is one of the most important markers of cardiovascular health. Cardiac ultrasound imaging (i.e. “Echocardiography”) is the primary method used by cardiologists to evaluate heart function. Yet for many years, cardiologists could not, by looking at an echo, tell whether the patient was fit, or a “couch potato”. The standard metric to express cardiac function, the ejection fraction (EF), or the percentage of blood ejected with each heartbeat (normal is 55% to 65%), simply does not reflect exercise capacity. Evidence suggests that the cardiovascular benefits of fitness are strongly influenced by the health of cardiac mechanics, which are measured using an advanced echocardiographic technique called 2D speckle-tracking echocardiography. This method has the capability of quantifying subtle aspects of cardiac motion and “fitness” based on the way the heart moves – shortening and twisting when it contracts, or “pumps”, and reversing its motion to relax. This study of cardiac mechanics in health and ischemic heart disease, will enroll 150 healthy subjects and assess the effects of different forms of exercise on cardiac mechanics in FIT-TWIST/Health. We hypothesize that the cardiac mechanics of normal subjects will change in a favorable way and guide ultimate selection of the most beneficial form of cardiovascular exercise. In FIT-TWIST/MI, we will assess 50 patients who have had a “heart attack” (myocardial infarction, MI), an insult to cardiac structure that leads to major disruption of cardiac mechanics. In these patients, we will study the effects of a standard cardiac rehabilitation program, a program of 36 sessions of graded exercise over a 12-week period. We hypothesize that cardiac rehabilitation restores some degree of normality to cardiac mechanics, thus explaining the extreme benefit on post-MI survival of cardiac rehab participation.
- Brian Shapiro, MD/Bryan Taylor, PhD, Mayo Clinic Jacksonville, research study entitled: “Exercise Training to Improve Pulmonary Haemodynamic and Right Ventricular Function in Heart Failure Patients with Pulmonary Hypertension”. A common and very dangerous consequence of heart failure is disease of the blood vessels that supply the lungs, which results in a large increase in lung blood pressure; this is known as pulmonary hypertension. Pulmonary hypertension is actually a group of conditions. It may be caused by disease of the lung arteries themselves (“Group 1”), occur due to heart disease (“Group 2”) or lung disease (“Group 3”), or as a consequence of previous blockage of the lung blood vessels (“Group 4”). However, heart failure is one of the leading causes of pulmonary hypertension worldwide. Compared to heart failure patients without pulmonary hypertension, those with pulmonary hypertension have worse symptoms, are more limited in their ability to exercise and perform routine daily tasks, have to be hospitalized more regularly, suffer greater heart damage, are more likely to need a heart transplant, and are at a much greater risk of premature death. Worryingly, drugs typically used to treat pulmonary hypertension do not typically work, and may even worsen symptoms, in heart failure patients. As such, there is a real and urgent medical need to identify alternative safe and effect treatments for pulmonary hypertension due to heart failure. We know that improved physical activity through exercise training benefits patients with heart disease. There is clear evidence that moderate intensity exercise (e.g., brisk walking) can improve heart, blood vessel, and muscle function as well as overall health and well-being in heart failure patients. Preliminary work from our laboratory suggests that such exercise training is safe in heart failure patients with pulmonary hypertension. However, whether exercise therapy improves short-term clinical outcomes and overall physiological function in heart failure patients with pulmonary hypertension has yet to be addressed. The main aim of this project is to examine the safety and impact of supervised exercise training on short-term clinical outcomes (including disease severity and health-related quality-of-life), exercise capacity, and heart and lung blood vessel function in heart failure patients with pulmonary hypertension. Completion of this project will provide a critical first-step towards understanding the potential clinical and therapeutic benefit of exercise training in heart failure patients with pulmonary hypertension. Overall, our findings will have the potential to positively influence the therapeutic options available for the treatment of heart failure patients with pulmonary hypertension, and may help drive the acceptance of exercise training delivered by local, generic heart and lung rehabilitation services as a standard of care for patients with any form of pulmonary hypertension.
THE 2020 CONTINUED RESEARCH RECIPIENTS/PROJECTS ARE:
- Jose A Adams, MD, Mount Sinai Medical Center, research study entitled: "Whole Body Periodic Acceleration (pGz) in Heart Failure". Heart failure (HF) is a devastating problem which occurs in more than 50 per 1000 individuals greater than 65 years of age. The lifetime risk of heart failure from ages 45 through 95 years is 20-45%. The symptoms of HF are varied but include; shortness of breath, easy fatigue, intolerance to exercise, fluid retention, and congestion of the lungs. The causes of HF include; scarring of the heart due to previous heart attack, uncontrolled diabetes and hypertension, genetics and other still unknown causes. Death from HF remains at approximately 50% within 5 years of diagnosis. Additionally, HF accounts for over 1 million hospitalizations annually. Furthermore, the total cost of HF in the US exceeds $30 billion annually, making HF a significant public health problem and economic burden. Whole Body Periodic Acceleration (pGz) is the back and forth motion of the body in a head to foot direction utilizing a bed like platform. The motion is similar to “a mother pushing a baby carriage back and forth”. The pGz motion induces pulsations to the body in the in all blood vessels, liberating beneficial substances from the cells which line these vessels. Previous grant support from the Miami Heart Research Institute/Florida Heart Research Foundation have allowed our laboratory to show that pGz improves the function of the heart after cardiac arrest. Additionally, pGz performed before (pre-conditioning) cardiac arrest or a heart attack, improved recovery, and heart function when compared with no treatment. This project investigates the use of pGz in models of the most common causes of HF. The study will determine whether or not pGz will improve heart function after established HF and will seek to determine if such improvements in heart function are related to the effects of pGz on heart scarring, excess inflammation, and other biochemical pathways. The findings of this study when applied to populations with HF could have a tremendous impact in reducing death, improving quality of life, and reducing healthcare costs in those affected by HF.
- Joerg Herrmann, MD, Mayo Clinic, research study entitled: "TACTIC - TrAstuzumab Cardiomyopathy Therapeutic Intervention with Carvedilol Trial". Breast cancer patients undergoing trastuzumab treatment are at risk of heart function decline or heart failure symptoms, but it is unknown if, when, and for how long cardiovascular protective strategies, e.g. with a beta-blocker, could help. This study randomly assigns those taking curative-intent trastuzumab to the beta-blocker carvedilol—either when significant heart function decline or subtle early signs of heart injury (either by elevation of a cardiac blood biomarker, i.e. cardiac troponin, or by an abnormal heart ultrasound marker, i.e. global longitudinal strain) are noted, or preventatively before beginning trastuzumab therapy. This study will further randomly assign those patients on carvedilol in these three groups to either discontinue at the end of trastuzumab therapy or to continue for another year, providing much needed clinical trial data on what the best strategy (“tactic”) for those at risk of cardiotoxicity with trastuzumab therapy is.
- Chunming Dong, MD, University of Miami, research study entitled: "MicroRNA Regulation of Cocaine Effects in the Cardiovascular System". The adverse cardiovascular (CV) consequences of cocaine use include hypertension (HTN), aortic stiffness, and atherosclerosis. Cocaine stimulates the sympathetic nervous system by inhibiting norepinephrine (NE) reuptake at nerve terminals; however, recent evidence suggests that inhibition of NE reuptake may not be the major driver of cocaine-induced CV effects. As such, the mechanisms mediating the effects of cocaine on the CV system remain elusive. With the support from Miami Heart Research Institute (MHRI), we performed small RNA and RNA sequencing in the aortas from mice treated with cocaine, cocaine methiodide (CM, which does not enter the CNS) or saline to identify potential microRNA (miR)—mRNA pathways that mediate the CV effects of cocaine. Two miR—mRNA pathways were implicated: 1) ↑miR-30c—↓Malic Enzyme 1 (ME1)—↑reactive oxygen species (ROS) activity, which is crucial in HTN and vascular aging (aortic stiffness); and 2) ↓miR-423—↑Cacna2d2 (encoding the α2δ-2 subunit of voltage-dependent calcium channels) —↑calcium influx resulting in increased intracellular calcium concentration ([Ca2+]i) which is critical in controlling vascular smooth muscle cell (SMC) contractility and blood pressure (BP). We thoroughly investigated the ↑miR-30c—↓ME1—↑ROS pathway in our published paper entitled: “Cocaine Exposure Increases Blood Pressure and Aortic Stiffness via the miR-30c-5p-Malic Enzyme 1-Reactive Oxygen Species Pathway”. In the last funding cycle from MHRI, we have generated data showing that cocaine- and CM-induced silencing of miR-423-5p and subsequent upregulation of Cacna2d2 led to increased [Ca2+]i, resulting in augmented contractility of SMCs. Furthermore, miR-423-5p overexpression ameliorated cocaine-induced BP elevation in vivo. We also determined the causal relationships among components of the ↓miR-423—↑Cacna2d2—↑[Ca2+]i axis by using gene knock-down and knock-in approaches. These studies have laid the foundation for our future work to characterize the interactions and synergism between ↑miR-30c—↓ME1—↑ROS pathway and the ↓miR-423—↑Cacna2d2—↑[Ca2+]i axis in mediating the cardiovascular effects of cocaine and identify novel therapeutic targets for this dreadful disease that affects millions of Americans.
- Jeffrey J Goldberger, MD, MBA, University of Miami, research study entitled: "4D Flow MRI for Assessment of Left Atrial Stasis". Stroke is a serious complication of atrial fibrillation (a rapid heart rhythm disorder) and occurs because of diminished blood flow (stasis) that occurs in the top chamber of the heart (left atrium) in atrial fibrillation. Current treatment to prevent stroke in patients with atrial fibrillation who are deemed to be at substantial risk is a blood thinner (anticoagulant) which has significant risk of bleeding complications. Anticoagulant use must balance the benefit of stroke prevention against the risk of bleeding complications. Currently, this is done with the use of a score based on the presence or absence of certain clinical factors, such as age and high blood pressure. These scores have only mediocre predictive value. Improving our ability to predict who is at enough risk for a stroke to merit anticoagulant treatment will likely require a more direct evaluation for stasis within the left atrium. Over the last several years, we have developed and have been testing a novel MRI technique, the first such noninvasive technique, that can measure the blood flow velocities within the left atrium. In these studies, we are assessing the effect of restoring normal heart rhythm on the blood flow velocity. The preliminary data show that when patients with atrial fibrillation undergo cardioversion (a shock) to restore normal rhythm, blood flow velocity does improve. Further multi-institutional collaboration is required to test this new technique in a large clinical study.
- Lina Shehadeh, PhD, University of Miami, research study entitled: "The Role of Osteopontin in Heart Failure with Preserved Ejection Fraction". Patients with chronic kidney disease (CKD) and coincident heart failure with preserved ejection fraction (HFpEF) may constitute a distinct HFpEF phenotype. Osteopontin (OPN) is a biomarker of HFpEF and predictive of disease outcome. We recently reported that OPN blockade reversed hypertension, mitochondrial dysfunction, and kidney failure in Col4a3-/- mice, a model of human Alport syndrome. With the funding from the Miami Heart Research Institute, we secured funding from the NIH, and were able to characterize the cardiac phenotype of Col4a3-/- mice, relate this to HFpEF, and investigate possible causative roles for OPN in driving the cardiomyopathy. We found that Col4a3-/- mice demonstrated cardiomyopathy with similarities to HFpEF, including diastolic dysfunction, cardiac hypertrophy and fibrosis, pulmonary edema, and impaired mitochondrial function. The cardiomyopathy was ameliorated by OPN knockout coincident with improved renal function and increased expression of a mitochondrial protein (OGDHL). Heart-specific overexpression of the mitochondrial protein in Col4a3-/- mice also improved cardiac function and cardiomyocyte energy state. In conclusion, the Col4a3-/- mice present a model of HFpEF secondary to CKD wherein OPN and OGDHL are intermediates, and possibly therapeutic targets.
- Raul Mitrani, MD, University of Miami, research study entitled: “Anti-arrhythmic Effects of Mesenchymal Stem Cell Injection in a Swine Model of Post Myocardial Infarct Ventricular Tachycardia". Ventricular tachycardia (VT) is a potentially lethal heart rhythm disorder that can occur in patients following heart attacks. VT is one of the major causes of sudden cardiac death, which occurs in approximately 350,000 Americans/year. The VT is generated from scar tissue that forms as a result of a heart attack. At the Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, we have pioneered the use of mesenchymal stem cells (MSCs) as a therapy to reduce scar tissue in patients who have had heart attacks and have congestive heart failure. The MSCs have shown beneficial effects when given to these patients. It is unknown whether MSCs can reduce the occurrence of VT following a heart attack. Therefore, we have conducted preclinical experiments on a model of VT following a heart attack (myocardial infarction), induced by blocking one of the heart arteries in a series of pigs. IN 5 pigs with inducible VT, the MSCs have either prevented induction of VT or slowed the VT rate. A slower VT rate would make the VT more survivable. We are planning a series of experiments to compare with placebo to determine the optimal dosing and injection strategy. This would serve as a basis for a future placebo-controlled study in humans.
- Nanette Bishopric, MD, Georgetown University, research study entitled: "Restoration of Heart Function by Novel Chemical Probes Targeting Remodeling in the Ischemic Heart". We started this project with the hypothesis that some of the damage associated with heart attacks and blockages in the coronary arteries is caused by the same molecules that cause damage in other kinds of stress. With support from MHRI, we have made initial findings that suggest this is correct. Our current experiments are aimed at confirming these findings. First, we will use our cardiac hypertrophy-blocking compounds in a mouse model of coronary artery occlusion (heart attack). We will assess the amount of cell death, inflammation, scarring, and heart failure in treated mice and compare the results in mice that received a placebo. Second, we will use the same DNA technologies we use in Project 1 to explore the molecules involved in heart attack damage and protection, and compare these with the molecular agents of damage in our other models of heart stress. This approach will help us to expand the range of therapies available to people recovering from heart attacks, and help to prevent heart failure in these patients
- Nanette Bishopric, MD, Georgetown University, research study entitled: “Reversal of Hypertrophy: Feasibility, Safety and Biological Consequences”. When we started this project a number of years ago, it was widely thought that cardiac hypertrophy was a natural way for the heart to adapt to increased work, in the same way that biceps and pectoral muscles get bigger when a weightlifter works out. But cardiac hypertrophy in the stressed heart is not the same growth process that happens in the athlete’s muscles or even the athlete’s heart. Through work from our laboratory that was supported by MHRI, as well from other groups, we now know that hypertrophy under stress involves harmful changes in the working proteins in the heart, as well as inflammation, scarring and cell death. These changes all together mean that the hypertrophied heart does not work as well as a normal one. What we have also shown is that much of this damage can be reversed by blocking the molecules that direct the damage in the first place. In this project we are working to get a better, more detailed map of the parts of the hypertrophy-associated, damage-inducing molecular network, using a mouse model of cardiac hypertrophy in which the heart has to beat against increased resistance. This model produces effects similar to those of high blood pressure or malfunctioning heart valves. We will also explore the ways in which these molecules are created inside the heart cell. To do this, we will use powerful new DNA technologies that allow us to “see” the genetic material in the heart turning on and off, and coiling and uncoiling inside the nucleus of the cell.
- Sana Nasim, PhD Candidate, Florida International University, research entitled: "Phenotypic and functional characterization of neural crest derived-aortic valve interstitial cells". The opening and closing of the aortic valve is essential for the directionality of blood flow during each heartbeat. Proper functioning of the aortic valve depends on its mechanical properties that are associated with the patterning of its constituents, including cells and matrix components. The major goal of my study is to fully characterize a subset of the aortic valve cells that are responsible for producing elastin. Alterations in elastin production may lead to aortic valve disease. I have combined various experimental approaches including genetically modified mouse models, wholemount fluorescence and structural imaging, echocardiography and atomic force microscopy. I found that a population of cells with characteristics of both smooth muscle cells and pigment cells make elastin, and that alterations in these cells lead to disruption of elastic fiber network and the mechanical properties of the aortic valves.
- Gervasio A. Lamas, MD, Mount Sinai Medical Center, research study entitled: "Trial to Assess Chelation Therapy 3a (TACT3a)". Diabetes triples the risk for fatty deposits in arteries, including in the heart, brain, and legs. We will use the most severe manifestation of arterial blockages, critical limb-threatening leg and foot artery blockage, as a marker of extreme risk for patients with diabetes. TACT3A will test a novel therapy, chelation, to try and reduce risk in these very ill patients. Chelation is a process by which a medication “sticks” to various toxins in the blood, usually toxic metals, like lead and cadmium, acquired from the environment, and allows them to be harmlessly excreted. Edetate disodium is a repurposed old drug, a chelator with high affinity for lead and cadmium, 2 common toxic metals that are toxic to coronary and other arteries. We will enroll 50 patients at Mount Sinai with diabetes and severe blockages of the leg arteries and try to prevent major amputation, coronary revascular-ization, stroke, MI, or death (all-cause) during an average 1.25 years of follow-up. Patients will be randomly assigned to chelation or placebo. Treatment will consist of 40 active or placebo infusions over 30 weeks. This study, if successful, will be presented to FDA as part of the rapidly growing evidence that environmentally acquired metal pollutants are a reversible risk factor for cardiovascular disease and that chelation is a safe and effective therapeutic intervention in patients with extremely high risk of cardiovascular events.
- Jose R. Lopez, MD, Mount Sinai Medical Center, research study entitled: “Cardioprotection in Diabetic Cardiomyopathy via upregulation of ATP-sensitive K+ channels”. Diabetes is a major public health problem that represents a huge health concern for Americans and the global population. Studies estimate that the number of people living with diabetes today ranges from 415 million to 425 million, and currently, 1.5 million deaths are attributed to diabetes worldwide every year. There are two main types of diabetes, type 1 (T1D) and the more common type 2 (T2D) diabetes. Both T1D and T2D patients develop heart failure even in the absence of other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease. Nearly 80% of the deaths related to diabetes are attributed to cardiac complications. Although drugs and insulin have been successfully used to treat high blood glucose levels in diabetic patients. Despite maintaining adequate blood glucose levels in diabetic patients, the latter has not been enough to prevent cardiac complications. Plant-based dietary nutrients referred to as nutraceuticals have been the basis for innovative strategies to promote health and prevent or slow the progression of chronic diseases. The term nutraceutical is defined as a food or portion of food, that has a medical or health benefits, including the prevention and treatment of chronic disease. Citrus fruits such as oranges, mandarins, grapefruit are notably rich in flavonoids, and citrus flavonoids have been demonstrated to protect against diabetic complications. Among them, naringin found mainly in grapefruits and oranges has been reported to be helpful for the treatment of obesity, hypertension, cardiovascular diseases, and blood glucose levels in diabetic patients. However, no studies have been carried to determine if naringin, in addition to helping to maintain normal blood sugar levels, can protect diabetic patients from developing heart failure. In two experimental mouse models of diabetes, we have previously found that their heart cells have elevated intracellular calcium concentrations, elevated production of free radicals, a decrease in cell viability, reduced glucose transport into the cells, and low expression of ATP sensitive potassium channels. This project will explore whether or not naringin provides cardioprotection in diabetic models, and whether or not this protection is elicited via the expression of the ATP sensitive potassium channels. Our preliminary work suggests that naringin represents a novel therapeutic approach and an exciting and promising new direction for treating diabetic patients. We hope that this new therapy can eventually prevent or modify the progression of diabetic heart failure.
- Sharan Ramaswamy, PhD, Florida International University, research entitled: "Stem Cell-seeded bioscaffolds supporting somatic growth, function and remodeling in the treatment of critical congenital valve disease in the young". Heart valve replacements with the capacity to regenerate are conceptually very appealing in the treatment of critical valve diseases in the young, because of their potential to grow with the child. Our previous work demonstrated the utility of a bio-scaffold valve derived from the small intestine of pigs, which functioned well as a mitral valve replacement, in the order of months. However, longer term function was limited by the inability of the valves to continue growing with the host. In the current investigation, we seeded the bio-scaffold valve with stem cells and exposed the constructs to specific mechanical environments that enable the cells to deposit new valvular-like tissues that are of the same species of the host. Accordingly, the goals of the current study are to rigorously characterize the previously utilized, and now explanted, raw bio-scaffold mitral valves, and to subsequently assess the feasibility of these valves, now layered with baboon stem cell-secreted tissues, in a juvenile, non-human primate, baboon model for mitral heart valve replacement. If successful, this project will enable us to extend this work towards a longer-term investigation of valvular growth potential, spanning the entire duration of child-to-adulthood in the baboon model, which is about 5 years (as opposed to 18 years in humans). Subsequently, this technology can be optimized for first-in-human evaluation as a more effective treatment for critical valve diseases in children, for whom the current prognosis remains poor.
THE 2019 RESEARCH RECIPIENT/PROJECTS ARE:
- Nanette Bishopric, MD, Georgetown University, research study entitled: "Restoration of Heart Function by Novel Chemical Probes Targeting Remodeling in the Ischemic Heart".
- Nanette Bishopric, MD, Georgetown University, research study entitled: “Reversal of Hypertrophy: Feasibility, Safety and Biological Consequences”.
- Chunming Dong, MD, University of Miami, research study entitled "MicroRNA Regulation of Cocaine Effects in the Cardiovascular System".
- Jeffrey J Goldberger, MD, MBA, University of Miami, research study entitled "Novel Assessments in Atrial Fibrillation".
- Lina Shehadeh, PhD, University of Miami, research study entitled "The Role of Osteopontin in Heart Failure with Preserved Ejection Fraction".
- Raul Mitrani, MD, University of Miami, research study entitled “Anti-arrhythmic Effects of Mesenchymal Stem Cell Injection in a Swine Model of Post Myocardial Infarct Ventricular Tachycardia".
- A. Allen Seals, MD, Florida Cardiovascular Quality Network Foundation, research study entitled “Florida Cardiovascular Quality Network Hyperlipidemia: Application of Clinical Decision Support Software Tools at the Point of Care in Patients with Hyperlipidemia—a Quality Outcomes Registry”
THE 2018 - 2019 SUPPLEMENTAL RESEARCH RECIPIENTS/PROJECTS ARE:
- Gervasio A. Lamas, MD, Mount Sinai Medical Center, research study entitled: "Trial to Assess Chelation Therapy 3a (TACT3a)".
- Jose R. Lopez, MD, Mount Sinai Medical Center, research study entitled “Cardioprotection in Diabetic Cardiomyopathy via upregulation of ATP-sensitive K+ channels”.
- Sharan Ramaswamy, PhD, Florida International University, research entitled "Stem Cell-seeded bioscaffolds supporting somatic growth, function and remodeling in the treatment of critical congenital valve disease in the young"
- Sana Nasim, PhD Candidate, Florida International University, research entitiled "Phenotypic and functional characterization of neural crest derived-aortic valve interstitial cells"
THE 2018 RESEARCH RECIPIENTS/PROJECTS ARE:
- Nanette Bishopric, MD, University of Miami, research study entitled: "Restoration of Heart Function by Novel Chemical Probes Targeting Remodeling in the Ischemic Heart".
- Chunming Dong, MD, University of Miami, research study entitled "MicroRNA Regulation of Cocaine Effects in Atheroslerosis".
- Jeffrey J Goldberger, MD, MBA, University of Miami, research study entitled "4D Flow MRI for Assessment of Left Atrial Stasis".
- Lina Shehadeh, PhD, University of Miami, research study entitled "The Role of Osteopontin in Heart Failure with Preserved Ejection Fraction".
- Lina Shehadeh, PhD, University of Miami, research study entitled "New Model and Novel Therapies for Heart Failure with Preserved Ejection Fraction”
- Joshua M. Hare, MD, University of Miami, research study entitled “Biomarker analysis from the POSEIDON-DCM – The PercutaneOus StEm Cell Injection Delivery Effects On Neomyogenesis in Dilated CardioMyopathy”
- Claudia Rodrigues, PhD, University of Miami, research study entitled “Molecular Mechanisms of Anthracycline-Induced Cardiovascular Toxicity”
- Brian Shapiro, MD, Mayo Clinic, research study entitled "Diagnostic Utility of Exercise Cardiac Magnetic Resonance in the Assessment of Cardiac Dyspnea”
- Nanette Bishopric, MD, University of Miami, research study entitled: “Reversal of Hypertrophy: Feasibility, Safety and Biological Consequences”
- Jose A Adams, MD, Mount Sinai Medical Center, research study entitled: "Whole Body Periodic Acceleration (pGz) in Heart Failure"