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Awarded Research Grants
2016 HFSA Grant Awardees
Heart failure (HF) is associated with significant morbidity and mortality in large part due to the failed development of most investigational treatments. Nevertheless, many of these treatments have identified a viable target that adversely affects cardiac function. Biomarkers to match patients with the most appropriate treatment may improve the success rate of novel therapeutic development.
Although the genetic determinants of drug response variability have been extensively studied, pharmacogenomics has not significantly improved clinical outcomes. While the genome cannot account for non-coded effectors, the metabolome reflects the sum influence of both coded (i.e., genetic) and non-coded (i.e., proteomic, environmental) effectors and is the ‘ome’ most proximal to the clinically observable phenotype. These unique properties, in conjunction with advances in high-throughput technologies and computational biology, position metabolomics to positively impact the study of variation and complexity in human biology and disease.
We propose to conduct a pharmametabolomics analysis of the REDHART study, a Phase 2a, 2:1 randomized, double-blind, placebo controlled clinical trial comparing the effects of anakinra, an IL-1 receptor antagonist, with placebo on cardiorespiratory fitness, assessed at 2 and 12 weeks. Plasma previously collected and stored at baseline will be subjected to high performance liquid chromatography-mass spectrometry and computational analysis to identify metabolite predictors of response to IL-1 blockade, as measured by cardiorespiratory fitness. These analyses will provide insight into the metabolic determinants of responses to IL-1 blockade as well as proof-of-concept for future pharmacometabolomic investigations.
Hemolysis is a potential limitation of all mechanical circulatory support (MCS) devices. No studies have prospectively studied these biomarkers in the setting of acute MCS (AMCS) device utilization for cardiogenic shock. Use of AMCS devices for cardiogenic shock is growing exponentially. In light of the recent FDA approval for the Impella micro-axial flow catheter for the treatment of cardiogenic shock (CS), use of this platform is expected to grow. In a small retrospective analysis, we recently identified that the change in plasma-free hemoglobin (pf-Hb), not lactate dehydrogenase (LDH), values within 24 hours after Impella activation are a highly sensitive and specific marker of hemolysis in the setting of CS. These findings are of potentially crucial importance given the growing use of these devices and the challenges with diagnosing hemolysis in shock. We now propose to prospectively measure pf-Hb levels using a bedside point-of-care system (HemoCue America; Brea, CA) in all patients receiving a left-sided Impella support device for CS over a one year period at our institution. Specifically, we will measure LDH and pf-Hb levels every 12 hours starting immediately before and for 72 hours after device activation. Clinical measures of hemolysis will be collected as per our standard protocol which includes daily monitoring for anemia, hemoglobinuria, peripheral smears, and hemolysis panels. Successful completion of this study will identify routine bedside measurement of pf-Hb, not LDH, as an important approach to identify hemolysis, thereby allowing for early intervention and improving survival for patients with CS supported by micro-axial flow catheters.
The reporting of national trends and the measurement of disparities in heart failure (HF) hospitalization rates by ethnicity is lacking. The Centers for Disease Control outlines epidemiologic guidance for the age adjustment of disease rates using the 2000 U.S. standard population to facilitate appropriate comparisons (Klein & Schoenborn, 2001). The purpose of this research project to report the HF hospitalization trends over the last decade using the National Inpatient Sample (NIS) provided through the Agency for Healthcare Research and Quality (AHRQ).
The study will investigate how standardization methods contribute to an under-appreciation of disparities in HF burden between ethnic groups. HF is a leading cause of hospitalization for adults with approximately 1 million inpatient stays per year. African Americans are known to be at higher risk for HF when compared to Whites when studied in cohort and registry studies (Bahrami et al., 2008; Feinstein et al., 2012). The rates of HF for Hispanics and Asians is less clear and requires further study. This study will estimate the hospitalization rate per year by ethnic group adjusted by single-year of age. Using single year of age adjustments will eliminate any residual age bias that may be produced through shifting age demographics over time. Before 2010, approximately 25% of the ethnicity classifications in the NIS dataset are missing. Multinomial logistic imputation will be used to account for missing ethnicity data. Age standardized rates of hospitalization will be reported for each ethnic group by gender and trended over time. Relative rates of differences will be used to identify possible improvements in disparities of HF hospitalization burden over time.
Despite advances in cardiovascular risk factor control and prophylaxis against infection and rejection, cardiac allograft vasculopathy (CAV), an immune-mediated form of coronary artery disease (CAD), remains the leading cause of late morbidity and mortality following orthotopic heart transplantation (OHT) and costs an estimated $60,000 per patient to treat annually.1, 2 Endothelial dysfunction appears to be the final common pathway in the pathogenesis of CAV.3 Endothelin-1 (ET-1), a potent vasoconstrictor, is a key mediator of vascular homeostasis. Small retrospective studies in OHT patients have reported that ET-1 is associated with more CAV.4, 5
The goal of my proposed project entitled END-CAV (Impact of ENDothelin-1 on Cardiac Allograft Vasculopathy) is to define the mechanistic contribution of ET-1 to the progression of CAV. END-CAV is a prospective biomarker substudy of the recently completed NIH-funded (R01 HL093475-01A1) parent trial led by my sponsor, Dr. William Fearon, examining the effect of angiotensin converting enzyme inhibition on the development of CAV among 105 OHT recipients. Specifically, I will investigate the association of plasma levels of ET-1 with changes in 1) coronary structure using intravascular ultrasound (IVUS), and 2) coronary physiology using fractional flow reserve (FFR), index of microcirculatory resistance (IMR), and endothelial function testing.
By gaining mechanistic insights into CAV at the structural and physiologic level, I will improve the understanding of CAV to help guide early, more intensive treatment. These advances will m the heart failure (HF) arena and will aid national health policy efforts to maximize value-based care.
The enormous and rapidly growing burden of Heart Failure with Preserved Ejection Fraction (HFpEF) has led to a need to understand the pathogenesis and treatment options for this morbid disease. Recent research from our group and others has shown that pulmonary hypertension (PH) is highly prevalent in HFpEF, and more recently we have observed that right ventricular (RV) dysfunction is present in roughly a third of patients with HFpEF. In a separate study of early stage HFpEF, we have also observed deficits in RV systolic and diastolic reserve even in the absence of resting dysfunction. These abnormalities are coupled with limitations in pulmonary vasodilation during exercise. There are no therapies directly targeted at the pulmonary vasculature that have been clearly shown to be effective in HFpEF.
A recent study by our group has demonstrated pulmonary vasodilation with dobutamine (a beta 2 agonist) in HFpEF. As an intravenous therapy, this is not feasible for outpatient use. Hospitalized patients with heart failure often demonstrate symptomatic improvement with inhaled beta 2 agonist therapy (such as inhaled albuterol) even in the absence of pulmonary disease. Animal studies have also shown an effect of inhaled albuterol on resolution of pulmonary edema.
In the proposed randomized, placebo-controlled double blinded trial, we seek to evaluate whether the commonly used inhaled bronchodilator albuterol, administered through a high-efficiency nebulizer device that achieves true alveolar drug delivery, improves pulmonary vascular resistance (PVR) at rest and during exercise in patients with HFpEF as compared to placebo. This has the potential to lead to a simple cost effective intervention to improve symptoms in HFpEF, and potentially be tested in other WHO PH groups. PVR is an excellent surrogate marker for pulmonary vasodilation and has been used in previous early trials of PH therapy.
We will enroll 30 patients (15 in each arm) over a 1 year period. With 14 patients enrolled in each arm, this will provide us with 80% power (alpha=0.05) to detect a drop in exercise pulmonary vascular resistance by 0.5 Wood units with albuterol as compared to inhaled placebo. This is based on an expected exercise PVR standard deviation of 0.5 Wood units from analysis of our previous data. Given that we currently perform more than 250 exercise right heart catheterizations per year at the Mayo clinic and have successfully completed similar acute hemodynamic studies over this time frame, we plan to reach the target of 30 enrolled HFpEF patients within 12 months.
Individuals with heart failure (HF) often rely on others, primarily family members, for assistance with self-care and disease management.1 HF management is extensive and caregivers frequently describe caregiving demands as overwhelming physically and psychologically.2 Ambiguity regarding HF, inadequate knowledge and guidance from health care providers,2-3 as well as assisting individuals with HF in coping with physical and psychological sequelae4-5 may result in caregiver burden and distress.6-7 In turn, caregiving burden and distress may influence caregivers’ physical and psychological well-being6-7 and impact caregiver perceptions of life changes since becoming a caregiver.8
Social support and social problem-solving are important coping resources9 that may influence self-care, depressive symptoms, and caregiver perceptions of life changes. Research suggests social support and social problem-solving are related to self-care and depressive symptoms in HF patients;10 yet, studies examining whether these coping resources exert a similar influence on HF caregiver outcomes is lacking.
Hence, the primary goal of this descriptive, cross-sectional, correlational multi-site study is to investigate whether social support and social problem-solving mediate relationships among caregiving burden and distress, self-care, depressive symptoms, and caregiver perceptions of life changes in caregivers of individuals with HF. To accomplish this goal, we have assembled a team of content and methodological experts to accomplish the following specific aims:
- Examine relationships among caregiver burden, caregiver distress, self-care, depressive symptoms, and caregiver perceptions of life
Hypothesis 1a: Caregiver burden and distress will have a negative relationship with self- care.
Hypothesis 1b: Caregiver burden and distress will have a negative relationship with depressive symptoms.
Hypothesis 1c: Caregiver burden and distress will have a negative relationship with caregiver perceptions of life changes.
2. Examine whether social support and social problem-solving mediate relationships among caregiver burden, caregiver distress, self-care, depressive symptoms, and caregiver perceptions of life
Hypothesis 2a: Caregiver burden and distress will have a positive relationship with self-care through social support and social problem-solving.
Hypothesis 2b: Caregiver burden and distress will have a positive relationship with depressive symptoms through social support and social problem-solving.
Hypothesis 2c: Caregiver burden and distress will have a positive relationship with caregiver perceptions of life changes though social support and social problem-solving.
Achieving these aims is significant, as it will help us to explore whether social support and social problem-solving are useful intervention components to assist with coping for this population. The project is innovative, as coping resources have been previously unexplored in caregivers of HF patients. This study will employ multiple recruitment methods to enhance variability in our sample, which is essential in mediational analysis and is novel in approach. Further, mediation analysis is a prerequisite step in identifying useful components of interventions, so that future interventions may be developed and tested, with funding sought from national and federal agencies.
Heart failure (HF) is the fastest growing cardiovascular condition and the leading cause of hospitalization among older adults.1-3 Symptom exacerbations result in hospitalizations4-6 and after getting discharged many patients experience decreased functional capacity (post-hospital syndrome),7 psychological distress8,9 and lower quality of life.10,11 Major clinical guidelines recommend the inclusion of symptom monitoring interventions as part of routine self-care management of patients with heart failure,12 and yet challenging to implement in the context of significant health disparities,13 prevalent cognitive impairment,14-16 and poor health literacy.17,18 Actively engaging in effective symptom monitoring and self-care management is also important for reducing hospital admissions5,19 and the subsequent societal and cost burden of heart failure.5,19
In addition to a heavy symptom burden, patients with heart failure also face the challenge of polypharmacy and keeping track of multiple medications. If completed with rigor, a thorough medication reconciliation process with a healthcare provider can take over 1 hour.20 Actively involving patients in this process may enhance communication between patients and providers and increase error detection, resulting in higher quality and safer care.21-26
In response to the challenges of symptom monitoring and medication reconciliation, we have developed two web-based prototypes, “mi.Symptoms,” for reporting patient’s holistic symptom experience and a web-based application that enables patients to directly review and comment on electronic health record medication lists.
AIM: Integrate medication reconciliation into “mi.Symptoms,” translate into Spanish and employ user-centered design principles and the Health IT Usability Evaluation Model to refine it.
Research questions: Can the user use the system to accomplish the task? How can the design and functionality of mi.Symptoms be adjusted to fit user expectations, goals and needs? What components of mi.Symptoms needs to be refined based on findings from semi-structured interviews and a usability questionnaire to be compatible with the clinical workflow, goals and needs?
This study is focused on symptom science, fostering self-management and medication reconsolidation using a mHealth web app. At the end of this two-year award period, we will have a mHealth application, mi.Symptoms, that can be used by patients with heart failure to report and monitor symptoms and reconcile medications in both English and Spanish. The significance of this web-based application is that it combines symptom monitoring with medication reconciliation for more comprehensive self-care management and patient-centered care. The innovation is that the use of web-based mobile health (mHealth) applications (apps) to bridge socioeconomic barriers and engage patients in self-care management using smartphone devices that are owned by 60% of Latino adults, including those with lower socioeconomic status.27
This application is directly aligned with the mission of the HFSA by promoting clinically based research that enhances the quality of life, improving patient-provider communication and patient-reported and clinical outcomes in underserved populations with heart failure. In addition, it also serves to educate an early career-nursing investigator to help improve patient-centered care and to help patients perform better symptom monitoring and self-care management of
The goal of the proposed study is tate the development and implementation of mHealth-based interventions in heart failure (HF) self-management by addressing the gap in knowledge regarding individual characteristics and perceptions that influence the older HF patient’s intention to adopt mHealth. The specific aims of the proposed study are as follows:
1. Examine the relationship between eHealth literacy, social influence, and perceptions about mHealth (usefulness, ease of use, and financial cost) in older people with
Hypothesis 1.1: eHealth Literacy will be positively correlated with Perceived Ease of Use of mHealth even after adjusting for the following covariates: age, sex, race, income, education, health literacy, and smartphone ownership.
Hypothesis 1.2: Social Influence will be positively correlated with Perceived Usefulness of mHealth even after adjusting for the covariates.
Hypothesis 1.3: Perceived Ease of Use will be positively correlated with Perceived Usefulnesseven after adjusting for the covariates.
2. Examine the relationship between perceptions about mHealth (usefulness, ease of use, and financial cost) and intention to use mHealth in older people with
Hypothesis 2.1: Perceived Ease of Use will be positively correlated with Behavioral Intention (intention to use mHealth) even after adjusting for the covariates.
Hypothesis 2.2: Perceived Usefulness will be positively correlated with Behavioral Intention (intention to use mHealth) even after adjusting for the covariates.
Hypothesis 2.3: Perceived Financial Cost will be negatively correlated with Behavioral Intention (intention to use mHealth) even after adjusting for the covariates.
3. Examine for the presence of effect modification and mediation
Hypothesis 3.1: Perceived Ease of Use moderates the relationship between Perceived Usefulness and Behavioral Intention (intention to use mHealth).
Hypothesis 3.2: Perceived Ease of Use mediates the impact of eHealth Literacy on Behavioral Intention (intention to use mHealth)
Hypothesis 3.3: Perceived Usefulness mediates the impact of Social Influence on Behavioral Intention (intention to use mHealth)
4. Explore perceptions regarding mHealth in older people with HF, specifically on the following topics: (a) ease of use, (b) usefulness of mHealth, (c) potential applications for mHealth, (d) interest in adopting mHealth, and (e) facilitators and barriers to adoption of
Mixed Methods Aim:
5. To describe and compare the facilitators and barriers that influence intention to adopt mHealth between older people with HF whose intention to adopt mHealth is high vs. those whose intention to adopt mHealth is
We will examine the long-term characteristics of cardiovascular parameters derived from an implantable hemodynamic monitor in patients with both end-stage renal disease (ESRD) and heart failure (HF), with a focus on parameter changes occurring during meaningful clinical events. This includes determining changes in parameters that occur during both clinically relevant and clinically irrelevant events (including hemodynamic changes that occur on dialysis days, on non-dialysis days, and prior to HF exacerbation/hospital readmissions).
We will also prospectively examine clinical outcomes of our ESRD HF patients with a comparison group consisting of non-ESRD HF patients concurrently undergoing clinically-indicated CardioMEMS implantation at the Keck Medical Center of USC. Using a comparison interval of “before implantation” and “3 months after implant,” outcomes to be investigated include change in quality of life, number of HF medication changes in response to pulmonary artery pressures, change in HF medication dosage strength, and change in mean pulmonary artery pressure from baseline.
The overall objective of this proposal is to allow for an in-depth examination of the relationship
between blood volume and dynamic measures of pulmonary artery pressures in a high-risk heart failure population. It will permit us to examine the effects of diuretics―the key intervention used to achieve euvolemia in patients with heart failure― on both invasive hemodynamics and direct measures of intravascular volume. The findings that result from this project will allow for an improved understanding of how data from the CardioMEMS device might be used to guide management of heart failure.
Excess volume overload drives many of the symptoms and adverse outcomes in heart failure. As a result, the assessment of intravascular volume status is a principle focus of clinical evaluations in heart failure, and the foundation for decision making about many of our therapies. The current method used in clinical practice to gauge intravascular volume status is direct measurement of the pulmonary capillary wedge pressure (PCWP) using right heart catheterization. However, despite a well-defined association between PCWP and adverse outcomes, guiding therapies based on this parameter is limited because: (a) it is invasive and thus makes repeated measures risky and impractical, (b) static measures of PCWP at rest do not provide an adequate representation of this highly variable parameter, and (c) it provides only a metric of pressure, rather than a direct measurement of intravascular volume. In order to address some of these limitations, an implantable device (CardioMEMS) that allows therapeutic adjustment based on continuously measures pulmonary artery pressures was recently tested in a randomized trial of 550 highly symptomatic heart failure patients and showed that the pulmonary artery pressure guided treatment group had a 37% reduction in heart failure hospitalizations compared with the control group. The favorable results of the CHAMPION trial let to its approval for clinical use by the FDA. Nevertheless, the mechanisms by which continuously measured pulmonary artery pressures might improve treatment of heart failure remains unclear, especially when considered in light of prior negative studies evaluating the efficacy of invasive hemodynamics for the management of heart failure. Key insights into these mechanisms can be gauged via precise blood volume measurements that be performed at the bedside in patients with the
CardioMEMS device using a using a well-described, safe, and validated technique that utilizes radiolabeled albumin.
Heart failure is a serious and growing health problem frequently seen in the emergency department. Many of these patients are readmitted within 30 days. Transitional care programs are dedicated to help admitted patients coordinate their care at home. However, a significant portion of patients are placed under observation status, and there are no programs tailored to this population. This work will build a collaboration between Emergency Medicine and Heart Failure faculty, and form the Jefferson Emergency Department (ED)/Observation Unit Telehealth Transition of Care for Heart Failure (JETT-HF) and has the overall goal to develop and test a telehealth intervention for patients discharged from the observation unit for heart failure. The specific aims for this project are: 1. Develop a telehealth based transitional care program tailored to ED heart failure patients being directly discharged without inpatient hospitalization and 2. In a group of acute heart failure patients discharged from the ED observation unit, we will pilot a randomized controlled trial comparing usual care to usual care plus post-discharge telehealth transitional care program as developed in Aim 1. This training program will allow Dr. Chang, the junior investigator, to work with Dr. Whellan, an established heart failure expert and cardiologist, and Dr. Hollander, an established emergency medicine researcher and director of the Jefferson telemedicine program. The goals of the training plan are to launch Dr. Chang’s career as an independent clinical heart failure investigator with specific training in healthcare quality research and implementation science.
Heart failure (HF) resulting in congestion is the leading cause for admission in persons ≥65 years of age and 20-25% of such patients are readmitted within 30 days of discharge. Efforts to treat HF are difficult without a simple method to detect early signs of congestion to direct therapy. Ultrasound can detect evidence of congestion by increased cardiac filling pressures two weeks prior to other markers of congestion such as weight gain or patient symptoms. Corrected flow time (FTc) measured by ultrasound, is an easy to perform vascular measure and correlates with cardiac filling pressures. Despite the relationship between FTc and filling pressures, this measure has never been studied in HF. Our primary aim is to determine if FTc can predict patients at risk of readmission within 30 days. As a secondary aim, we plan to validate a small study of patients reporting the ability of pulmonary ultrasound to predict readmissions. This study demonstrated pulmonary ultrasound was 100% sensitive and 68% specific for predicting readmission at 3 months, however this investigation was small and validation is needed. As a final aim we propose to merge our findings for FTc and pulmonary ultrasound to see if they have an improved combined sensitivity and specificity for predicting readmission at 30 days. We hypothesize ultrasound will be able to accurately and safely predict patients who will be readmitted within 30 days of discharge. This proposal is aimed at identifying a noninvasive measure to better assess congestion from HF and predict readmissions. If this proposal were successful, further investigation of these ultrasound measures as an outpatient to monitor HF and direct therapy would be promising next steps to improve the care of HF
2015 HFSA Grant Awardees
Echocardiographic Predictors of Late RV Failure in Patients with Left Ventricular Assist Devices
Paul Kim, MD – Stanford University
Sex Differences in Myocarditis
Kevin Morine, MD – Tufts Medical Center
Evaluation of the Pulmonary Artery Pulsatory Index as a Determinant of Post-operative Right Ventricular Failure in a HVAD Clinical Trial Population
Abhinav Sharma, MD, FRCPC, ABIM – University of Alberta
Diabetes and Heart Failure
Ana Alba, MD, PhD – Toronto General Hospital
Predicting survival in HF Patients with an ICD
Jenica Upshaw, MD – Tufts Medical Center
HF Disease Management Strategies to Reduce Hospitalizations and Improve Health Related Quality of Life
Douglas Stoller, MD, PhD – University of Texas Southwestern
Discovery of Unique microRNA signatures in muscular dystrophy patients
Brian Houston, MD – Johns Hopkins Hospital
Gastrointestinal Bleeding in Patients
Self –Care Among Low Socioeconomic Status Heart Failure Patients with Unplanned Hospital Readmission
Carolyn Lekavich, PhD – Duke University Hospital
The Identification of Biomarkers that Predict Impending Incident HF Preserved Ejection Fraction