Browsing by Subject "Heart Failure"

Now showing 1 - 5 of 5
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    The Digestive Tract Microbiome and Cardiometabolic Disease: Exploring Nitric Oxide and Lipopolysaccharide Synthesis as Mechanistic Intermediates
    (2023) Bohn, Bruno
    Introduction: The role of the digestive tract microbiomes on cardiometabolic health is becoming ever clearer. However, mechanistic remain largely unexplored and methods exploring metabolic outputs are lacking. This dissertation explores a novel approach to quantify the microbiome's lipopolysaccharides (LPS) and nitric oxide (NO) producing potential, two molecules with known health effects. We investigated the association between functional metrics and cardiometabolic health among healthy individuals and heart failure (HF) patients.Methods: Cross-sectional data from adults free of cardiometabolic disease (ORIGINS) and with HF (HFM) were used. Blood pressure was measured and biomarkers or inflammation and/or endotoxemia quantified from blood serum. Oral (saliva) and/or gut microbiomes were characterized with 16S rRNA (HFM/ORIGINS) and/or metagenomic sequencing (ORIGINS). Pathway- and gene-level functional profiles were operationalized as metrics of LPS- and NO-producing potentials. Metrics were compared across sequencing approaches (ORIGINS). For each cohort, multivariable linear regression was used to explore associations between: i) blood pressure and NO-producing potential; ii) inflammation and NO-producing potential; iii) inflammation and LPS-producing potential; and iv) endotoxemia and LPS-producing potential (HFM). Results: In ORIGINS, 253 and 170 participants had 16S and metagenomic data, respectively. A modest positive association was observed between functional metrics, with more features detected through 16S methods. Metagenomic and 16S-derived NO-reducing potential metrics were linked to lower inflammation and blood pressure, respectively. No meaningful associations were observed for LPS-producing potential. In HFM, saliva and gut 16S sequencing data was available for 146 and 128 participants, respectively. No correlations were observed between gut and oral microbiomes. No meaningful associations were observed between NO-producing potential and blood pressure. Gut LPS-producing potential, but not oral, was associated with endotoxemia. Inflammation was not meaningfully linked to either functional feature. Conclusions: A novel approach to utilized microbiome functional profile metrics was explored. Findings were mixed, but highlighted the potential use of these approaches in population-based studied of the human microbiome and cardiometabolic health.
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    Investigating Infection-Related Hospitalization as a Risk Factor for Incident Heart Failure and Mortality among Heart Failure Patients
    (2023-06) Molinsky, Rebecca
    HF is a growing epidemic with an estimated prevalence of 6.5 million individuals in the U.S., and poor outcomes persist despite recent therapeutic advancements. Studies have shown that an inflammatory response to infections may become dysregulated, thereby promoting collateral myocardial damage that may result in HF. Infection is also a common cause of hospitalization among HF patients and may lead to poor prognosis and high mortality. Limited data exist examining the relationship between infection-related hospitalization (IRH) and HF along with HF subtypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). Further, few studies have explored mortality rates following an IRH in HF patients or whether certain types of IRH are stronger predictors of mortality. This dissertation leveraged the strengths of large claims data (MarketScan) and a community-based study (ARIC) to address these limitations and parse out the dynamic relationship between infection-related hospitalization and HF with several manuscripts. The first manuscript, a case-crossover study of beneficiaries in the MarketScan databases, assessed the association between IRH and incident HF. IRH was associated with incident HF after both 1- and 3-months. The second manuscript investigated the association between IRH and long-term incident HF in the Atherosclerosis Risk in Communities study (ARIC). IRH was associated with a two-fold greater risk of incident HF, HFrEF, and HFpEF. Findings were stronger among those with HFpEF, for which treatment options are limited. Results from the first manuscript aligned with those of the second manuscript and both found respiratory, pneumonia, and blood/circulatory infections to have the strongest associations with incident HF. The third manuscript explored the relationship between IRH and mortality among HF patients in ARIC. IRH was associated with a two-fold greater risk of mortality among those with HFpEF, HFrEF, or unclassified HF. Respiratory, pneumonia, and other infections had the strongest associations with mortality. Our findings support prior literature linking IRH to HF risk and increased mortality among HF patients. These findings may have significant population-level implications given the high prevalence of IRH and the burden of HF on our aging society. Aim 1: Investigate the association between infection-related hospitalization and incident HF using U.S.-based claims data from MarketScan. Aim 2: Investigate the association between infection-related hospitalization and incident HF and HF subtypes (HFrEF or HFpEF) using a longitudinal community-based cohort study, ARIC. Aim 3: Among HF (HFrEF and HFpEF) patients, investigate the association between infection-related hospitalization and mortality using a longitudinal community-based cohort study, ARIC.
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    Molecular dissection of compensatory pathways in models of severe heart failure
    (2015-01) Heinis, Frazer
    Cardiovascular diseases are the leading cause of death in America, and heart failure (HF) is an important and increasingly difficult to manage disease. HF, a clinical syndrome of impaired heart pump function, has poor prognosis, increasing incidence, and no cure. Clinical treatment guidelines focus on the treatment of symptoms rather than acting to directly restore heart pump function, and better therapeutics are necessary to reverse the course of HF pathology. Normal heart pump function is driven by the release and reuptake of Ca2+ ions from the cytoplasm of cardiac myocytes. In healthy cardiac tissue, transient release of Ca2+ occurs rapidly to trigger contraction, and removal is likewise swift in order to allow the heart to relax and refill with blood for the next beat. In failing myocardium, Ca2+ release is weak and reuptake is slow, which leads to inadequate ejection of blood to the body and poor refilling for the next beat. Over time, this results in the progressive loss of cardiac pump function and, subsequently, worsening quality of life. The protein responsible for most diastolic Ca2+ reuptake to the cardiac sarcoplasmic reticulum (SR) compartment is the SR Ca2+ ATPase, SERCA2a. SERCA2a expression and activity are decreased in failing hearts, and experimental therapeutics are currently under development to restore its activity in humans. We have utilized a mouse model of inducible Serca2 deletion, the Serca2fl/fl mouse, to study the progression of cardiac dysfunction as this key enzyme is lost. Surprisingly, Serca2KO mice survive 7-10 weeks following inducible Serca2 deletion and loss of most SERCA2a protein. The mechanisms by which Serca2KO mice maintain survival for so long with minimal apparent in vivo pathology are not well defined, so we investigated cardiac performance in Serca2KO hearts and mice by several methods. We determined the function of KO hearts outside the body, in the absence of systemic signaling that may be supporting function in vivo, and found that isolated KO hearts had severely impaired function even at short times following gene deletion; we studied adaptive changes in cardiac Ca2+ handling proteins, including SERCA2a, that occur in hibernating mammals between the summer and winter seasons; and we enacted a thorough mechanistic dissection of ß-adrenergic signaling pathways in SERCA2a-depleted hearts. We found that Serca2KO hearts deficient in normal Ca2+ handling remained able to support a significant functional response to adrenergic stimulation, despite the near complete absence of SERCA2a, which is normally a key functional substrate for the adrenergic response. This finding indicated that other targets of adrenergic signaling in SERCA-deficient heart were surprisingly capable of supporting significant pump function despite poor cardiac Ca2+ transport capabilities, and we have identified the myofilament protein, cardiac troponin I (cTnI), as a key component of an intact adrenergic response under pathological Ca2+ handling conditions.
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    The Relationship of Resting Cardiopulmonary Function to Peak and Submaximal Cardiopulmonary Exercise Testing in Older Adults with Heart Failure
    (2016-12) Webb, Marjorie
    Background: Heart failure (HF) is a challenging disease that affects more than five million people, half of whom are at least 75 years old. Peak oxygen consumption (VO2peak), the minute ventilation/carbon dioxide production (VE/VCO2) slope, and the 6MWT are powerful prognostic indicators of all-cause mortality and cardiovascular-related mortality. VO2peak and the VE/VCO2 slope, obtained during CPX, have been shown to be useful for monitoring the efficacy of symptom and therapeutic management. Peak cardiac output (Qpeak) would also be an excellent prognostic indicator but traditionally it has been difficult to measure since the measurement is usually highly invasive. At the University of Minnesota, we are able to measure Qpeak noninvasively using the acetylene washin method. Despite the body of evidence supporting these measures, CPX and the 6MWT are not routinely performed on an outpatient basis as a part of HF symptom assessment and management. Additionally, older patients with HF often do not recognize worsening symptoms which frequently lead to hospitalization. In order for nurses to maximize quality of life for patients with HF and affect morbidity and mortality, usable methods for the evaluation of therapeutic efficacy of symptom management and prescribed treatments must be available. N-terminal prohormone brain natriuretic peptide (NT-pro BNP), New York Heart Association (NYHA) classification, and inspiratory capacity, are all obtainable in an office visit and may explain enough variance in peak Q, VO2, the VE/VCO2 slope, 6MWT distance, or all three measurements to be useful in the outpatient setting. Objective: The purpose of this study was to explore the potential of a model that incorporates resting measures, NT-Pro BNP, NYHA classification, and inspiratory capacity, for the evaluation of therapeutic efficacy of symptom management and prescribed treatments for older patients with HF. We hypothesized that there is a relationship between Qpeak, VO2peak, the VE/VCO2 slope, and/or 6MWT distance with NT-pro BNP, NYHA classification, and inspiratory capacity. Method: Twenty-three older patients (mean age 73.6 + 4.5 years old) with HF underwent venipuncture, inspiratory capacity measurement, and performed the 6MWT and CPX per standardized protocol. Qpeak, VO2 peak and the VE/VCO2 slope measurements were recorded during the CPX. NYHA classification was obtained from chart review and assessment. Results: The strongest relationships were between inspiratory capacity and Qpeak (R = 0.77, p <0.0001), and between NT-pro BNP and the VE/VCO2 slope (R = 0.71, p <0.001). Additionally, there was a moderate relationship between NT-pro BNP and VO2peak (R = -0.47, p <0.03) and between inspiratory capacity and VO2peak (R = 0.51, p <0.02). Due to the lack of variance NYHA classification was not included in the regression analysis. The 6MWT distance did not correlate with NT-pro BNP or inspiratory capacity. NT-pro BNP accounted for 22% of variance in VO2peak and 50% of variance in the VE/VCO2 slope. Mean inspiratory capacity accounted for 59% of variance in Qpeak and 26% of variance in VO2peak. The combined measurements of inspiratory capacity and NT-pro BNP explained 42% of the variance in VO2peak (adjusted R2 = 0.42, F (2, 20) = 8.82, p < 0.002). A model of prediction for either Qpeak or the VE/VCO2 slope could not be constructed since only one predictor variable for each outcome variable was statistically significant.
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    Retrospective Analysis of Prescription Drug Claims, with Applications to Risk Score Construction and Treatment of Heart Failure in End Stage Renal Disease
    (2015-05) Weinhandl, Eric
    There are more than 450,000 patients receiving chronic dialysis in the US. Patients with end stage renal disease are statutorily eligible for Medicare, regardless of age. Due to high prevalence of poverty, many are dually enrolled in Medicare and Medicaid and are automatically enrolled in Part D (prescription drug insurance). This dissertation comprises 3 studies involving prescription drug claims in dialysis patients. In the first study, I constructed and validated risk scores based on Part D claims in incident and prevalent dialysis patients. Comorbidity indices derived from administrative data are typically based on diagnosed diseases, but the middling sensitivity of diagnosis codes limits the accuracy of these indices. In contrast, prescription drug claims are bona fide evidence of medication dispensation. I investigated aspects of newly developed scores and compared their performance in predicting risk with older scores based on diseases. In the second study, I assessed the efficacy and safety of pharmacologic inhibition of the renin-angiotensin system in dialysis patients with congestive heart failure. ACE inhibitors and ARBs are recommended for the treatment of heart failure with reduced ejection fraction. However, pivotal clinical trials all excluded patients on dialysis. I used propensity score matching to identify matched controls for treated patients that were newly dispensed an ACE inhibitor or ARB shortly after discharge from hospitalization for heart failure. I described the relative hazards of mortality and morbidity with treatment. In the third study, I assessed relative hazards of death and hospitalization associated with 4 ACE inhibitors and 2 ARBs in dialysis patients with congestive heart failure. The existence of class effects is generally presumed, but not necessarily supported by evidence regarding clinical outcomes. I showed that the most widely used agent (lisinopril) in this patient population is not necessarily associated with best outcomes.