Impaired Cardiorespiratory Fitness Following Thoracic Radiotherapy

Cancer (CA) is the second leading cause of death in the United States preceded only by cardiovascular disease (CVD). Over the past 30 years, the 5-year survival rate for all cancers combined has increased by more than 20%. This improved survival rate is due to early diagnosis and advances in treatment involving a multimodality treatment approach that includes radiotherapy [RT] with about half of all CA patients receiving some type of RT sometime during the course of their treatment. Cardiotoxicity is one of the most important adverse reactions of RT and leads to a meaningful risk of CVD-related morbidity and mortality. Radiotherapy-related cardiotoxicity is a heterogeneous clinical syndrome characterized by symptoms related to impaired cardiac function due to radiation-injury to one or more cardiac structures. Furthermore, the relative risk of CVD increases with increasing incidental radiation dose to the heart. There is not a unified consensus on the definition of CA-related cardiotoxicity although most trials have focused on changes in resting systolic function, and/or development of cardiac symptoms.Commonly used tools to assess cardiac function are insensitive to minor injury hence subtle changes may go unnoticed for many years. Cardiotoxicity definitions should include a dynamic functional assessment of the CV system. This may allow detection of latent CV abnormalities before the precipitous decline of resting myocardial function or the development of CV symptomology that may impact quality of life. Cardiopulmonary exercise testing (CPET) including measurement of peak oxygen consumption (VO2) is the gold standard for the assessment of cardiorespiratory fitness (CRF). Cardiorespiratory fitness is a strong, independent predictor of mortality, CVD-related mortality, HF-related morbidity and mortality, CA-related mortality and may be involved in the pathophysiologic link between anti-CA related treatments and the increased risk of late CVD events. Emerging evidence indicates CRF may be reduced in CA survivors and have utility to detect subclinical cardiotoxicity, but this has not been evaluated in CA survivors treated with RT with significant heart involvement. This dissertation consists of one literature review and one comprehensive paper that will examine the ability of CPET to detect subclinical cardiotoxicity

A Comparison of Maximal Exercise Responses among Patients with a Total Artificial Heart, a Left Ventricular Assist Device, or Advanced Heart Failure

The purpose of this study was to evaluate graded exercise responses to treadmill exercise in patients with a total artificial heat (SynCardia, Tucson, AZ). Additionally, this study sought to compare the exercise response in total artificial heart (TAH) patients to both advanced heart failure (HF) patients on medical management only and HeartMate II (Thoratec Corp., Pleasanton, CA) left‐ventricular assist device (HMII) patients. For patients with biventricular heart failure the TAH is a viable option to bridge patients until transplant becomes available. Its demonstrated improvement in mortality and increasing usage necessitates a shift in focus to quality of life in the TAH patient including functional ability. The evaluation of cardiorespiratory responses to graded exercise provides an objective measure of functional ability. There is very limited information in the literature on the exercise response of the mechanical circulatory support (MCS) device patient, particularly the TAH patient. A review was performed on MCS patients who underwent symptom‐limited cardiopulmonary exercise testing (CPET) following device implant of either TAH or HMII. ANOVA was performed to compare differences between the two device groups and HF patients listed for heart transplant. Fourteen TAH patients underwent CPET (9 male, 5 female) with peak oxygen consumption (VȩO2) of 0.926 + .168 L∙min, 36 + 8% % predicted, 11.0 + 2.3 ml.kg.min or 3.1 + 0.7 METs. Ventilatory anaerobic threshold (VAT) was 0.706 + .181 L∙min. Peak (VȩO2, % pred. (VȩO2 and VAT were significantly lower in the TAH compared with HMII and advanced HF (p = 0.0012, p = 0.0106, p = 0.0009, respectively). Peak RER was significantly higher (p = \u3c.0001) and OUES was significantly lower (p = 0.0004) in the TAH. Exercise capacity is significantly reduced in the TAH patient below that observed in HMII LVAD and advanced HF patients. This provides a baseline for expected functional status and has implications on the ADL tolerance of these individuals. The next step is to develop strategies to ameliorate this continued exercise intolerance. The documents herein contain a review of literature including a background in heart failure and the use of the exercise response in the heart failure patient. An overview is also presented on the use of MCS describing physiology, device function, and exercise physiology of the MCS device patient. A manuscript has also been included detailing a cross‐sectional review of the effects of graded exercise in the TAH patient and comparing it to the HMII and advanced HF patient

Impaired myocardial relaxation with exercise determines peak aerobic exercise capacity in heart failure with preserved ejection fraction

Background Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by impaired exercise capacity due to shortness of breath and/or fatigue. Assessment of diastolic dysfunction at rest and with exercise may provide insight into the pathophysiology of exercise intolerance in HFpEF. Aims To measure echocardio-Doppler-derived parameters of diastolic function as they relate to various indices of aerobic exercise capacity in HFpEF. Methods We selected 16 subjects with clinically stable HFpEF, no evidence of volume overload, but impaired functional capacity by cardiopulmonary exercise testing [peak oxygen consumption (VO2)]. We measured the transmitral E and A flow velocities, E/A ratio, and E deceleration time (DT) and tissue Doppler E′ velocity. We also indexed the E′ to the DT, as additional measure of impaired relaxation (E′DT), and calculated the diastolic functional reserve index (DFRI), as the product of E′ at rest and change in E′ with exercise. Results E′ velocity, at rest and peak exercise, as well as the DFRI positively correlated with peak VO2, whereas DT, E′DT, and E/E′ with exercise inversely correlated with peak VO2. Of note, the E′DT at rest also significantly predicted E′ velocity at peak exercise (R = +0.81, P \u3c 0.001). Exercise E′ was the only independent predictor of peak VO2 at multivariable analysis (R = +0.67, P = 0.005). Conclusions The E′ velocity at peak exercise is a strong and independent predictor of aerobic exercise capacity as measured by peak VO2 in patients with HFpEF, providing the link between abnormal myocardial relaxation with exercise and impaired aerobic exercise capacity in HFpEF

Interleukin-1 blockade in recently decompensated systolic heart failure: study design of the recently decompensated heart failure anakinra response trial (RED-HART)

Heart Failure (HF) is a clinical syndrome characterized by dyspnea, fatigue, and poor exercise capacity due to impaired cardiac function. The incidence of HF is increasing and represents the leading cause of hospitalization in the United States among patients > 65 years of age. Neurohormonal blockade has proven to reduce morbidity and mortality; however the persistent toll of HF demonstrates the urgent need to continue to develop novel drugs that target other pathophysiological paradigms. The presence of inflammation in cardiovascular disease has been well-established and interleukin-1 (IL-1), the prototypical proinflammatory agent, has been shown in preclinical animal models to induce cardiac dysfunction. The current study will investigate the role of IL-1 as an inflammatory mediator of HF progression and investigate whether IL-1 blockade with anakinra, recombinant human IL-1 receptor antagonist, improves aerobic exercise performance in patients with recently decompensated systolic HF. This study will be composed of 3 treatment arms (20 patients each): 1) anakinra 100mg daily for 12 weeks; 2) anakinra 100mg daily for 2 weeks followed by placebo for 10 weeks; or 3) placebo for 12 weeks. All patients will be followed for at least 24 weeks. The co-primary endpoints will be placebo-corrected interval changes in peak oxygen consumption (VO2) and ventilatory efficiency (VE/VCO2 slope) measured by Cardiopulmonary Exercise Testing (CPX) after 2 weeks of anakinra treatment. Secondary endpoints will include interval changes in 1) CPX variables at 4, 12 and 24 weeks; 2) echocardiographic measures of cardiac dimension/function; 3) quality of life assessments; 4) inflammatory biomarkers; and 5) clinical outcome including days alive outside of the hospital and survival free of re-hospitalization for HF. The RED-HART study will be the first study to address the potential benefits of IL-1 blockade on aerobic exercise performance in patients with recently decompensated HF

Low NT-proBNP levels in overweight and obese patients do not rule out a diagnosis of heart failure with preserved ejection fraction

Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that presents clinicians with a diagnostic challenge. The use of natriuretic peptides to exclude a diagnosis of HFpEF has been proposed. We sought to compare HFpEF patients with N-terminal pro-brain natriuretic peptide (NT-proBNP) level above and below the proposed cut-off. Methods Stable patients (n = 30) with left ventricular (LV) ejection fraction ≥ 50% were eligible if they had a diagnosis of HF according to the European Society of Cardiology diagnostic criteria. Characteristics of patients with NT-proBNP below (≤125 pg/mL) and above (\u3e125 pg/mL) the diagnostic criterion were compared. Results There were 19 (66%) women with median age 54 years. Half were African American (16, 53%), and most were obese. There were no significant differences in clinical characteristics or medication use between groups. LV end-diastolic volume index was greater in high NT-proBNP patients (P = 0.03). Left atrial volume index, E/e\u27 ratio, and E/e\u27 ratio at peak exercise were not significantly different between NT-proBNP groups. Peak oxygen consumption (VO2), VO2 at ventilatory threshold, and ventilatory efficiency measures were impaired in all patients and were not significantly different between high and low NT-proBNP patients. Conclusions NT-proBNP was below the proposed diagnostic cut-off point of 125 pg/mL in half of this obese study cohort. Cardiac diastolic dysfunction and cardiorespiratory fitness were not significantly different between high and low NT-proBNP patients. These data indicate that excluding the diagnosis of HFpEF based solely on NT-proBNP levels should be discouraged

Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2)

Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of con-firmed HF cases in the United States. However, there are no highly effective evidence-basedtreatments currently available for these patients. Inflammation correlates positively withadverse outcomes in HF patients. Interleukin (IL)-1, a prototypical inflammatory cytokine, hasbeen implicated as a driver of diastolic dysfunction in preclinical animal models and a pilot clini-cal trial. The Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2) is a phase 2, 2:1 ran-domized, double-blind, placebo-controlled clinical trial that will test the hypothesis that IL-1blockade with anakinra (recombinant human IL-1 receptor antagonist) improves (1) cardiorespi-ratory fitness, (2) objective evidence of diastolic dysfunction, and (3) elevated inflammation inpatients with HFpEF (http://www.ClinicalTrials.gov NCT02173548). The co–primary endpointswill be placebo-corrected interval changes in peak oxygen consumption and ventilatory effi-ciency at week 12. In addition, secondary and exploratory analyses will investigate the effectsof IL-1 blockade on cardiac structure and function, systemic inflammation, endothelial function,quality of life, body composition, nutritional status, and clinical outcomes. The D-HART2 clinicaltrial will add to the growing body of evidence on the role of inflammation in cardiovascular dis-ease, specifically focusing on patients with HFpEF

Metabolic Modulation Predicts Heart Failure Tests Performance

The metabolic changes that accompany changes in Cardiopulmonary testing (CPET) and heart failure biomarkers (HFbio) are not well known. We undertook metabolomic and lipidomic phenotyping of a cohort of heart failure (HF) patients and utilized Multiple Regression Analysis (MRA) to identify associations to CPET and HFBio test performance (peak oxygen consumption (Peak VO2), oxygen uptake efficiency slope (OUES), exercise duration, and minute ventilation-carbon dioxide production slope (VE/VCO2 slope), as well as the established HF biomarkers of inflammation C-reactive protein (CRP), beta-galactoside-binding protein (galectin-3), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP)). A cohort of 49 patients with a left ventricular ejection fraction \u3c 50%, predominantly males African American, presenting a high frequency of diabetes, hyperlipidemia, and hypertension were used in the study. MRA revealed that metabolic models for VE/VCO2 and Peak VO2 were the most fitted models, and the highest predictors’ coefficients were from Acylcarnitine C18:2, palmitic acid, citric acid, asparagine, and 3-hydroxybutiric acid. Metabolic Pathway Analysis (MetPA) used predictors to identify the most relevant metabolic pathways associated to the study, aminoacyl-tRNA and amino acid biosynthesis, amino acid metabolism, nitrogen metabolism, pantothenate and CoA biosynthesis, sphingolipid and glycerolipid metabolism, fatty acid biosynthesis, glutathione metabolism, and pentose phosphate pathway (PPP). Metabolite Set Enrichment Analysis (MSEA) found associations of our findings with pre-existing biological knowledge from studies of human plasma metabolism as brain dysfunction and enzyme deficiencies associated with lactic acidosis. Our results indicate a profile of oxidative stress, lactic acidosis, and metabolic syndrome coupled with mitochondria dysfunction in patients with HF tests poor performance. The insights resulting from this study coincides with what has previously been discussed in existing literature thereby supporting the validity of our findings while at the same time characterizing the metabolic underpinning of CPET and HFBio

Molecular Predictors of Anakinra Treatment Success in Heart Failure Patients with Reduced Ejection Fraction

Background. Kineret (Anakinra) is an interleukin-1 antagonist that is under investigation for its novel clinical application treating patients that have heart failure with reduced (\u3c50%) ejection fraction (HFrEF). A prior study from our group indicated that Anakinra may restore heart function by addressing dysregulations in HFrEF metabolic pathways. Herein, we attempt to elicit Anakinra’s effects on both metabolome and lipidome. Methods. Lipids and metabolites that had previously been quantified by mass spectrometry (MS) from patients (n=49) who had ≥2 mg/L of high-sensitivity C-reactive protein (hs-CRP) were mTIC normalized and transformed. We conducted a stepwise Linear Discriminant Analysis (r- LDA) to test Anakinra (2 and 12 weeks) vs placebo for separation from combined baseline. Metabolic pathway analysis was performed with Fisher’s exact test algorithm for detection of over-represented and enriched analytes. Univariate analysis (one tailed t-test p\u3c0.05) compared placebo and Anakinra after 12-weeks for effect(s). Metaboanalyst 4.0, JMP Pro 14.0, and a proprietary package in R (version 3.4.4) were the software for all analyses and data wrangling. Results. Analytes such as acylcarnitines C10:0 and C16:0 and hsCRP showed significant improvements after 12 weeks of Anakinra, leading to improved mitochondrial function, reduced inflammation, and overall better health outcomes. Statistically significant (p\u3c0.05) pathways including the citrate cycle, cysteine and methionine metabolism, galactose metabolism among others were associated with treatment. Conclusions. We were able to determine significant alterations to metabolomic and lipidomic concentrations after 12 weeks of Anakinra therapy. Our biochemical analyses verifies that Anakinra did improve heart function within our HFrEF pilot cohort.https://scholarscompass.vcu.edu/gradposters/1081/thumbnail.jp

Dietary Fat, Sugar Consumption, and Cardiorespiratory Fitness in Patients With Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is associated with obesity and, indirectly, with unhealthy diet. The role of dietary components in HFpEF is, however, largely unknown. In this study, the authors showed that in obese HFpEF patients, consumption of unsaturated fatty acids (UFA), was associated with better cardiorespiratory fitness, and UFA consumption correlated with better diastolic function and with greater fat-free mass. Similarly, mice fed with a high-fat diet rich in UFA and low in sugars had preserved myocardial function and reduced weight gain. Randomized clinical trials increasing dietary UFA consumption and reducing sugar consumption are warranted to confirm and expand our findings