Research Interests: Cardiology, Risk assessment, Medicine, Humans, United States, and 13 moreHiv Infection, Risk factors, Prediction Model, Clinical Sciences, Coronary heart disease, Public health systems and services research, Circulation, Risk Factors, Risk Assessment, American Heart Association, Coronary Artery Disease, Cardiovascular medicine and haematology, and HIV infections
In a complex system of interrelated reactions, the heart converts chemical energy to mechanical energy. Energy transfer is achieved through coordinated activation of enzymes, ion channels, and contractile elements, as well as structural... more
In a complex system of interrelated reactions, the heart converts chemical energy to mechanical energy. Energy transfer is achieved through coordinated activation of enzymes, ion channels, and contractile elements, as well as structural and membrane proteins. The heart's needs for energy are difficult to overestimate. At a time when the cardiovascular research community is discovering a plethora of new molecular methods to assess cardiac metabolism, the methods remain scattered in the literature. The present statement on "Assessing Cardiac Metabolism" seeks to provide a collective and curated resource on methods and models used to investigate established and emerging aspects of cardiac metabolism. Some of those methods are refinements of classic biochemical tools, whereas most others are recent additions from the powerful tools of molecular biology. The aim of this statement is to be useful to many and to do justice to a dynamic field of great complexity.
Research Interests: Molecular Biology, Computational Biology, Systems Biology, Biology, Medicine, and 12 moreEnergy Metabolism, Humans, United States, Animals, Radionuclide imaging, Clinical Sciences, Myocardium, Circulation, Cardiovascular Diseases, American Heart Association, Metabolic Pathways, and Cardiovascular medicine and haematology
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Dietary nitrate, a source of nitric oxide (NO), improves the contractile properties of human muscle. We present the hypothesis that this is due to nitrosylation of the ryanodine receptor and increased NO signaling via the soluble guanyl... more
Dietary nitrate, a source of nitric oxide (NO), improves the contractile properties of human muscle. We present the hypothesis that this is due to nitrosylation of the ryanodine receptor and increased NO signaling via the soluble guanyl cyclase-cyclic guanosine monophosphate-protein kinase G pathway, which together increase the free intracellular Ca2+ concentration along with the Ca2+ sensitivity of the myofilaments themselves.
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Systemic arterial compliance (C) and vascular resistance (R) regulate effective arterial elastance (Ea), an index of artery load. Increases in Ea during exercise are due primarily to reductions of C and maintain optimal... more
Systemic arterial compliance (C) and vascular resistance (R) regulate effective arterial elastance (Ea), an index of artery load. Increases in Ea during exercise are due primarily to reductions of C and maintain optimal ventricular-arterial coupling. Because C at rest and left ventricular functional reserve are greater in endurance-trained (ET) compared with sedentary control (SC) humans, we hypothesized that reductions of C and increases in Ea are greater in ET than SC individuals. The aim of this study was to investigate C, R, and Ea during exercise in ET and SC humans. C, R, Ea, and cardiac cycle length (T) were measured at rest and during exercise of 40, 60, and 80% maximal oxygen uptake using Doppler ultrasonography in 12 SC and 13 ET men. C decreased in an exercise intensity-dependent manner in both groups, but its reductions were greater in the ET than SC subjects. Consequently, although C at rest was greater in the ET than SC group, the intergroup difference in C disappeared...
Research Interests: Cardiology, Compliance, Medicine, Biological Sciences, Humans, and 15 moreInternal Medicine, Male, Exercise, American, Adult, Endurance Training, Vasodilation, Blood Flow Velocity, Oxygen Consumption, Case Control Studies, Vascular Resistance, Physical Endurance, Arteries, Cardiac output, and Medical and Health Sciences
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Research Interests: Obesity, Energy Metabolism, Heart Failure, Insulin Resistance, Humans, and 15 moreGlucose, Insulin, Fatty acids, Female, Male, Clinical Sciences, Middle Aged, Adult, Myocardium, Blood Flow, Assessment Model, Coronary Circulation, Indexation, Oxygen Consumption, and Cardiovascular medicine and haematology
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The expression of myocardial fatty acid β-oxidation enzymes is downregulated at the gene transcriptional level in animal models of left ventricular hypertrophy and of heart failure. Humans with idiopathic dilated cardiomyopathy have... more
The expression of myocardial fatty acid β-oxidation enzymes is downregulated at the gene transcriptional level in animal models of left ventricular hypertrophy and of heart failure. Humans with idiopathic dilated cardiomyopathy have decreased myocardial fatty acid oxidation. The extent to which molecular mechanisms, such as a reduction in myocardial fatty acid oxidation, regulate the cardiac hypertrophic response in humans in vivo is unknown. Positron emission tomography was used to measure myocardial blood flow, oxygen consumption, fatty acid utilization, and oxidation in two groups of patients: (1) hypertensive left ventricular hypertrophy (n=19; left ventricular mass, 211±39 g; left ventricular ejection fraction, 67±4%) and (2) left ventricular dysfunction (n=9; left ventricular mass, 210±36 g; left ventricular ejection fraction, 31±10%); these were compared with a normal control group (n=36; left ventricular mass, 139±25 g; left ventricular ejection fraction, 66±6%). Left ventri...
Research Interests: Heart Failure, Humans, Hypertension, Fatty acids, Female, and 15 moreMale, Fatty Acid Oxidation, Animal Model, Body Mass Index, Left Ventricular Dysfunction, Enzyme, Clinical Sciences, Adult, Fatty Acid, Left ventricular hypertrophy, Coronary Circulation, Cardiac function, Fatty acid metabolism, Cardiovascular medicine and haematology, and Coronary Vessels
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Research Interests: Soccer, Medicine, Echocardiography, Football, Humans, and 14 moreLeft Ventricular Assist Device, Male, Physical Fitness, Adult, Tissue Doppler Imaging, Left ventricular hypertrophy, Ventricular Remodeling, Aorta, Blood Flow Velocity, Physical Education and training, Diastole, Left Ventricular, Cardiovascular medicine and haematology, and Heart atria
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Background— Obesity is a risk factor for impaired cardiac performance, particularly in women. Animal studies suggest that alterations in myocardial fatty acid metabolism and efficiency in obesity can cause decreased cardiac performance.... more
Background— Obesity is a risk factor for impaired cardiac performance, particularly in women. Animal studies suggest that alterations in myocardial fatty acid metabolism and efficiency in obesity can cause decreased cardiac performance. In the present study, we tested the hypothesis that myocardial fatty acid metabolism and efficiency are abnormal in obese women. Methods and Results— We studied 31 young women (body mass index [BMI] 19 to 52 kg/m 2 ); 19 were obese (BMI >30 kg/m 2 ). Myocardial oxygen consumption (MV̇ o 2 ) and fatty acid uptake (MFAUp), utilization (MFAU), and oxidation (MFAO) were quantified by positron emission tomography. Cardiac work was measured by echocardiography, and efficiency was calculated as work/MV̇ o 2 . BMI correlated with MV̇ o 2 ( r =0.58, P =0.0006), MFAUp ( r =0.42, P <0.05), and efficiency ( r =−0.40, P <0.05). Insulin resistance, quantified by the glucose area under the curve (AUC) during an oral glucose tolerance test, correlated with ...
Research Interests: Energy Metabolism, Echocardiography, Humans, Glucose, Blood Glucose, and 15 moreFatty acids, Hemodynamics, Female, Heart, Body Mass Index, Clinical Sciences, Adult, Cardiac Output Monitoring, Circulation, Glucose Tolerance Test, Area Under Curve, Experimental Model, Cardiac output, Fatty acid metabolism, and Cardiovascular medicine and haematology
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Although saphenous vein graft (SVG) markers have been available for many years, they have not been widely used in coronary artery bypass graft (CABG) surgery. This is likely due to the paucity of data regarding the utility of these... more
Although saphenous vein graft (SVG) markers have been available for many years, they have not been widely used in coronary artery bypass graft (CABG) surgery. This is likely due to the paucity of data regarding the utility of these markers in postsurgery cardiac catheterization. We performed a prospective study of all post-CABG patients undergoing cardiac catheterization at Barnes-Jewish Hospital over a 6-month period to test our hypothesis that SVG markers would have a beneficial effect on these procedures. Differences in total procedure (arterial) time, time to image only the SVGs, fluoroscopy time, amount of contrast used, number of aortotomies, and number of views required were compared in patients with and without markers. Post-CABG patients undergoing catheterization who had markers (n = 76) required significantly less total procedure time (p = 0.007), fluoroscopy time (p = 0.02), and contrast use (p = 0.008). Even after adjusting for the numbers of SVG ostia and numbers of cine views, patients with markers still required less catheterization and fluoroscopy time (p &lt; 0.01, p &lt; 0.02) and time to image only the SVGs (p &lt; 0.05) than those without markers (n = 106). SVG markers improve the efficiency of post-CABG catheterizations; they decrease the exposure of patients and cardiologists to ionizing radiation, and they decrease the exposure of patients to potentially toxic contrast agents. SVG markers are beneficial to the vast majority of post-CABG patients.
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The benefits of mobile cardiac catheterization laboratories include keeping patients closer to their families, communities, local hospitals, and primary care physicians while receiving services comparable to those available at tertiary... more
The benefits of mobile cardiac catheterization laboratories include keeping patients closer to their families, communities, local hospitals, and primary care physicians while receiving services comparable to those available at tertiary centers. However, there are very few studies regarding the safety of performing cardiac catheterization in mobile laboratories at remote locations. Thus, the authors performed an observational study of 1,775 consecutive patients undergoing a diagnostic cardiac catheterization in a mobile catheterization laboratory at primary care hospitals served by the Appleton Heart Institute (AHI) from August 1, 1991, to December 31, 1998. Twenty-three percent (1,775/7,637) of all AHI diagnostic cases in this time period were performed in the mobile catheterization laboratory. Urgent transfer to the tertiary care facility via ambulance or helicopter was used for 2.3% of patients (n=41). The overall complication rate was 1.2% (n=21). Of the patients who underwent ca...
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Research Interests: Medicine, Echocardiography, Biological Sciences, Elasticity, Humans, and 15 moreBlood Pressure, Applied, Female, Male, Heart rate, Exercise, Applied Physiology, Aged, Oxygen Consumption, Physical Education and training, Cardiopulmonary Physical Therapy, Arteries, Cardiac output, Left Ventricular, and Medical and Health Sciences
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Research Interests: Medicine, Quantitative analysis, Insulin Resistance, Humans, Female, and 15 moreMale, Heart, Time Delay, ROC Curve, Clinical Sciences, Middle Aged, Early Detection, Adult, Quantitative Analysis, Cardiomyopathies, Nonparametric Estimation, Early Diagnosis, Region of Interest, Tissue Characterization, and High risk
Methods and Results We studied 31 young women (body mass index [BMI] 19 to 52 kg/m 2 ); 19 were obese (BMI >30 kg/m 2 ). Myocardial oxygen consumption (M O 2 ) and fatty acid uptake (MFAUp), utilization (MFAU), and oxidation (MFAO)... more
Methods and Results We studied 31 young women (body mass index [BMI] 19 to 52 kg/m 2 ); 19 were obese (BMI >30 kg/m 2 ). Myocardial oxygen consumption (M O 2 ) and fatty acid uptake (MFAUp), utilization (MFAU), and oxidation (MFAO) were quantified by positron emission ...
Research Interests: Energy Metabolism, Echocardiography, Insulin Resistance, Humans, Glucose, and 15 moreBlood Glucose, Fatty acids, Hemodynamics, Female, Heart, Body Mass Index, Left Ventricular Dysfunction, Clinical Sciences, Adult, Cardiac Output Monitoring, Circulation, Glucose Tolerance Test, Area Under Curve, Cardiac output, and Cardiovascular medicine and haematology
Increased myocardial lipid delivery is a determinant of myocardial substrate metabolism and function in animal models of type 2 diabetes (T2DM). Sex also has major effects on myocardial metabolism in the human heart. Our aims were to... more
Increased myocardial lipid delivery is a determinant of myocardial substrate metabolism and function in animal models of type 2 diabetes (T2DM). Sex also has major effects on myocardial metabolism in the human heart. Our aims were to determine whether 1) sex affects the myocardial metabolic response to lipid lowering in T2DM, 2) altering lipid [fatty acid (FA) or triglyceride] delivery to the heart would lower the elevated myocardial lipid metabolism associated with T2DM, and 3) decreasing lipid delivery improves diastolic dysfunction in T2DM. To this end, we studied 78 T2DM patients (43 women) with positron emission tomography, echocardiography, and whole body tracer studies before and 3 mo after randomization to metformin (MET), metformin + rosiglitazone (ROSI), or metformin + Lovaza (LOV). No treatment main effects were found for myocardial substrate metabolism, partly because men and women often had different responses to a given treatment. In men, MET decreased FA clearance, wh...
Research Interests: Physiology, Sex, Positron Emission Tomography, Medicine, Energy Metabolism, and 15 moreHumans, Metformin, Fatty acids, Female, Male, Missouri, Dietary Supplements, Medical Physiology, Middle Aged, Myocardium, Analysis of Variance, Chi Square Distribution, Eicosapentaenoic Acid, Recovery of Function, and Diastole
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Research Interests: Medicine, Electrocardiography, Humans, Female, Male, and 15 moreConfidence intervals, Acute Myocardial Infarction, Registries, Aged, Middle Aged, Myocardial Infarction, Retrospective Studies, Prognosis, Multivariate Regression, Hospital Mortality, Recombinant Proteins, Confidence Interval, Coronary artery bypass graft, Cardiovascular medicine and haematology, and Coronary Artery Bypass
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OBJECTIVENormal human myocardium switches substrate metabolism preference, adapting to the prevailing plasma substrate levels and hormonal milieu, but in type 1 diabetes, the myocardium relies heavily on fatty acid metabolism for energy.... more
OBJECTIVENormal human myocardium switches substrate metabolism preference, adapting to the prevailing plasma substrate levels and hormonal milieu, but in type 1 diabetes, the myocardium relies heavily on fatty acid metabolism for energy. Whether ...
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Background Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC’s excessive reliance on glucose metabolism for its metabolic needs provides a target for... more
Background Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC’s excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear. Methods We performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma ch...
To compare the effects of exercise training and hydrochlorothiazide on left ventricular (LV) geometry and mass, blood pressure (BP), and hyperinsulinemia in older hypertensive adults, we studied 28 patients randomized either to a group... more
To compare the effects of exercise training and hydrochlorothiazide on left ventricular (LV) geometry and mass, blood pressure (BP), and hyperinsulinemia in older hypertensive adults, we studied 28 patients randomized either to a group (age 66.4 ± 1.3 yr; n = 16) that exercised or to a group (age 65.3 ± 1.2 yr; n = 12) that received hydrochlorothiazide for 6 mo. Endurance exercise training induced a 15% increase in peak aerobic power. The reduction in systolic BP was twofold greater with thiazide than with exercise (26.6 ± 12.2 vs. 11.5 ± 10.9 mmHg). Exercise and thiazide reduced LV wall thickness, LV mass index (14% in each group), and the LV wall thickness-to-radius ratio ( h/ r) similarly (exercise: before 0.48 ± 0.2, after 0.42 ± 0.01; thiazide: before 0.47 ± 0.04, after 0.40 ± 0.04; P = 0.017). The reductions in systolic BP and h/ r were correlated in the exercise group ( r = 0.70, P = 0.005) but not in the thiazide group. Exercise training reduced glucose-stimulated hyperinsul...
Research Interests: Endocrinology, Biological Sciences, Insulin Resistance, Lipids, Humans, and 15 moreInternal Medicine, Blood Glucose, Hypertension, Hyperinsulinemia, Blood Pressure, Diuretics, Female, Body Composition, Heart rate, Exercise, Angiotensins, Body Mass Index, Hydrochlorothiazide, Aged, and Left Ventricular
In many cancers, including lymphoma, males have higher incidence and mortality than females. Emerging evidence demonstrates that one mechanism underlying this phenomenon is sex differences in metabolism, both with respect to tumor... more
In many cancers, including lymphoma, males have higher incidence and mortality than females. Emerging evidence demonstrates that one mechanism underlying this phenomenon is sex differences in metabolism, both with respect to tumor nutrient consumption and systemic alterations in metabolism, i.e., obesity. We wanted to determine if visceral fat and tumor glucose uptake with fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) could predict sex-dependent outcomes in patients with diffuse large B-cell lymphoma (DLBCL). We conducted a retrospective analysis of 160 patients (84 males; 76 females) with DLBCL who had imaging at initial staging and after completion of therapy. CT-based relative visceral fat area (rVFA), PET-based SUVmax normalized to lean body mass (SULmax), and end-of-treatment FDG-PET 5PS score were calculated. Increased rVFA at initial staging was an independent predictor of poor OS only in females. At the end of therapy, increase in visceral ...
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Cardiac dysfunction in type 2 diabetes (T2D) is associated with excessive fatty acid uptake, oxidation, and generation of toxic lipid species by the heart. It is not known whether decreasing lipid delivery to the heart can effect... more
Cardiac dysfunction in type 2 diabetes (T2D) is associated with excessive fatty acid uptake, oxidation, and generation of toxic lipid species by the heart. It is not known whether decreasing lipid delivery to the heart can effect improvement in cardiac function in humans with T2D. Thus, our objective was to test the hypothesis that lowering lipid delivery to the heart would result in evidence of decreased ‘lipotoxicity’ — improved cardiac function, and salutary effects on plasma biomarkers of cardiovascular risk. Thus, we performed a double-blind, randomized, placebo-controlled, parallel design study of the effects of 12 weeks of fenofibrate-induced lipid-lowering on cardiac function, inflammation and oxidation biomarkers, and on the ratio of two plasma ceramides — Cer d18:1 (4E) (1OH, 3OH)/24:0 and Cer d18:1 (4E) (1OH, 3OH)/16:0 — (i.e., ‘C24:0/C16:0’), which is associated with decreased risk of cardiac dysfunction and heart failure. Fenofibrate lowered plasma TG and cholesterol ...
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In animal models of heart failure (HF), myocardial metabolism shifts from high-energy fatty acid (FA) metabolism toward glucose. However, FA (vs glucose) metabolism generates more ATP/mole; thus, FA metabolism may be especially... more
In animal models of heart failure (HF), myocardial metabolism shifts from high-energy fatty acid (FA) metabolism toward glucose. However, FA (vs glucose) metabolism generates more ATP/mole; thus, FA metabolism may be especially advantageous in HF. Sex modulates myocardial blood flow (MBF) and substrate metabolism in normal humans. Whether sex affects MBF and metabolism in patients with HF is unknown. We studied 19 well-matched men and women with nonischemic HF (EF ≤ 35%). MBF and myocardial substrate metabolism were quantified using positron emission tomography. Women had higher MBF (mL/g/minute), FA uptake (mL/g/minute), and FA utilization (nmol/g/minute) (P < 0.005, P < 0.005, P < 0.05, respectively) and trended toward having higher FA oxidation than men (P = 0.09). These findings were independent of age, obesity, and insulin resistance. There were no sex-related differences in fasting myocardial glucose uptake or metabolism. Higher MBF was related to improved event-free ...
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Context: Excessive cardiac long-chain fatty acid (LCFA) metabolism/storage causes cardiomyopathy in animal models of type 2 diabetes. Medium-chain fatty acids (MCFAs) are absorbed and oxidized efficiently. Data in animal models of... more
Context: Excessive cardiac long-chain fatty acid (LCFA) metabolism/storage causes cardiomyopathy in animal models of type 2 diabetes. Medium-chain fatty acids (MCFAs) are absorbed and oxidized efficiently. Data in animal models of diabetes suggest MCFAs may benefit the heart. Objective: Our objective was to test the effects of an MCFA-rich diet vs an LCFA-rich diet on plasma lipids, cardiac steatosis, and function in patients with type 2 diabetes. Design: This was a double-blind, randomized, 2-week matched-feeding study. Setting: The study included ambulatory patients in the general community. Patients: Sixteen patients, ages 37–65 years, with type 2 diabetes, an ejection fraction greater than 45%, and no other systemic disease were included. Intervention: Fourteen days of a diet rich in MCFAs or LCFAs, containing 38% as fat in total, was undertaken. Main Outcome Measures: Cardiac steatosis and function were the main outcome measures, with lipidomic changes considered a secondary ou...
Research Interests: Endocrinology, Diet, Medicine, Prospective studies, Humans, and 15 moreInternal Medicine, Diabetes mellitus, Fatty acids, Blood Pressure, Female, Male, Lipid metabolism, Clinical Sciences, Aged, Middle Aged, Adult, Cardiomyopathy, Ejection Fraction, Pilot Projects, and Paediatrics and reproductive medicine
Research Interests: Chemistry, Medicine, Muscle strength, Biological Sciences, Humans, and 15 moreInternal Medicine, Female, Male, Dietary Supplements, Bioavailability, CHEMICAL SCIENCES, Middle Aged, Adult, Muscle Fatigue, Muscle contraction, Biological Availability, Knee Joint, Dietary nitrate, Medical and Health Sciences, and crossover study
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Research Interests: Cardiology, Medicine, Parameter estimation, Echocardiography, Humans, and 15 moreInternal Medicine, Diabetes mellitus, Female, Animals, Male, Piecewise Linear, Coefficient of Variation, Clinical Sciences, Middle Aged, Adult, Cardiovascular Diseases, Bayes Theorem, Asymptomatic, Left Ventricle, and cardiac cycle
Research Interests: Algorithms, Biomedical Engineering, Spectroscopy, Magnetic Resonance Imaging, Nuclear Magnetic Resonance, and 12 moreMagnetic Resonance Spectroscopy, Medicine, Linear models, Biopsy, Humans, Triglycerides, In Vivo, Myocardium, Reproducibility of Results, Heart Transplantation, Case Control Studies, and Nuclear Magnetic Resonance Spectroscopy
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Research Interests: Endocrinology, Insulin Resistance, Humans, Internal Medicine, Glucose, and 15 moreGlucose Metabolism, Diabetes mellitus, Fatty acids, Left Ventricular Assist Device, Female, Animal Model, Body Mass Index, Adult, Carbohydrate metabolism, Fatty Acid, Cardiomyopathies, Left Ventricular Function, Glucose Uptake, Left Ventricular, and Cardiovascular medicine and haematology
Previous studies have demonstrated that frail octogenarians have an attenuated capacity for cardiovascular adaptations to endurance exercise training. In the present study, we determined the magnitude of cardiovascular and metabolic... more
Previous studies have demonstrated that frail octogenarians have an attenuated capacity for cardiovascular adaptations to endurance exercise training. In the present study, we determined the magnitude of cardiovascular and metabolic adaptations to high-intensity endurance exercise training in healthy, nonfrail elderly subjects. Ten subjects [8 men, 2 women, 80.3 yr (SD2.5)] completed 10–12 mo (108 exercise sessions) of a supervised endurance exercise training program consisting of 2.5 sessions/wk (SD 0.2), 58 min/session (SD 6), at an intensity of 83% (SD 5) of peak heart rate. Primary outcomes were maximal attainable aerobic power [peak aerobic capacity (V̇o2peak)]; serum lipids, oral glucose tolerance, and insulin action during a hyperglycemic cl& body composition by dual-energy X-ray absorptiometry, and energy expenditure using doubly labeled water and indirect calorimetry. The training program resulted in an increase in V̇o2peakof 15% (SD 7) [22.9 (SD 3.3) to 26.2 ml·kg−1·min−1(...