Linda Peterson - Profile on Academia.edu (original) (raw)

Papers by Linda Peterson

Background—Obesity is a risk factor for impaired cardiac performance, particularly in women. Anim... 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/m2); 19 were obese (BMI 30 kg/m2). Myocardial oxygen consumption (MV ˙ O2) 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/MV ˙ O2. BMI correlated with MV ˙ O2 (r0.58, P0.0006), MFAUp (r0.42, P0.05), and efficiency (r0.40, P0.05). Insulin resistance, quantified by the glucose area under the curve (AUC) during an

It is widely recognized that obesity and insulin resistance can contribute to an increased risk o... more It is widely recognized that obesity and insulin resistance can contribute to an increased risk of coronary disease, but it has also become increasingly apparent that they may contribute directly to cardiac dysfunction even in the absence of significant coronary disease. Recently, obesity, which is frequently accompanied by insulin resistance, has been independently related to clinically diagnosed heart failure. Thus, there is renewed interest in the pathophysiology of myocardial disease related to obesity and insulin resistance, as well as in the specific cellular mechanisms by which obesity may cause detrimental cardiac structural and functional changes. Alterations in hemodynamics, plasma volume, neurohormonal status, and myocardial substrate metabolism all appear to contribute to these changes. Improving our understanding of cardiac dysfunction related to obesity and insulin resistance may provide clues for new strategies to prevent and treat this alarmingly prevalent condition.

Journal of Lipid and Atherosclerosis

Objective: Total ceramide concentrations are linked with increased insulin resistance and cardiac... more Objective: Total ceramide concentrations are linked with increased insulin resistance and cardiac dysfunction. However, recent studies have demonstrated that plasma concentrations of specific very-long-chain fatty ceramides (C24:0 and C22:0) are associated with a reduced incidence of coronary heart disease and all-cause mortality. We hypothesized that specific genetic loci are associated with plasma C22:0 and C24:0 concentrations. Methods: Heritability and genome-wide association studies of plasma C24:0 and C22:0 ceramide concentrations were performed among 2,217 participants in the Framingham Heart Study Offspring Cohort, adjusting for cardiovascular risk factor covariates and cardiovascular drug treatment. Results: The multivariable-adjusted heritability for C22:0 and C24:0 ceramides was 0.42 (standard error [SE], 0.07; p=1.8E-9) and 0.25 (SE, 0.08; p=0.00025), respectively. Nineteen single nucleotide polymorphisms (SNPs), all on chromosome 20, significantly associated with C22:0 concentrations; the closest gene to these variants was SPTLC3. The lead SNP (rs4814175) significantly associated with 3% lower plasma C22:0 concentrations (p=2. 83E-11). Nine SNPs, all on chromosome 20 and close to SPTLC3, were significantly associated with C24:0 ceramide concentrations. All 9 were also significantly related to plasma C22:0 levels. The lead SNP (rs168622) was significantly associated with 10% lower plasma C24:0 ceramide concentrations (p=9.94E-09). Conclusion: SNPs near the SPTLC3 gene, which encodes serine palmitoyltransferase long chain base subunit 3 (SPTLC3; part of the enzyme that catalyzes the rate-limiting step of de novo sphingolipid synthesis) were associated with plasma C22:0 and C24:0 ceramide concentrations. These results are biologically plausible and suggest that SPTLC3 may be a potential therapeutic target for C24:0 and C22:0 ceramide modulation.

PloS one, 2018

Barth syndrome (BTHS) is an ultra-rare, X-linked recessive disorder characterized by cardio-skele... more Barth syndrome (BTHS) is an ultra-rare, X-linked recessive disorder characterized by cardio-skeletal myopathy, exercise intolerance, and growth delay. Oxygen uptake during peak exercise (VO2peak) has been shown to be severely limited in individuals with BTHS however; the trajectory of VO2peak from childhood to young adulthood is unknown. The objective of this study was to describe VO2peak from childhood through young adulthood in BTHS. VO2peak over time was presented through cross-sectional (n = 33 participants) and a longitudinal analyses (n = 12 participants). Retrospective data were obtained through maximal exercise testing on a cycle ergometer from individuals with BTHS who were or are currently enrolled in a research study during July 2006-September 2017. Participants included in the cross-sectional analysis were divided into 3 groups for analysis: 1) children (n = 13), 2) adolescents (n = 8), and 3) young adults (n = 12). Participants in the longitudinal analysis had at least ...

Journal of the American Heart Association, Jan 3, 2018

Recent studies suggest that circulating concentrations of specific ceramide species may be associ... more Recent studies suggest that circulating concentrations of specific ceramide species may be associated with coronary risk and mortality. We sought to determine the relations between the most abundant plasma ceramide species of differing acyl chain lengths and the risk of coronary heart disease (CHD) and mortality in community-based samples. We developed a liquid chromatography/mass spectrometry assay to quantify plasma C24:0, C22:0, and C16:0 ceramides and ratios of these very-long-chain/long-chain ceramides in 2642 FHS (Framingham Heart Study) participants and in 3134 SHIP (Study of Health in Pomerania) participants. Over a mean follow-up of 6 years in FHS, there were 88 CHD and 90 heart failure (HF) events and 239 deaths. Over a median follow-up time in SHIP of 5.75 years for CHD and HF and 8.24 years for mortality, there were 209 CHD and 146 HF events and 377 deaths. In meta-analysis of the 2 cohorts and adjusting for standard CHD risk factors, C24:0/C16:0 ceramide ratios were inv...

Obesity (Silver Spring, Md.), Feb 1, 2018

To determine the effects of gastric bypass on myocardial lipid deposition and function and the pl... more To determine the effects of gastric bypass on myocardial lipid deposition and function and the plasma lipidome in women with obesity and heart failure with preserved ejection fraction (HFpEF). A primary cohort (N = 12) with HFpEF and obesity underwent echocardiography and magnetic resonance spectroscopy both before and 3 months and 6 months after bariatric surgery. Plasma lipidomic analysis was performed before surgery and 3 months after surgery in the primary cohort and were confirmed in a validation cohort (N = 22). After surgery-induced weight loss, Minnesota Living with Heart Failure questionnaire scores, cardiac mass, and liver fat decreased (P < 0.02, P < 0.001, and P = 0.007, respectively); echo-derived e' increased (P = 0.03), but cardiac fat was unchanged. Although weight loss was associated with decreases in many plasma ceramide and sphingolipid species, plasma lipid and cardiac function changes did not correlate. Surgery-induced weight loss in women with HFpEF a...

Journal of Cardiac Failure

Acute dietary NO 3 intake increased VO 2 peak in patients with HF by 8±2% (P<0.05).  Time to fat... more Acute dietary NO 3 intake increased VO 2 peak in patients with HF by 8±2% (P<0.05).  Time to fatigue during exercise improved by 7±3 % (P<0.05).  Dietary NO 3 may be a means of enhancing exercise capacity in patients with HF.

Physiological reports, 2017

Barth syndrome (BTHS) is an X-linked condition characterized by altered cardiolipin metabolism an... more Barth syndrome (BTHS) is an X-linked condition characterized by altered cardiolipin metabolism and cardioskeletal myopathy. We sought to compare cardiac and skeletal muscle bioenergetics in children, adolescents, and young adults with BTHS and unaffected controls and examine their relationships with cardiac function and exercise capacity. Children/adolescents and young adults with BTHS (n = 20) and children/adolescent and young adult control participants (n = 23, total n = 43) underwent (31)P magnetic resonance spectroscopy ((31)P-MRS) of the lower extremity (calf) and heart for estimation of skeletal muscle and cardiac bioenergetics. Peak exercise testing (VO2peak) and resting echocardiography were also performed on all participants. Cardiac PCr/ATP ratio was significantly lower in children/adolescents (BTHS: 1.5 ± 0.2 vs. 2.0 ± 0.3, P < 0.01) and adults (BTHS: 1.9 ± 0.2 vs. 2.3 ± 0.2, P < 0.01) with BTHS compared to Control groups. Adults (BTHS: 76.4 ± 31.6 vs. 35.0 ± 7.4 se...

JIMD Reports, 2016

Background: Barth syndrome (BTHS) is a rare X-linked disorder that is characterized by mitochondr... more Background: Barth syndrome (BTHS) is a rare X-linked disorder that is characterized by mitochondrial abnormalities, cardio-skeletal myopathy, exercise intolerance, and premature mortality. The effect on endurance exercise training on exercise tolerance, cardio-skeletal function, and quality of life in BTHS is unknown. Methods: Four young adults (23 AE 5 years, n ¼ 4) with BTHS participated in a 12-week, supervised, individualized endurance exercise training program. Exercise training was performed on a cycle ergometer for 30-45 0 three times per week at a moderate intensity level.

Current Heart Failure Reports, 2016

Heart failure (HF) patients suffer from exercise intolerance that diminishes their ability to per... more Heart failure (HF) patients suffer from exercise intolerance that diminishes their ability to perform normal activities of daily living and hence compromises their quality of life. This is due largely to detrimental changes in skeletal muscle mass, structure, metabolism, and function. This includes an impairment of muscle contractile performance, i.e., a decline in the maximal force, speed, and power of muscle shortening. Although numerous mechanisms underlie this reduction in contractility, one contributing factor may be a decrease in nitric oxide (NO) bioavailability. Consistent with this, recent data demonstrate that acute ingestion of NO 3 −-rich beetroot juice, a source of NO via the NO synthase-independent enterosalivary pathway, markedly increases maximal muscle speed and power in HF patients. This review discusses the role of muscle contractile dysfunction in the exercise intolerance characteristic of HF, and the evidence that dietary NO 3 − supplementation may represent a novel and simple therapy for this currentlyunderappreciated problem.

Journal of Nuclear Cardiology, 2016

Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology, Jan 5, 2016

In animal models of heart failure (HF), myocardial metabolism shifts from high-energy fatty acid ... 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 ...

Circulation. Heart failure, Jan 15, 2015

Background-Skeletal muscle strength, velocity, and power are markedly reduced in patients with he... more Background-Skeletal muscle strength, velocity, and power are markedly reduced in patients with heart failure, which contributes to their impaired exercise capacity and lower quality of life. This muscle dysfunction may be partially because of decreased nitric oxide (NO) bioavailability. We therefore sought to determine whether ingestion of inorganic nitrate (NO 3 −) would increase NO production and improve muscle function in patients with heart failure because of systolic dysfunction. Methods and Results-Using a double-blind, placebo-controlled, randomized crossover design, we determined the effects of dietary NO 3 − in 9 patients with heart failure. After fasting overnight, subjects drank beetroot juice containing or devoid of 11.2 mmol of NO 3 −. Two hours later, muscle function was assessed using isokinetic dynamometry. Dietary NO 3 − increased (P<0.05-0.001) breath NO by 35% to 50%. This was accompanied by 9% (P=0.07) and 11% (P<0.05) increases in peak knee extensor power at the 2 highest movement velocities tested (ie, 4.71 and 6.28 rad/s). Maximal power (calculated by fitting peak power data with a parabola) was therefore greater (ie, 4.74±0.41 versus 4.20±0.33 W/kg; P<0.05) after dietary NO 3 − intake. Calculated maximal velocity of knee extension was also higher after NO 3 − ingestion (ie, 12.48±0.95 versus 11.11±0.53 rad/s; P<0.05). Blood pressure was unchanged, and no adverse clinical events occurred. Conclusions-In this pilot study, acute dietary NO 3 − intake was well tolerated and enhanced NO bioavailability and muscle power in patients with systolic heart failure. Larger-scale studies should be conducted to determine whether the latter translates into an improved quality of life in this population. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01682356.

American Journal of Physiology - Heart and Circulatory Physiology, 2015

Type 2 diabetes, obesity, and sex difference affect myocardial glucose uptake and utilization. Ho... more Type 2 diabetes, obesity, and sex difference affect myocardial glucose uptake and utilization. However, their effect on the intramyocellular fate of glucose in humans has been unknown. How the heart uses glucose is important, because it affects energy production and oxygen efficiency, which in turn affect heart function and adaptability. We hypothesized that type 2 diabetes, sex difference, and obesity affect myocardial glucose oxidation, glycolysis, and glycogen production. In a first-in-human study, we measured intramyocardiocellular glucose metabolism from time-activity curves generated from previously obtained positron emission tomography scans of 110 subjects in 3 groups: nonobese, obese, and diabetes. Group and sex difference interacted in the prediction of all glucose uptake, utilization, and metabolism rates. Group independently predicted fractional glucose uptake and its components: glycolysis, glycogen deposition, and glucose oxidation rates. Sex difference predicted glyco...

The purpose of this study was to determine if myocardial fatty acid utilization (MFAU) and myocar... more The purpose of this study was to determine if myocardial fatty acid utilization (MFAU) and myocardial fatty acid oxidation (MFAO) are increased in diabetic patients. BACKGROUND Experimental models of diabetes mellitus demonstrate that MFAU and MFAO are increased, and that this dependence on myocardial fatty acid metabolism may be detrimental to cardiac function. Whether similar metabolic changes occur in humans with diabetes mellitus is unclear. Eleven healthy non-diabetic control patients (5 women, ages 25 Ϯ 5 years) and 11 otherwise healthy patients with type 1 diabetes mellitus (T1DM) (8 women, ages 36 Ϯ 10 years, HbA1c 8.4 Ϯ 1.9%) underwent positron emission tomography for the determination of myocardial blood flow (MBF); myocardial oxygen consumption (MVO 2 ); myocardial glucose utilization (MGU); and MFAU, MFAO, and %MFAO. Plasma lactate, insulin, and MBF levels were similar between the two groups. However, plasma glucose (5.71 Ϯ 0.98 mol/ml vs. 5.28 Ϯ 0.65 mol/ml, p ϭ 0.04), free fatty acid levels (0.60 Ϯ 0.24 mol/ml vs. 0.19 Ϯ 0.07 mol/ml, p Ͻ 0.0001), and MVO 2 (6.64 Ϯ 2.21 vs. 4.51 Ϯ 1.39 mol/g/min, p ϭ 0.007) levels were higher in the T1DM subjects. Furthermore, compared with control patients, T1DM subjects exhibited higher MFAU (213 135 nmol/g/min vs. 57 Ϯ 28 nmol/g/min, p ϭ 0.0004), MFAO (206 Ϯ 131 nmol/g/min s. 50 Ϯ 26 nmol/g/min, p ϭ 0.0002), and %MFAO (94 Ϯ 6% vs. 81 Ϯ 19%, respectively, p ϭ 0.04). In contrast, MGU was lower in T1DM subjects than in controls (207 Ϯ 108 nmol/g/min vs. 403 Ϯ 191 nmol/g/min, p ϭ 0.0008). CONCLUSIONS Humans with diabetes mellitus exhibit increased MFAU and MFAO and reduced MGU consistent with observations obtained in experimental models of diabetes. (

Journal of the American College of Cardiology, 2004

Background: Myocardial uptake of flourine-18 labeled 2-deoxyglucose (FDG) parallels endogenous gl... more Background: Myocardial uptake of flourine-18 labeled 2-deoxyglucose (FDG) parallels endogenous glucose uptake. Experimental data have shown that glucose utilization increases during acute myocardial ischemia in proportion to its severity and duration, and may persist for up to 24 hours. Whether FDG uptake can be imaged as a memory marker of ischemia in humans is unknown. Methods: Patients with mild to moderate ischemia on a clinical exercise SPECT myocardial perfusion imaging (MPI) underwent repeat exercise testing within 1-2 weeks, to an equivalent workload after overnight fast. Positron emission tomography (PET) was performed after injection of FDG 60 minutes post exercise. SPECT and PET images were assessed visually and quantitatively using regions of interest for heart:lung ratios and a circumferential profile-based analysis modified for "hotspot" imaging. A change in regional maximal uptake >10% on SPECT and regional FDG PET uptake >110% was considered as evidence of ischemia. Results: Ten males with stress SPECT ischemia (mean age 69 years, 7 known coronary artery disease[CAD]) were studied. The mean difference in the rate pressure product between the 2 exercise tests was 1.5+19%. FDG was injected 66+10 min after exercise. Visually, 5 of 10 patients had enhanced regional FDG uptake (mean [range] heart:lung ratio 5. 3 [3.5-7.8] in visually abnormal vs. 3.0 [2.5-3.4] without visual uptake, p=0.02 respectively). Using circumferential profiles, 7 patients had maximal FDG uptake >110%; mean FDG uptake in these regions was 120+12%. Overall, 8 of 10 patients studied had evidence of FDG uptake by visual and/or quantitative analysis. All patients with a visually and/or quantitatively positive FDG scan had uptake in either an ischemic SPECT region or a territory with known CAD by angiography. Conclusion: Regional myocardial uptake of FDG is enhanced even when injected 1 hour post-exercise stress in a subset of patients with ischemia on exercise SPECT MPI. Enhanced FDG uptake localized with regional SPECT ischemia and/or angiographic CAD. The ability to image FDG uptake injected 1 hour after an ischemic episode suggests the potential utility of FDG as a memory marker of transient ischemia.

Drug Discovery Today: Therapeutic Strategies, 2008

Obesity is a risk factor for cardiovascular disease, including coronary artery disease and heart ... more Obesity is a risk factor for cardiovascular disease, including coronary artery disease and heart failure, but the mechanisms by which it may cause them are not completely clear. Currently, therapies aimed at obesity-related cardiovascular disease include weight loss strategies and reduction of the other risk factors that are associated with obesity and cardiovascular disease. Other pathways with for potential drug development for obesity-related CVD are also discussed.

Current Hypertension Reports, 2006

Cardiovascular Diabetology, 2011

Background: In the general population, peripheral metabolic complications (MC) increase the risk ... more Background: In the general population, peripheral metabolic complications (MC) increase the risk for left ventricular dysfunction. Human immunodeficiency virus infection (HIV) and combination anti-retroviral therapy (cART) are associated with MC, left ventricular dysfunction, and a higher incidence of cardiovascular events than the general population. We examined whether myocardial nutrient metabolism and left ventricular dysfunction are related to one another and worse in HIV infected men treated with cART vs. HIV-negative men with or without MC. Methods: Prospective, cross-sectional study of myocardial glucose and fatty acid metabolism and left ventricular function in HIV+ and HIV-negative men with and without MC. Myocardial glucose utilization (GLUT), and fatty acid oxidation and utilization rates were quantified using 11 C-glucose and 11 C-palmitate and myocardial positron emission tomography (PET) imaging in four groups of men: 23 HIV+ men with MC+ (HIV+/MC+, 42 ± 6 yrs), 15 HIV + men without MC (HIV+/MC-, 41 ± 6 yrs), 9 HIV-negative men with MC (HIV-/MC+, 33 ± 5 yrs), and 22 HIVnegative men without MC (HIV-/MC-, 25 ± 6 yrs). Left ventricular function parameters were quantified using echocardiography. Results: Myocardial glucose utilization was similar among groups, however when normalized to fasting plasma insulin concentration (GLUT/INS) was lower (p < 0.01) in men with metabolic complications (HIV+: 9.2 ± 6.2 vs. HIV-: 10.4 ± 8.1 nmol/g/min/μU/mL) than men without metabolic complications (HIV+: 45.0 ± 33.3 vs. HIV-: 60.3 ± 53.0 nmol/g/min/μU/mL). Lower GLUT/INS was associated with lower myocardial relaxation velocity during early diastole (r = 0.39, p < 0.001). Conclusion: Men with metabolic complications, irrespective of HIV infection, had lower basal myocardial glucose utilization rates per unit insulin that were related to left ventricular diastolic impairments, indicating that wellcontrolled HIV infection is not an independent risk factor for blunted myocardial glucose utilization per unit of insulin.

Journal of Applied …, 2004