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Normal values of regional and global myocardial wall motion in young and elderly individuals using navigator gated tissue phase mapping
The purpose of this study was to evaluate normal values for regional and global myocardial wall motion parameters in young and elderly individuals, as detected by navigator gated high temporal resolution tissue phase mapping. Radial, longitudinal and circumferential ventricular wall motion, as well as ventricular torsion and longitudinal strain rates, were assessed in two age groups of volunteers, 23±3 (n=14) and 66±7 years old (n=9), respectively. All subjects were healthy, non-smokers without known cardiac disease. An increased global left ventricular (LV) torsion rate (peak systolic torsion rate 20.6±2.0 versus 14.5±1.0°/s/cm, peak diastolic torsion rate -25.2±1.8 versus -14.1±1.3°/s/cm) and a decrease in longitudinal LV motion (peak systolic values at mid-ventricle 5.9±0.5 versus 8.5±0.8 cm/s, peak diastolic values -10.7±0.7 versus -15.2±0.9 cm/s) in the older age group were the most prominent findings. Lower peak diastolic radial velocities with a longer time-to-peak values, most pronounced at the apex, are consistent with reduced diastolic function with ageing. Lower peak clockwise and counter-clockwise velocities at all LV levels revealed limitations in resting LV rotational motions in the older group. Significant changes in the undulating pattern of the rotational motions of the left ventricle were also observed. The results demonstrate distinct changes in regional and global myocardial wall motion in elderly individuals. Increased LV torsion rate and reduced LV longitudinal motion were particularly prominent in the older group. These parameters may have a role in the assessment of global LV contractility and help differentiate age-related changes from cardiac disease. © American Aging Association 2013.
Effect of isoproterenol on myocardial perfusion, function, energy metabolism and nitric oxide pathway in the rat heart - a longitudinal MR study
The chronic administration of the β-adrenoreceptor agonist isoproterenol (IsoP) is used in animals to study the mechanisms of cardiac hypertrophy and failure associated with a sustained increase in circulating catecholamines. Time-dependent changes in myocardial blood flow (MBF), morphological and functional parameters were assessed in rats in vivo using multimodal cardiac MRI. Energy metabolism, oxidative stress and the nitric oxide (NO) pathway were evaluated in isolated perfused rat hearts following 7 days of treatment. Male Wistar rats were infused for 7 days with IsoP or vehicle using osmotic pumps. Cine-MRI and arterial spin labeling were used to determine left ventricular morphology, function and MBF at days 1, 2 and 7 after pump implantation. Isolated hearts were then perfused, and high-energy phosphate compounds and intracellular pH were followed using 31P MRS with simultaneous measurement of contractile function. Total creatine and malondialdehyde (MDA) contents were measured by high-performance liquid chromatography. The NO pathway was evaluated by NO synthase isoform expression and total nitrate concentration (NOx). In IsoP-treated rats, left ventricular mass was increased at day 1 and maintained. Wall thickness was increased with a peak at day 2 and a tendency to return to baseline values at day 7. MBF was markedly increased at day 1 and returned to normal values between days 1 and 2. The rate-pressure product and phosphocreatine/adenosine triphosphate ratio in perfused hearts were reduced. MDA, endothelial NO synthase expression and NOx were increased. Sustained high cardiac function and normal MBF after 24 h of IsoP infusion indicate imbalance between functional demand and blood flow, leading to morphological changes. After 1 week, cardiac hypertrophy and decreased function were associated with impaired phosphocreatine, increased oxidative stress and up-regulation of the NO pathway. These results provide supplemental information on the evolution of the different contributing factors leading to morphological and functional changes in this model of cardiac hypertrophy and failure. © 2014 John Wiley & Sons, Ltd.
Cardiac ketone body metabolism.
The ketone bodies, d-β-hydroxybutyrate and acetoacetate, are soluble 4-carbon compounds derived principally from fatty acids, that can be metabolised by many oxidative tissues, including heart, in carbohydrate-depleted conditions as glucose-sparing energy substrates. They also have important signalling functions, acting through G-protein coupled receptors and histone deacetylases to regulate metabolism and gene expression including that associated with anti-oxidant activity. Their concentration, and hence availability, increases in diabetes mellitus and heart failure. Whilst known to be substrates for ATP production, especially in starvation, their role(s) in the heart, and in heart disease, is uncertain. Recent evidence, reviewed here, indicates that increased ketone body metabolism is a feature of heart failure, and is accompanied by other changes in substrate selection. Whether the change in myocardial ketone body metabolism is adaptive or maladaptive is unknown, but it offers the possibility of using exogenous ketones to treat the failing heart.
Myocardial substrate metabolism in heart disease.
Cardiac disease is commonly associated with changes in energy substrate metabolism. Fatty acid and glucose represent the main fuels used by the heart, and characteristic alterations in substrate preference and utilisation occur early in many cardiac disease processes. Different substrate classes (lipids, carbohydrates) have different metabolic efficiencies, both in terms of energy (ATP) yield and in terms of oxygen requirement; changes in metabolic efficiency may affect, positively and negatively, cardiac function. Furthermore, metabolic diseases alter substrate supply to the heart, which may have an impact on cardiac function. One challenge is to establish whether a primary metabolic abnormality in myocardial fuel utilisation leads to cardiac dysfunction, or whether changes in substrate selection are a consequence of the disease state. The distinction is important as the ability to manipulate cardiac substrate utilisation may offer a therapeutic opportunity for cardiac disease.
Dietary long-chain, but not medium-chain, triglycerides impair exercise performance and uncouple cardiac mitochondria in rats.
Short-term consumption of a high-fat diet impairs exercise capacity in both rats and humans, and increases expression of the mitochondrial uncoupling protein, UCP3, in rodent cardiac and skeletal muscle via activation of the transcription factor, peroxisome proliferator-activated receptor α (PPARα). Unlike long-chain fatty acids however, medium-chain fatty acids do not activate PPARα and do not increase muscle UCP3 expression. We therefore investigated exercise performance and cardiac mitochondrial function in rats fed a chow diet (7.5% kcal from fat), a long-chain triglyceride (LCT) rich diet (46% kcal from LCTs) or a medium-chain triglyceride (MCT) rich diet (46% kcal from MCTs). Rats fed the LCT-rich diet for 15 days ran 55% less far than they did at baseline, whereas rats fed the chow or MCT-rich diets neither improved nor worsened in their exercise capacities. Moreover, consumption of an LCT-rich diet increased cardiac UCP3 expression by 35% and decreased oxidative phosphorylation efficiency, whereas consumption of the MCT-rich diet altered neither UCP3 expression nor oxidative phosphorylation efficiency. Our results suggest that the negative effects of short-term high-fat feeding on exercise performance are predominantly mediated by long-chain rather than medium-chain fatty acids, possibly via PPARα-dependent upregulation of UCP3.
Details of left ventricular remodeling and the mechanism of paradoxical ventricular septal motion after coronary artery bypass graft surgery
Objective: The purpose of this study was to obtain new details of three-dimensional left ventricular wall motion related to ventricular remodeling in patients undergoing coronary artery bypass graft (CABG) surgery. Methods: Cardiac-gated, phase-contrast measurements using navigator-gated, high temporal resolution, tissue phase mapping were obtained on 19 patients (66 ± 7 years old) before and after CABG. Left ventricular motion patterns and myocardial velocities were recorded for radial, circumferential and longitudinal motion. Radial, circumferential and longitudinal velocity curves were obtained separately for 16 ventricular segments. Ventricular torsion rate and longitudinal strain rate were also derived pre-and post-surgery. Results: After CABG, there was a significant improvement in apical contraction, with an apparent paradoxical decrease in the radial inward motion of the septal segments at the left ventricular base. Despite improved ventricular contractility during systole, peak longitudinal and rotational velocities decreased or showed no significant changes. An altered pattern of rotational motion with decreased initial counter-clockwise rotation at the beginning of systole and subsequent lower amplitude of reversed motions in diastole was also noted in most left ventricular segments. Lower peak clockwise rotational velocities were recorded in the basal anteroseptal segment with relatively higher values in the rest of the basal segments. Conclusion: Our results suggest that post-operative changes after CABG are limiting ventricular rotational and longitudinal motions, despite an increase in ventricular contractility due to revascularization. At the ventricular base, the restrained rotational motion of basal anteroseptal segment, located proximally to the right ventricular insertion, and higher rotational velocities of the rest of the segments are pushing the septum toward the right ventricle during ventricular twisting. At the ventricular apex, the restrain in rotational motion caused by post-operative adhesions is affecting all apical segments due to a much smaller left ventricular diameter at this level. The rotating apex and the apical septum are similarly displaced toward the right ventricle during ventricular twisting.
A comparison of visual and quantitative assessment of left ventricular ejection fraction by cardiac magnetic resonance
To determine the accuracy of visual analysis of left ventricular (LV) function in comparison with the accepted quantitative gold standard method, Cardiac Magnetic Resonance (CMR). Cine CMR imaging was performed at 1.5 T on 44 patients with a range of ejection fractions (EF, 5-80%). Clinicians (n = 18) were asked to visually assess EF after sequentially being shown cine images of a four chamber (horizontal long axis; HLA), two chamber (vertical long axis; VLA) and a short axis stack (SAS) and results were compared to a commercially available analysis package. There were strong correlations between visual and quantitative assessment. However, the EF was underestimated in all categories (by 8.4% for HLA, 8.4% for HLA + VLA and 7.9% for HLA + VLA + SAS, P all < 0.01) and particularly underestimated in mild LV impairment (17.4%, P < 0.01), less so for moderate (4.9%) and not for severe impairment (1%). Assessing more than one view of the heart improved visual assessment of LV, EF, however, clinicians underestimated EF by 8.4% on average, with particular inaccuracy in those with mild dysfunction. Given the important clinical information provided by LV assessment, quantitative analysis is recommended for accurate assessment. © 2010 Springer Science+Business Media, B.V.
MR spectroscopy in heart failure.
Magnetic resonance spectroscopy (MRS) is an established technique for the non-invasive assessment of myocardial metabolism. MRS is ideal for the evaluation of heart failure, as it allows quantification of the primary energy source for all myocardial cellular functions (ATP), the energy reserve phosphocreatine (PCr), and the creatine kinase reaction, which maintains cellular energy equilibrium. PCr forms the primary ATP buffer in the cell via the creatine kinase (CK) reaction and is involved in transporting the chemical energy from the ATP-producing mitochondria to the ATP-consuming contractile proteins. Using 31phosphorus (31P) MRS, a low cardiac PCr/ATP has consistently been found in patients with heart failure, supporting the hypothesis that the failing heart is energy starved. The use of 1H MRS has allowed the detection of total creatine, which when combined with 31P MRS, provides an in depth examination of the creatine kinase reaction. MRS signals from 31P, 1H, 23Na and 13C, including novel hyperpolarization techniques, have provided considerable insight into the understanding of energy metabolism in the healthy and diseased heart.
Cardiac peroxisome proliferator-activated receptor-alpha activation causes increased fatty acid oxidation, reducing efficiency and post-ischaemic functional loss.
AIMS: Myocardial fatty acid (FA) oxidation is regulated acutely by the FA supply and chronically at the transcriptional level owing to FA activation of peroxisome proliferator-activated receptor-alpha (PPARalpha). However, in vivo administration of PPARalpha ligands has not been shown to increase cardiac FA oxidation. In this study we have examined the cardiac response to in vivo administration of tetradecylthioacetic acid (TTA, 0.5% w/w added to the diet for 8 days), a PPAR agonist with primarily PPARalpha activity. METHODS AND RESULTS: Despite the fact that TTA treatment decreased plasma concentrations of lipids [FA and triacylglycerols (TG)], hearts from TTA-treated mice showed increased mRNA expression of PPARalpha target genes. Cardiac substrate utilization, ventricular function, cardiac efficiency, and susceptibility to ischaemia-reperfusion were examined in isolated perfused hearts. In accordance with the mRNA changes, myocardial FA oxidation was increased 2.5-fold with a concomitant reduction in glucose oxidation. This increase in FA oxidation was abolished in PPARalpha-null mice. Thus, it appears that the metabolic effects of TTA on the heart must be owing to a direct stimulatory effect on cardiac PPARalpha. Hearts from TTA-treated mice also showed a marked reduction in cardiac efficiency (because of a two-fold increase in unloaded myocardial oxygen consumption) and decreased recovery of ventricular contractile function following low-flow ischaemia. CONCLUSION: This study for the first time observed that in vivo administration of a synthetic PPARalpha ligand elevated FA oxidation, an effect that was also associated with decreased cardiac efficiency and reduced post-ischaemic functional recovery.
VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5.
We have identified an ethylnitrosourea (ENU)-induced recessive mouse mutation (Vcc) with a pleiotropic phenotype that includes cardiac, tracheoesophageal, anorectal, anteroposterior patterning defects, exomphalos, hindlimb hypoplasia, a presacral mass, renal and palatal agenesis, and pulmonary hypoplasia. It results from a C470R mutation in the proprotein convertase PCSK5 (PC5/6). Compound mutants (Pcsk5(Vcc/null)) completely recapitulate the Pcsk5(Vcc/Vcc) phenotype, as does an epiblast-specific conditional deletion of Pcsk5. The C470R mutation ablates a disulfide bond in the P domain, and blocks export from the endoplasmic reticulum and proprotein convertase activity. We show that GDF11 is cleaved and activated by PCSK5A, but not by PCSK5A-C470R, and that Gdf11-deficient embryos, in addition to having anteroposterior patterning defects and renal and palatal agenesis, also have a presacral mass, anorectal malformation, and exomphalos. Pcsk5 mutation results in abnormal expression of several paralogous Hox genes (Hoxa, Hoxc, and Hoxd), and of Mnx1 (Hlxb9). These include known Gdf11 targets, and are necessary for caudal embryo development. We identified nonsynonymous mutations in PCSK5 in patients with VACTERL (vertebral, anorectal, cardiac, tracheoesophageal, renal, limb malformation OMIM 192350) and caudal regression syndrome, the phenotypic features of which resemble the mouse mutation. We propose that Pcsk5, at least in part via GDF11, coordinately regulates caudal Hox paralogs, to control anteroposterior patterning, nephrogenesis, skeletal, and anorectal development.
Ketotherapeutics for neurodegenerative diseases.
Alzheimer's disease (AD) and Parkinson's disease (PD) are, respectively, the most prevalent and fastest growing neurodegenerative diseases worldwide. The former is primarily characterized by memory loss and the latter by the motor symptoms of tremor and bradykinesia. Both AD and PD are progressive diseases that share several key underlying mitochondrial, inflammatory, and other metabolic pathologies. This review will detail how these pathologies intersect with ketone body metabolism and signaling, and how ketone bodies, particularly d-β-hydroxybutyrate (βHB), may serve as a potential adjunctive nutritional therapy for two of the world's most devastating conditions.
Multi-Loop Model of Alzheimer Disease: An Integrated Perspective on the Wnt/GSK3β, α-Synuclein, and Type 3 Diabetes Hypotheses.
As the prevalence of Alzheimer disease (AD) continues to rise unabated, new models have been put forth to improve our understanding of this devastating condition. Although individual models may have their merits, integrated models may prove more valuable. Indeed, the reliable failures of monotherapies for AD, and the ensuing surrender of major drug companies, suggests that an integrated perspective may be necessary if we are to invent multifaceted treatments that could ultimately prove more successful. In this review article, we discuss the Wnt/Glycogen Synthase Kinase 3β (GSK3β), α-synuclein, and type 3 diabetes hypotheses of AD, and their deep interconnection, in order to foster the integrative thinking that may be required to reach a solution for the coming neurological epidemic.
No Evidence of Myocardial Oxygen Deprivation in Nonischemic Heart Failure.
BACKGROUND: Whether the myocardium in nonischemic heart failure experiences oxygen limitation remains a long-standing controversy. We addressed this question in patients with dilated cardiomyopathy (DCM) using a dual approach. First, we tested the changes in myocardial oxygenation between rest and stress states, using oxygenation-sensitive cardiovascular magnetic resonance. Second, we sought to assess the functional consequences of oxygen limitation at rest by measuring myocardial energetics before and after short-term oxygen supplementation. METHODS AND RESULTS: Twenty-six subjects (14 DCM and 12 normal) underwent cardiac magnetic resonance imaging at 3 Tesla to assess cardiac volumes, function, oxygenation, and first-pass perfusion (0.03 mmol/kg Gd-DTPA bolus) at stress and rest (4-6 minutes IV adenosine, 140 μg/kg per minute). Signal intensity change (SIΔ) and myocardial perfusion reserve index (MPRI) were measured from oxygenation and perfusion images, respectively. Furthermore, the effect of oxygen supplementation on resting myocardial energy metabolism was tested using (31)P MR spectroscopy, measuring PCr/ATP ratios in both groups at baseline and after 4 hours of oxygen via facemask in the DCM group. During stress, there were equivalent rises in rate pressure product in both groups (DCM, 76±15% and normal, 79±9%; P=0.84). MPRI was significantly reduced in DCM (1.51±0.11 versus normal 1.86±0.10; P=0.03). However, there was no difference in oxygenation between groups: SIΔ in DCM 17±3% versus normal 20±2% (P=0.38). Furthermore, at a left ventricular segmental level, there was no correlation between oxygenation-sensitive SIΔ and MPRI (R=0.06; P=0.43). Resting PCr/ATP was reduced in DCM (1.66±0.07 versus normal 2.12±0.06; P=0.002). With oxygen supplementation, there was no change in PCr/ATP (1.61±0.08; P=0.58; Δ=0.04±0.05). There was also no effect of oxygen on systolic function (ejection fraction pre oxygen, 34±1%; post oxygen, 36±2%; P=0.46; Δ 2±1%). CONCLUSIONS: Our results demonstrate dissociation between microvascular dysfunction and oxygenation in DCM, suggesting that the impairment of perfusion is not sufficient to cause deoxygenation during stress. Cardiac energetics are unaffected by oxygen supplementation, indicating the absence of relevant myocardial hypoxia at rest. Our study suggests that novel treatments for nonischemic heart failure should focus on efforts to directly target cardiomyocyte function and metabolism rather than oxygen delivery and microvascular function.
Chronic High-Fat Feeding Affects the Mesenchymal Cell Population Expanded From Adipose Tissue but Not Cardiac Atria.
UNLABELLED: Mesenchymal stem cells offer a promising approach to the treatment of myocardial infarction and prevention of heart failure. However, in the clinic, cells will be isolated from patients who may be suffering from comorbidities such as obesity and diabetes, which are known to adversely affect progenitor cells. Here we determined the effect of a high-fat diet (HFD) on mesenchymal stem cells from cardiac and adipose tissues. Mice were fed a HFD for 4 months, after which cardiosphere-derived cells (CDCs) were cultured from atrial tissue and adipose-derived mesenchymal cells (ADMSCs) were isolated from epididymal fat depots. HFD raised body weight, fasted plasma glucose, lactate, and insulin. Ventricle and liver tissue of HFD-fed mice showed protein changes associated with an early type 2 diabetic phenotype. At early passages, more ADMSCs were obtained from HFD-fed mice than from chow-fed mice, whereas CDC number was not affected by HFD. Migratory and clonogenic capacity and release of vascular endothelial growth factor did not differ between cells from HFD- and chow-fed animals. CDCs from chow-fed and HFD-fed mice showed no differences in surface marker expression, whereas ADMSCs from HFD-fed mice contained more cells positive for CD105, DDR2, and CD45, suggesting a high component of endothelial, fibroblast, and hematopoietic cells. Both Noggin and transforming growth factor β-supplemented medium induced an early stage of differentiation in CDCs toward the cardiomyocyte phenotype. Thus, although chronic high-fat feeding increased the number of fibroblasts and hematopoietic cells within the ADMSC population, it left cardiac progenitor cells largely unaffected. SIGNIFICANCE: Mesenchymal cells are a promising candidate cell source for restoring lost tissue and thereby preventing heart failure. In the clinic, cells are isolated from patients who may be suffering from comorbidities such as obesity and diabetes. This study examined the effect of a high-fat diet on mesenchymal cells from cardiac and adipose tissues. It was demonstrated that a high-fat diet did not affect cardiac progenitor cells but increased the number of fibroblasts and hematopoietic cells within the adipose-derived mesenchymal cell population.