Nicotinic acid receptor agonists impair myocardial contractility by energy starvation.

Nicotinic acid receptor agonists have previously been shown to cause acute reductions in cardiac contractility. We sought to uncover the changes in cardiac metabolism underlying these alterations in function. In nine humans, we recorded cardiac energetics and function before and after a single oral dose of nicotinic acid using cardiac MRI to demonstrate contractile function and Phosphorus-31 (31 P) magnetic resonance spectroscopy to demonstrate myocardial energetics. Nicotinic Acid 400 mg lowered ejection fraction by 4% (64 ± 8% to 60 ± 7%, P = .03), and was accompanied by a fall in phosphocreatine/ATP ratio by 0.4 (2.2 ± 0.4 to 1.8 ± 0.1, P = .04). In four groups of eight Wistar rats, we used pyruvate dehydrogenase (PDH) flux studies to demonstrate changes in carbohydrate metabolism induced by the nicotinic acid receptor agonist, Acipimox, using hyperpolarized Carbon-13 (13 C) magnetic resonance spectroscopy. In rats which had been starved overnight, Acipimox caused a fall in ejection fraction by 7.8% (67.5 ± 8.9 to 60 ± 3.1, P = .03) and a nearly threefold rise in flux through PDH (from 0.182 ± 0.114 to 0.486 ± 0.139, P = .002), though this rise did not match pyruvate dehydrogenase flux observed in rats fed carbohydrate rich chow (0.726 ± 0.201). In fed rats, Acipimox decreased pyruvate dehydrogenase flux (to 0.512 ± 0.13, P = .04). Concentration of plasma insulin fell by two-thirds in fed rats administered Acipimox (from 1695 ± 891 ng/L to 550 ± 222 ng/L, P = .005) in spite of glucose concentrations remaining the same. In conclusion, we demonstrate that nicotinic acid receptor agonists impair cardiac contractility associated with a decline in cardiac energetics and show that the mechanism is likely a combination of reduced fatty acid availability and a failure to upregulate carbohydrate metabolism, essentially starving the heart of fuel.

Late Peripheral Thoracic Aneurysms following Aortic Root Surgery in Patients with Loeys-Dietz Syndrome.

The Loeys-Dietz syndrome is a multisystem connective tissue disorder characterized by aortopathy, arterial tortuosity, peripheral aneurysms, and skeletal features. The peripheral arteriopathy is an important cause of morbidity and potential mortality. This report presents 2 cases: the first demonstrating a 5-cm pseudoaneurysm of the right internal mammary artery and the second demonstrating a 2.3-cm aneurysm of the left internal mammary artery, each following aortic root surgery. These were successfully treated with percutaneous techniques. No complications were seen at follow-up as long as 2 years. Patients with Loeys-Dietzs syndrome require comprehensive long-term vascular follow-up and are likely to require percutaneous vascular interventions.

Regulation of human metabolism by hypoxia-inducible factor.

The hypoxia-inducible factor (HIF) family of transcription factors directs a coordinated cellular response to hypoxia that includes the transcriptional regulation of a number of metabolic enzymes. Chuvash polycythemia (CP) is an autosomal recessive human disorder in which the regulatory degradation of HIF is impaired, resulting in elevated levels of HIF at normal oxygen tensions. Apart from the polycythemia, CP patients have marked abnormalities of cardiopulmonary function. No studies of integrated metabolic function have been reported. Here we describe the response of these patients to a series of metabolic stresses: exercise of a large muscle mass on a cycle ergometer, exercise of a small muscle mass (calf muscle) which allowed noninvasive in vivo assessments of muscle metabolism using (31)P magnetic resonance spectroscopy, and a standard meal tolerance test. During exercise, CP patients had early and marked phosphocreatine depletion and acidosis in skeletal muscle, greater accumulation of lactate in blood, and reduced maximum exercise capacities. Muscle biopsy specimens from CP patients showed elevated levels of transcript for pyruvate dehydrogenase kinase, phosphofructokinase, and muscle pyruvate kinase. In cell culture, a range of experimental manipulations have been used to study the effects of HIF on cellular metabolism. However, these approaches provide no potential to investigate integrated responses at the level of the whole organism. Although CP is relatively subtle disorder, our study now reveals a striking regulatory role for HIF on metabolism during exercise in humans. These findings have significant implications for the development of therapeutic approaches targeting the HIF pathway.

Accelerating 3D MTC-BOOST in patients with congenital heart disease using a joint multi-scale variational neural network reconstruction.

PURPOSE: Free-breathing Magnetization Transfer Contrast Bright blOOd phase SensiTive (MTC-BOOST) is a prototype balanced-Steady-State Free Precession sequence for 3D whole-heart imaging, that employs the endogenous magnetisation transfer contrast mechanism. This achieves reduction of flow and off-resonance artefacts, that often arise with the clinical T2prepared balanced-Steady-State Free Precession sequence, enabling high quality, contrast-agent free imaging of the thoracic cardiovascular anatomy. Fully-sampled MTC-BOOST acquisition requires long scan times (~10-24 min) and therefore acceleration is needed to permit its clinical incorporation. The aim of this study is to enable and clinically validate the 5-fold accelerated MTC-BOOST acquisition with joint Multi-Scale Variational Neural Network (jMS-VNN) reconstruction. METHODS: Thirty-six patients underwent free-breathing, 3D whole-heart imaging with the MTC-BOOST sequence, which is combined with variable density spiral-like Cartesian sampling and 2D image navigators for translational motion estimation. This sequence acquires two differently weighted bright-blood volumes in an interleaved fashion, which are then joined in a phase sensitive inversion recovery reconstruction to obtain a complementary fully co-registered black-blood volume. Data from eighteen patients were used for training, whereas data from the remaining eighteen patients were used for testing/evaluation. The proposed deep-learning based approach adopts a supervised multi-scale variational neural network for joint reconstruction of the two differently weighted bright-blood volumes acquired with the 5-fold accelerated MTC-BOOST. The two contrast images are stacked as different channels in the network to exploit the shared information. The proposed approach is compared to the fully-sampled MTC-BOOST and 5-fold undersampled MTC-BOOST acquisition with Compressed Sensing (CS) reconstruction in terms of scan/reconstruction time and bright-blood image quality. Comparison against conventional 2-fold undersampled T2-prepared 3D bright-blood whole-heart clinical sequence (T2prep-3DWH) is also included. RESULTS: Acquisition time was 3.0 ±â€¯1.0 min for the 5-fold accelerated MTC-BOOST versus 9.0 ±â€¯1.1 min for the fully-sampled MTC-BOOST and 11.1 ±â€¯2.6 min for the T2prep-3DWH (p < 0.001 and p < 0.001, respectively). Reconstruction time was significantly lower with the jMS-VNN method compared to CS (10 ±â€¯0.5 min vs 20 ±â€¯2 s, p < 0.001). Image quality was higher for the proposed 5-fold undersampled jMS-VNN versus conventional CS, comparable or higher to the corresponding T2prep-3DWH dataset and similar to the fully-sampled MTC-BOOST. CONCLUSION: The proposed 5-fold accelerated jMS-VNN MTC-BOOST framework provides efficient 3D whole-heart bright-blood imaging in fast acquisition and reconstruction time with concomitant reduction of flow and off-resonance artefacts, that are frequently encountered with the clinical sequence. Image quality of the cardiac anatomy and thoracic vasculature is comparable or superior to the clinical scan and 5-fold CS reconstruction in faster reconstruction time, promising potential clinical adoption.

Under Pressure: Post-Transplant Lymphoproliferative Disease: A Case of Pulmonary Artery External Compression.

Post-transplant lymphoproliferative disorder (PTLD) is an often fatal complication of cardiac transplantation that occurs in 2% to 6% of transplant recipients. We report a case in which PTLD led to pulmonary artery external compression and multimodality imaging showed key features in the diagnosis, management, and follow-up. (Level of Difficulty: Intermediate.).

European reference network for rare vascular diseases (VASCERN) consensus statement for the screening and management of patients with pathogenic ACTA2 variants.

The ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic aneurysm and/or dissection is the main clinical manifestation, a variety of occlusive vascular disease and extravascular manifestations occur in ACTA2-related vasculopathy. Current data suggest possible mutation-specific manifestations of vascular and extra-aortic traits.Despite its relatively high prevalence, comprehensive recommendations on the care of patients and families with pathogenic variants in ACTA2 have not yet been established. We aimed to develop a consensus document to provide medical guidance for health care professionals involved in the diagnosis and treatment of patients and relatives with pathogenic variants in ACTA2.The HTAD Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) convened to review current literature and discuss expert opinions on clinical management of ACTA2 related vasculopathy. This consensus statement summarizes our recommendations on diagnosis, monitoring, treatment, pregnancy, genetic counselling and testing in patients with ACTA2-related vasculopathy. However, there is a clear need for additional prospective multicenter studies to further define proper guidelines.

Process of Transition for Congenital Heart Patients: Preventing Loss to Follow-up.

PURPOSE: The aim of this article is to provide an overview of our nurse-led transition clinic provided to congenital heart disease patients moving from pediatric into adult care setting. DESCRIPTION OF THE SERVICE: Nurse-led transition clinic was analyzed at various stages of young adult care from an early stage of 12 to 14 years to entering adult setting at 16 years or older. METHODS: Overview of current transition service for young adults being transferred from pediatric into adult services highlights the integral role of clinical nurse specialist as a coordinator of care. RESULTS: The result of the service overview indicates that nurse-led transition service enables patients to build on their knowledge. This is achieved by providing them time and the opportunities to develop an understanding of their condition and the attitudes required to engage with the adult care setting as indicated in the psychology questionnaire from transition day. CONCLUSION: A nurse-led transition clinic enhances long-term care of patients by supporting the young adults and their family/carer through the transition and transfer of the care to promote the young adult's understanding of their condition and to prevent any lost to follow-up.

Exercise-Induced Systemic Venous Hypertension in the Fontan Circulation.

Increasingly end-organ injury is being demonstrated late after institution of the Fontan circulation, particularly liver fibrosis and cirrhosis. The exact mechanisms for these late phenomena remain largely elusive. Hypothesizing that exercise induces precipitous systemic venous hypertension and insufficient cardiac output for the exercise demand, that is, a possible mechanism for end-organ injury, we sought to demonstrate the dynamic exercise responses in systemic venous perfusion (SVP) and concurrent end-organ perfusion. Ten stable Fontan patients and 9 control subjects underwent incremental cycle ergometry-based cardiopulmonary exercise testing. SVP was monitored in the right upper limb, and regional tissue oxygen saturation was monitored in the brain and kidney using near-infrared spectroscopy. SVP rose profoundly in concert with workload in the Fontan group, described by the regression equation 15.97 + 0.073 watts per mm Hg. In contrast, SVP did not change in healthy controls. Regional renal (p <0.01) and cerebral tissue saturations (p <0.001) were significantly lower and decrease more rapidly in Fontan patients. We conclude that in a stable group of adult patients with Fontan circulation, high-intensity exercise was associated with systemic venous hypertension and reduced systemic oxygen delivery. This physiological substrate has the potential to contribute to end-organ injury.

Human hippocampal energy metabolism is impaired during cognitive activity in a lipid infusion model of insulin resistance.

Neuronal glucose uptake was thought to be independent of insulin, being facilitated by glucose transporters GLUT1 and GLUT3, which do not require insulin signaling. However, it is now known that components of the insulin-mediated glucose uptake pathway, including neuronal insulin synthesis and the insulin-dependent glucose transporter GLUT4, are present in brain tissue, particularly in the hippocampus. There is considerable recent evidence that insulin signaling is crucial to optimal hippocampal function. The physiological basis, however, is not clear. We propose that while noninsulin-dependent GLUT1 and GLUT3 transport is adequate for resting needs, the surge in energy use during sustained cognitive activity requires the additional induction of insulin-signaled GLUT4 transport. We studied hippocampal high-energy phosphate metabolism in eight healthy volunteers, using a lipid infusion protocol to inhibit insulin signaling. Contrary to conventional wisdom, it is now known that free fatty acids do cross the blood-brain barrier in significant amounts. Energy metabolism within the hippocampus was assessed during standardized cognitive activity. (31)Phosphorus magnetic resonance spectroscopy was used to determine the phosphocreatine (PCr)-to-adenosine triphosphate (ATP) ratio. This ratio reflects cellular energy production in relation to concurrent cellular energy expenditure. With lipid infusion, the ratio was significantly reduced during cognitive activity (PCr/ATP 1.0 ± 0.4 compared with 1.4 ± 0.4 before infusion, P = 0.01). Without lipid infusion, there was no reduction in the ratio during cognitive activity (PCr/ATP 1.5 ± 0.3 compared with 1.4 ± 0.4, P = 0.57). This provides supporting evidence for a physiological role for insulin signaling in facilitating increased neuronal glucose uptake during sustained cognitive activity. Loss of this response, as may occur in type 2 diabetes, would lead to insufficient neuronal energy availability during cognitive activity.

Increasing plasma free fatty acids in healthy subjects induces aortic distensibility changes seen in obesity.

BACKGROUND: Elevated free fatty acid (FFA) levels are known to impair aortic elastic function. In obesity, FFA levels are elevated and aortic distensibility (AD) reduced in a pattern that predominantly affects the distal aorta. Despite this, the role of FFAs in obesity-related aortic stiffness remains unclear. METHODS AND RESULTS: Using vascular MRI, we aimed to determine if (1) FFA level correlated with AD in obesity; and (2) whether elevating FFA acutely and subacutely in normal-weight subjects reproduced the distal pattern of AD change in obesity. To do this, regional AD was recorded in 35 normal-weight and 70 obese subjects and then correlated with FFA levels. When compared with normal weight, obesity was associated with reduced AD in a pattern predominantly affecting the distal aorta (ascending aorta by -22%, proximal descending aorta by -25%, and abdominal aorta by -35%; P<0.001). After controlling for age, blood pressure, and body mass index, FFA levels remained negatively correlated with abdominal AD (r=-0.43, P<0.01). In 2 further normal-weight groups, AD was recorded before and after elevation of FFA levels with intralipid infusion (by +535%, n=9) and a 5-day high-fat, low-carbohydrate diet (by +48%, n=14). CONCLUSIONS: Both intralipid infusion and a low-carbohydrate diet resulted in reduced abdominal AD (infusion -22%, diet -28%; both P<0.05), reproducing the distal pattern AD reduction seen in obesity. These findings suggest that elevated FFA impair AD in obesity and provide a potential therapeutic target to improve aortic elastic function in obesity.

Changes in cardiac substrate transporters and metabolic proteins mirror the metabolic shift in patients with aortic stenosis.

In the hypertrophied human heart, fatty acid metabolism is decreased and glucose utilisation is increased. We hypothesized that the sarcolemmal and mitochondrial proteins involved in these key metabolic pathways would mirror these changes, providing a mechanism to account for the modified metabolic flux measured in the human heart. Echocardiography was performed to assess in vivo hypertrophy and aortic valve impairment in patients with aortic stenosis (n = 18). Cardiac biopsies were obtained during valve replacement surgery, and used for western blotting to measure metabolic protein levels. Protein levels of the predominant fatty acid transporter, fatty acid translocase (FAT/CD36) correlated negatively with levels of the glucose transporters, GLUT1 and GLUT4. The decrease in FAT/CD36 was accompanied by decreases in the fatty acid binding proteins, FABPpm and H-FABP, the ß-oxidation protein medium chain acyl-coenzyme A dehydrogenase, the Krebs cycle protein α-ketoglutarate dehydrogenase and the oxidative phosphorylation protein ATP synthase. FAT/CD36 and complex I of the electron transport chain were downregulated, whereas the glucose transporter GLUT4 was upregulated with increasing left ventricular mass index, a measure of cardiac hypertrophy. In conclusion, coordinated downregulation of sequential steps involved in fatty acid and oxidative metabolism occur in the human heart, accompanied by upregulation of the glucose transporters. The profile of the substrate transporters and metabolic proteins mirror the metabolic shift from fatty acid to glucose utilisation that occurs in vivo in the human heart.

A high-fat diet impairs cardiac high-energy phosphate metabolism and cognitive function in healthy human subjects.

BACKGROUND: High-fat, low-carbohydrate diets are widely used for weight reduction, but they may also have detrimental effects via increased circulating free fatty acid concentrations. OBJECTIVE: We tested whether raising plasma free fatty acids by using a high-fat, low-carbohydrate diet results in alterations in heart and brain in healthy subjects. DESIGN: Men (n = 16) aged 22 ± 1 y (mean ± SE) were randomly assigned to 5 d of a high-fat, low-carbohydrate diet containing 75 ± 1% of calorie intake through fat consumption or to an isocaloric standard diet providing 23 ± 1% of calorie intake as fat. In a crossover design, subjects undertook the alternate diet after a 2-wk washout period, with results compared after the diet periods. Cardiac (31)P magnetic resonance (MR) spectroscopy and MR imaging, echocardiography, and computerized cognitive tests were used to assess cardiac phosphocreatine (PCr)/ATP, cardiac function, and cognitive function, respectively. RESULTS: Compared with the standard diet, subjects who consumed the high-fat, low-carbohydrate diet had 44% higher plasma free fatty acids (P < 0.05), 9% lower cardiac PCr/ATP (P < 0.01), and no change in cardiac function. Cognitive tests showed impaired attention (P < 0.01), speed (P < 0.001), and mood (P < 0.01) after the high-fat, low-carbohydrate diet. CONCLUSION: Raising plasma free fatty acids decreased myocardial PCr/ATP and reduced cognition, which suggests that a high-fat diet is detrimental to heart and brain in healthy subjects.

(31)P cardiac magnetic resonance spectroscopy during leg exercise at 3 Tesla.

Investigation of phosphorus ((31)P) magnetic resonance spectroscopy under stress conditions provides a non-invasive tool to examine alterations in cardiac high-energy phosphate metabolism that may not be evident at rest. Our aim was to establish cardiac (31)P MR spectroscopy during leg exercise at 3T. The increased field strength should provide a higher signal to noise ratio than at lower field strengths. Furthermore, relatively high temporal resolution at a sufficiently fine spatial resolution should be feasible. (31)P MR spectra were obtained with a 3D acquisition weighted chemical shift imaging sequence in 20 healthy volunteers at rest, during dynamic physiological leg exercise and after recovery at 3T. Haemodynamic measurements were made throughout and the rate pressure product calculated. With exercise, the mean heart rate increased by 73%, achieving a mean increase in rate pressure product of 115%. The corrected PCr/ATP ratio for subjects at rest was 2.02 +/- 0.43, exercise 2.14 +/- 0.67 (P = 0.54 vs. rest) and at recovery 2.03 +/- 0.52 (P = 0.91 vs. rest, P = 0.62 vs. exercise). A cardiac (31)P MR spectroscopy physiological exercise-recovery protocol is feasible at 3T. There was no significant change in high-energy cardiac phosphate metabolite concentrations in healthy volunteers at rest, during physiological leg exercise or during recovery. When applied to patients with heart disease, this protocol should provide insights into physiological and pathological cardiac metabolism.