Cameron Holloway

Myocardial Tissue Characterization Using Magnetic Resonance Noncontrast T1 Mapping in Hypertrophic and Dilated Cardiomyopathy

Background—Noncontrast magnetic resonance T1 mapping reflects a composite of both intra- and extracellular signal. We hypothesized that noncontrast T1 mapping can characterize the myocardium beyond that achieved by the well-established late gadolinium enhancement (LGE) technique (which detects focal fibrosis) in both hypertrophic (HCM) and dilated (DCM) cardiomyopathy, by detecting both diffuse and focal fibrosis. Methods and Results—Subjects underwent Cardiovascular Magnetic Resonance imaging at 3T (28 HCM, 18 DCM, and 12 normals). Matching short-axis slices were acquired for cine, T1 mapping, and LGE imaging (0.1 mmol/kg). Circumferential strain was measured in the midventricular slice, and 31P magnetic resonance spectroscopy was acquired for the septum of the midventricular slice. Mean T1 relaxation time was increased in HCM and DCM (HCM 1209±28 ms, DCM 1225±42 ms, normal 1178±13 ms, P<0.05). There was a weak correlation between mean T1 and LGE (r=0.32, P<0.001). T1 values were higher in segments with LGE than in those without (HCM with LGE 1228±41 ms versus no LGE 1192±79 ms, P<0.01; DCM with LGE 1254±73 ms versus no LGE 1217±52 ms, P<0.01). However, in both HCM and DCM, even in segments unaffected by LGE, T1 values were significantly higher than normal (P<0.01). T1 values correlated with disease severity, being increased as wall thickness increased in HCM; conversely, in DCM, T1 values were highest in the thinnest myocardial segments. T1 values also correlated significantly with circumferential strain (r=0.42, P<0.01). Interestingly, this correlation remained statistically significant even for the slices without LGE (r=0.56, P=0.04). Finally, there was also a statistically significant negative correlation between T1 values and phosphocreatine/adenosine triphosphate ratios (r=−0.59, P<0.0001). Conclusions—In HCM and DCM, noncontrast T1 mapping detects underlying disease processes beyond those assessed by LGE in relatively low-risk individuals.

How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines

Given that cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development, adverse drug reactions, and post‐approval withdrawal of medicines, the Medical Research Council Centre for Drug Safety Science hosted a workshop to discuss current challenges in determining, understanding and addressing ‘Cardiovascular Toxicity of Medicines’. This article summarizes the key discussions from the workshop that aimed to address three major questions: (i) what are the key cardiovascular safety liabilities in drug discovery, drug development and clinical practice? (ii) how good are preclinical and clinical strategies for detecting cardiovascular liabilities? and (iii) do we have a mechanistic understanding of these liabilities? It was concluded that in order to understand, address and ultimately reduce cardiovascular safety liabilities of new therapeutic agents there is an urgent need to:

Normal variation of magnetic resonance T1 relaxation times in the human population at 1.5 T using ShMOLLI

BackgroundQuantitative T1-mapping is rapidly becoming a clinical tool in cardiovascular magnetic resonance (CMR) to objectively distinguish normal from diseased myocardium. The usefulness of any quantitative technique to identify disease lies in its ability to detect significant differences from an established range of normal values. We aimed to assess the variability of myocardial T1 relaxation times in the normal human population estimated with recently proposed Shortened Modified Look-Locker Inversion recovery (ShMOLLI) T1 mapping technique.MethodsA large cohort of healthy volunteers (n = 342, 50% females, age 11–69 years) from 3 clinical centres across two countries underwent CMR at 1.5T. Each examination provided a single average myocardial ShMOLLI T1 estimate using manually drawn myocardial contours on typically 3 short axis slices (average 3.4 ± 1.4), taking care not to include any blood pool in the myocardial contours. We established the normal reference range of myocardial and blood T1 values, and assessed the effect of potential confounding factors, including artefacts, partial volume, repeated measurements, age, gender, body size, hematocrit and heart rate.ResultsNative myocardial ShMOLLI T1 was 962 ± 25 ms. We identify the partial volume as primary source of potential error in the analysis of respective T1 maps and use 1 pixel erosion to represent “midwall myocardial” T1, resulting in a 0.9% decrease to 953 ± 23 ms. Midwall myocardial ShMOLLI T1 was reproducible with an intra-individual, intra- and inter-scanner variability of ≤2%. The principle biological parameter influencing myocardial ShMOLLI T1 was the female gender, with female T1 longer by 24 ms up to the age of 45 years, after which there was no significant difference from males. After correction for age and gender dependencies, heart rate was the only other physiologic factor with a small effect on myocardial ShMOLLI T1 (6ms/10bpm). Left and right ventricular blood ShMOLLI T1 correlated strongly with each other and also with myocardial T1 with the slope of 0.1 that is justifiable by the resting partition of blood volume in myocardial tissue. Overall, the effect of all variables on myocardial ShMOLLI T1 was within 2% of relative changes from the average.ConclusionNative T1-mapping using ShMOLLI generates reproducible and consistent results in normal individuals within 2% of relative changes from the average, well below the effects of most acute forms of myocardial disease. The main potential confounder is the partial volume effect arising from over-inclusion of neighbouring tissue at the manual stages of image analysis. In the study of cardiac conditions such as diffuse fibrosis or small focal changes, the use of “myocardial midwall” T1, age and gender matching, and compensation for heart rate differences may all help to improve the method sensitivity in detecting subtle changes. As the accuracy of current T1 measurement methods remains to be established, this study does not claim to report an accurate measure of T1, but that ShMOLLI is a stable and reproducible method for T1-mapping.

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.

Comprehensive Cardiac Magnetic Resonance Imaging and Spectroscopy Reveal a High Burden of Myocardial Disease in HIV Patients

Background— HIV infection continues to be endemic worldwide. Although treatments are successful, it remains controversial whether patients receiving optimal therapy have structural, functional, or biochemical cardiac abnormalities that may underlie their increased cardiac morbidity and mortality. The purpose of this study was to characterize myocardial abnormalities in a contemporary group of HIV-infected individuals undergoing combination antiretroviral therapy. Methods and Results— Volunteers with HIV who were undergoing combination antiretroviral therapy and age-matched control subjects without a history of cardiovascular disease underwent cardiac magnetic resonance imaging and spectroscopy for the determination of cardiac function, myocardial fibrosis, and myocardial lipid content. A total of 129 participants were included in this analysis. Compared with age-matched control subjects (n=39; 30.23%), HIV-infected subjects undergoing combination antiretroviral therapy (n=90; 69.77%) had 47% higher median myocardial lipid levels (P <0.003) and 74% higher median plasma triglyceride levels (both P<0.001). Myocardial fibrosis, predominantly in the basal inferolateral wall of the left ventricle, was observed in 76% of HIV-infected subjects compared with 13% of control subjects (P<0.001). Peak myocardial systolic and diastolic longitudinal strain were also lower in HIV-infected individuals than in control subjects and remained statistically significant after adjustment for available confounders. Conclusions— Comprehensive cardiac imaging revealed cardiac steatosis, alterations in cardiac function, and a high prevalence of myocardial fibrosis in a contemporary group of asymptomatic HIV-infected subjects undergoing combination antiretroviral therapy. Cardiac steatosis and fibrosis may underlie cardiac dysfunction and increased cardiovascular morbidity and mortality in subjects with HIV.

Effects of Catecholamine Stress on Diastolic Function and Myocardial Energetics in Obesity

Background— Obesity is characterized by impaired cardiac energetics, which may play a role in the development of diastolic dysfunction and inappropriate shortness of breath. We assessed whether, in obesity, derangement of energetics and diastolic function is further altered during acute cardiac stress. Methods and Results— Normal-weight (body mass index, 22±2 kg/m2; n=9–17) and obese (body mass index, 39±7 kg/m2; n=17–46) subjects underwent assessment of diastolic left ventricular function (cine magnetic resonance imaging volume-time curve analysis) and cardiac energetics (phosphocreatine/ATP ratio; 31P-magnetic resonance spectroscopy) at rest and during dobutamine stress (heart rate increase, 65±22% and 69±14%, respectively; P=0.61). At rest, obesity was associated with a 22% lower peak filling rate (P<0.001) and a 15% lower phosphocreatine/ATP ratio (1.73±0.40 versus 2.03±0.28; P=0.048). Peak filling rate correlated with fat mass, left ventricular mass, leptin, waist-to-hip ratio, and phosphocreatine/ATP ratio. On multivariable analysis, phosphocreatine/ATP was the only independent predictor of peak filling rate (&bgr;=0.50; P=0.03). During stress, a further reduction in phosphocreatine/ATP occurred in obese (from 1.73±0.40 to 1.53±0.50; P=0.03) but not in normal-weight (from 1.98±0.24 to 2.04±0.34; P=0.50) subject. For similar levels of inotropic stress, there were smaller increases in peak filling rate in obesity (38% versus 70%; P=0.01). Conclusions— In obesity, cardiac energetics are further deranged during inotropic stress, in association with continued diastolic dysfunction. Myocardial energetics may play a key role in the impairment of diastolic function in obesity.

Cardiac response to hypobaric hypoxia: persistent changes in cardiac mass, function, and energy metabolism after a trek to Mt. Everest Base Camp

We postulated that changes in cardiac high‐energy phosphate metabolism may underlie the myocardial dysfunction caused by hypobaric hypoxia. Healthy volunteers (n=14) were studied immediately before, and within 4 d of return from, a 17‐d trek to Mt. Everest Base Camp (5300 m). 31P magnetic resonance (MR) spectroscopy was used to measure cardiac phosphocreatine (PCr)/ATP, and MR imaging and echocardiography were used to assess cardiac volumes, mass, and function. Immediately after returning from Mt. Everest, total body weight had fallen by 3% (P<0.05), but left ventricular mass, adjusted for changes in body surface area, had disproportionately decreased by 11% (P<0.05). Alterations in diastolic function were also observed, with a reduction in peak left ventricular filling rates and mitral inflow E/A, by 17% (P<0.05) and 24% (P<0.01), respectively, with no change in hydration status. Compared with pretrek, cardiac PCr/ATP ratio had decreased by 18% (P<0.01). Whether the abnormalities were even greater at altitude is unknown, but all had returned to pretrek levels after 6 mo. The alterations in cardiac morphology, function, and energetics are similar to findings in patients with chronic hypoxia. Thus, a decrease in cardiac PCr/ATP may be a universal response to periods of sustained low oxygen availability, underlying hypoxia‐induced cardiac dysfunction in healthy human heart and in patients with cardiopulmonary diseases.—Holloway, C. J., Montgomery, H. U., Murray, A. J., Cochlin, L. E., Codreanu, I. Hopwood, N., Johnson, A. W., Rider, O. J., Levett, D. Z. H., Tyler, D. J., Francis, J. M., Neubauer, S., Grocott, M. P. W., Clarke, K., for the Caudwell Xtreme Everest Research Group. Cardiac response to hypobaric hypoxia: persistent changes in cardiac mass, function, and energy metabolism after a trek to Mt. Everest Base Camp. FASEB J. 25, 792–796 (2011). www.fasebj.org

The Effect of High-Altitude on Human Skeletal Muscle Energetics: 31P-MRS Results from the Caudwell Xtreme Everest Expedition

Many disease states are associated with regional or systemic hypoxia. The study of healthy individuals exposed to high-altitude hypoxia offers a way to explore hypoxic adaptation without the confounding effects of disease and therapeutic interventions. Using 31P magnetic resonance spectroscopy and imaging, we investigated skeletal muscle energetics and morphology after exposure to hypobaric hypoxia in seven altitude-naïve subjects (trekkers) and seven experienced climbers. The trekkers ascended to 5300 m while the climbers ascended above 7950 m. Before the study, climbers had better mitochondrial function (evidenced by shorter phosphocreatine recovery halftime) than trekkers: 16±1 vs. 22±2 s (mean ± SE, p<0.01). Climbers had higher resting [Pi] than trekkers before the expedition and resting [Pi] was raised across both groups on their return (PRE: 2.6±0.2 vs. POST: 3.0±0.2 mM, p<0.05). There was significant muscle atrophy post-CXE (PRE: 4.7±0.2 vs. POST: 4.5±0.2 cm2, p<0.05), yet exercising metabolites were unchanged. These results suggest that, in response to high altitude hypoxia, skeletal muscle function is maintained in humans, despite significant atrophy.

Short-term consumption of a high-fat diet impairs whole-body efficiency and cognitive function in sedentary men

We recently showed that a short‐term high‐fat diet blunted exercise performance in rats, accompanied by increased uncoupling protein levels and greater respiratory uncoupling. In this study, we investigated the effects of a similar diet on physical and cognitive performance in humans. Twenty sedentary men were assessed when consuming a standardized, nutritionally balanced diet (control) and after7dof consuming a diet comprising 74% kcal from fat. Efficiency was measured during a standardized exercise task, and cognition was assessed using a computerized assessment battery. Skeletal muscle mitochondrial function was measured using 31P magnetic resonance spectroscopy. The diet increased mean ± se plasma free fatty acids by 44% (0.32±0.03 vs. 0.46±0.05 mM; P<0.05) and decreased whole‐body efficiency by 3% (21±1 vs. 18±1%;P<0.05), although muscle uncoupling protein (UCP3) content and maximal mitochondrial function were unchanged. High‐fat diet consumption also increased subjects’ simple reaction times (P<0.01) and decreased power of attention (P<0.01). Thus, we have shown that a high‐fat diet blunts whole‐body efficiency and cognition in sedentary men. We suggest that this effect may be due to increased respiratory uncoupling.—Edwards, L. M., Murray, A. J., Holloway, C. J., Carter, E. E., Kemp, G. J., Codreanu, I., Brooker, H., Tyler, D. J. Tyler, Robbins, P. A., Clarke, K. Short‐term consumption of a high‐fat diet impairs whole‐body efficiency and cognitive function in sedentary men. FASEB J. 25, 1088–1096 (2011). www.fasebj.org

Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes

Ketosis, the metabolic response to energy crisis, is a mechanism to sustain life by altering oxidative fuel selection. Often overlooked for its metabolic potential, ketosis is poorly understood outside of starvation or diabetic crisis. Thus, we studied the biochemical advantages of ketosis in humans using a ketone ester-based form of nutrition without the unwanted milieu of endogenous ketone body production by caloric or carbohydrate restriction. In five separate studies of 39 high-performance athletes, we show how this unique metabolic state improves physical endurance by altering fuel competition for oxidative respiration. Ketosis decreased muscle glycolysis and plasma lactate concentrations, while providing an alternative substrate for oxidative phosphorylation. Ketosis increased intramuscular triacylglycerol oxidation during exercise, even in the presence of normal muscle glycogen, co-ingested carbohydrate and elevated insulin. These findings may hold clues to greater human potential and a better understanding of fuel metabolism in health and disease.