Cost-Effectiveness of Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation in the Australian Health Care System.

BACKGROUND: Heart transplantation is an effective treatment for end-stage congestive heart failure, however, achieving the right balance of immunosuppression to maintain graft function while minimising adverse effects is challenging. Serial endomyocardial biopsies (EMBs) are currently the standard for rejection surveillance, despite being invasive. Replacing EMB-based surveillance with cardiac magnetic resonance (CMR)-based surveillance for acute cardiac allograft rejection has shown feasibility. This study aimed to assess the cost-effectiveness of CMR-based surveillance in the first year after heart transplantation. METHOD: A prospective clinical trial was conducted with 40 orthotopic heart transplant (OHT) recipients. Participants were randomly allocated into two surveillance groups: EMB-based, and CMR-based. The trial included economic evaluations, comparing the frequency and cost of surveillance modalities in relation to quality-adjusted life years (QALYs) within the first year post-transplantation. Sensitivity analysis encompassed modelled data from observed EMB and CMR arms, integrating two hypothetical models of expedited CMR-based surveillance. RESULTS: In the CMR cohort, 238 CMR scans and 15 EMBs were conducted, versus (vs) 235 EMBs in the EMB group. CMR surveillance yielded comparable rejection rates (CMR 74 vs EMB 94 events, p=0.10) and did not increase hospitalisation risk (CMR 32 vs EMB 46 events, p=0.031). It significantly reduced the necessity for invasive EMBs by 94%, lowered costs by an average of AUD$32,878.61, and enhanced cumulative QALY by 0.588 compared with EMB. Sensitivity analysis showed that increased surveillance with expedited CMR Models 1 and 2 were more cost-effective than EMB (all p<0.01), with CMR Model 1 achieving the greatest cost savings (AUD$34,091.12±AUD$23,271.86 less) and utility increase (+0.62±1.49 QALYs, p=0.011), signifying an optimal cost-utility ratio. Model 2 showed comparable utility to the base CMR model (p=0.900) while offering the benefit of heightened surveillance frequency during periods of elevated rejection risk. CONCLUSIONS: CMR-based rejection surveillance in orthotopic heart transplant recipients provides a cost-effective alternative to EMB-based surveillance. Furthermore, it reduces the need for invasive procedures, without increased risk of rejection or hospitalisation for patients, and can be incorporated economically for expedited surveillance. These findings have important implications for improving patient care and optimising resource allocation in post-transplant management.

Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation.

BACKGROUND: Endomyocardial biopsy (EMB) is the gold standard method for surveillance of acute cardiac allograft rejection (ACAR) despite its invasive nature. Cardiovascular magnetic resonance (CMR)-based myocardial tissue characterization allows detection of myocarditis. The feasibility of CMR-based surveillance for ACAR-induced myocarditis in the first year after heart transplantation is currently undescribed. METHODS: CMR-based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between CMR- and EMB-based ACAR and to determine CMR cutoff values between rejection grades. A prospective randomized noninferiority pilot study was then undertaken in adult orthotopic heart transplant recipients who were randomized at 4 weeks after orthotopic heart transplantation to either CMR- or EMB-based rejection surveillance. Clinical end points were assessed at 52 weeks. RESULTS: Four hundred one CMR studies and 354 EMB procedures were performed in 106 participants. Forty heart transplant recipients were randomized. CMR-based multiparametric assessment was highly reproducible and reliable at detecting ACAR (area under the curve, 0.92; sensitivity, 93%; specificity, 92%; negative predictive value, 99%) with greater specificity and negative predictive value than either T1 or T2 parametric CMR mapping alone. High-grade rejection occurred in similar numbers of patients in each randomized group (CMR, n=7; EMB, n=8; P=0.74). Despite similarities in immunosuppression requirements, kidney function, and mortality between groups, the rates of hospitalization (9 of 20 [45%] versus 18 of 20 [90%]; odds ratio, 0.091; P=0.006) and infection (7 of 20 [35%] versus 14 of 20 [70%]; odds ratio, 0.192; P=0,019) were lower in the CMR group. On 15 occasions (6%), patients who were randomized to the CMR arm underwent EMB for clarification or logistic reasons, representing a 94% reduction in the requirement for EMB-based surveillance. CONCLUSIONS: A noninvasive CMR-based surveillance strategy for ACAR in the first year after orthotopic heart transplantation is feasible compared with EMB-based surveillance. REGISTRATION: HREC/13/SVH/66 and HREC/17/SVH/80. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12618000672257.

Atrial Septal Aneurysms - A Clinically Relevant Enigma?

Atrial septal aneurysms (ASAs) are often seen during routine cardiac imaging, though their clinical relevance has been poorly defined. The aneurysmal, and often mobile, inter-atrial septum is frequently associated with other clinically relevant structural cardiac abnormalities, particularly patent foramen ovale (PFO). Whilst ASAs have previously been considered an incidental finding, a well-endowed atrial septum provides more than visual interest, including insights into atrial function and intra-atrial pressures, and has important clinical implications in PFO-associated stroke, migraines, and arrhythmias. This review outlines diagnostic challenges when assessing ASAs using all imaging modalities and the clinical implications of this common anatomical variant.

Evaluating the Effectiveness of an Online Cardiac Rehabilitation Resource (www.svhhearthealth.com.au) in Improving Knowledge and Confidence for Patients With Newly Diagnosed Cardiac Conditions: A Pre-Experimental Pilot Study.

BACKGROUND: Cardiac rehabilitation (CR) is an important tool for the secondary prevention of cardiac disease. Despite its proven effectiveness, CR remains vastly under-utilised especially amongst the most disadvantaged patients. As an adjunct to CR, the St Vincent's Heart Health website (SVHHH) was created by the St Vincent's Hospital CR team to provide information via simplified medical text, videos and animations. We evaluated the effectiveness of the website in educating patients about their heart condition. METHODS: Patients with a newly diagnosed cardiac condition were recruited from St Vincent's Hospital inpatient wards and outpatient clinics (n=67, age 63+/-11) and given 30minutes to interact with our online resource. Using a pre-test post-test design we evaluated the success of the website in improving patients' knowledge of their condition using a modified Brief Illness Perception Questionnaire and Patient Activation Questionnaire. RESULTS: After interacting with the website, participants rated a 50% improvement in the control they felt over their heart condition (p<0.01). Understanding of investigations, medications and management improved by 38%, 31% and 38%, respectively (all p<0.01). Subjects' understanding of their heart condition improved by 34% and confidence improved by more than 18% (p<0.01). These improvements were seen irrespective of age and primary place of residence. While older subjects had the lowest confidence using the internet, they demonstrated the greatest self-reported improvement in knowledge. There was no improvement in patients' perceived concern about their illness. CONCLUSIONS: The St Vincent's Heart Health website shows real promise as an educational tool for patients, as an adjunct to standard CR and for patients in remote settings. Online health resources will likely become an important adjunct to traditional teaching methods across all medical specialties to improve patient outcomes.

The interplay between metabolic alterations, diastolic strain rate and exercise capacity in mild heart failure with preserved ejection fraction: a cardiovascular magnetic resonance study.

BACKGROUND: Heart failure (HF) is characterized by altered myocardial substrate metabolism which can lead to myocardial triglyceride accumulation (steatosis) and lipotoxicity. However its role in mild HF with preserved ejection fraction (HFpEF) is uncertain. We measured myocardial triglyceride content (MTG) in HFpEF and assessed its relationships with diastolic function and exercise capacity. METHODS: Twenty seven HFpEF (clinical features of HF, left ventricular EF >50%, evidence of mild diastolic dysfunction and evidence of exercise limitation as assessed by cardiopulmonary exercise test) and 14 controls underwent 1H-cardiovascular magnetic resonance spectroscopy (1H-CMRS) to measure MTG (lipid/water, %), 31P-CMRS to measure myocardial energetics (phosphocreatine-to-adenosine triphosphate - PCr/ATP) and feature-tracking cardiovascular magnetic resonance (CMR) imaging for diastolic strain rate. RESULTS: When compared to controls, HFpEF had 2.3 fold higher in MTG (1.45 ± 0.25% vs. 0.64 ± 0.16%, p = 0.009) and reduced PCr/ATP (1.60 ± 0.09 vs. 2.00 ± 0.10, p = 0.005). HFpEF had significantly reduced diastolic strain rate and maximal oxygen consumption (VO2 max), which both correlated significantly with elevated MTG and reduced PCr/ATP. On multivariate analyses, MTG was independently associated with diastolic strain rate while diastolic strain rate was independently associated with VO2 max. CONCLUSIONS: Myocardial steatosis is pronounced in mild HFpEF, and is independently associated with impaired diastolic strain rate which is itself related to exercise capacity. Steatosis may adversely affect exercise capacity by indirect effect occurring via impairment in diastolic function. As such, myocardial triglyceride may become a potential therapeutic target to treat the increasing number of patients with HFpEF.

Cardiac energetics, oxygenation, and perfusion during increased workload in patients with type 2 diabetes mellitus.

AIMS: Patients with type 2 diabetes mellitus (T2DM) are known to have impaired resting myocardial energetics and impaired myocardial perfusion reserve, even in the absence of obstructive epicardial coronary artery disease (CAD). Whether or not the pre-existing energetic deficit is exacerbated by exercise, and whether the impaired myocardial perfusion causes deoxygenation and further energetic derangement during exercise stress, is uncertain. METHODS AND RESULTS: Thirty-one T2DM patients, on oral antidiabetic therapies with a mean HBA1c of 7.4 ± 1.3%, and 17 matched controls underwent adenosine stress cardiovascular magnetic resonance for assessment of perfusion [myocardial perfusion reserve index (MPRI)] and oxygenation [blood-oxygen level-dependent (BOLD) signal intensity change (SIΔ)]. Cardiac phosphorus-MR spectroscopy was performed at rest and during leg exercise. Significant CAD (>50% coronary stenosis) was excluded in all patients by coronary computed tomographic angiography. Resting phosphocreatine to ATP (PCr/ATP) was reduced by 17% in patients (1.74 ± 0.26, P = 0.001), compared with controls (2.07 ± 0.35); during exercise, there was a further 12% reduction in PCr/ATP (P = 0.005) in T2DM patients, but no change in controls. Myocardial perfusion and oxygenation were decreased in T2DM (MPRI 1.61 ± 0.43 vs. 2.11 ± 0.68 in controls, P = 0.002; BOLD SIΔ 7.3 ± 7.8 vs. 17.1 ± 7.2% in controls, P < 0.001). Exercise PCr/ATP correlated with MPRI (r = 0.50, P = 0.001) and BOLD SIΔ (r = 0.32, P = 0.025), but there were no correlations between rest PCr/ATP and MPRI or BOLD SIΔ. CONCLUSION: The pre-existing energetic deficit in diabetic cardiomyopathy is exacerbated by exercise; stress PCr/ATP correlates with impaired perfusion and oxygenation. Our findings suggest that, in diabetes, coronary microvascular dysfunction exacerbates derangement of cardiac energetics under conditions of increased workload.

Exacerbation of cardiac energetic impairment during exercise in hypertrophic cardiomyopathy: a potential mechanism for diastolic dysfunction.

AIMS: Hypertrophic cardiomyopathy (HCM) is the commonest cause of sudden cardiac death in the young, with an excess of exercise-related deaths. The HCM sarcomere mutations increase the energy cost of contraction and impaired resting cardiac energetics has been documented by measurement of phosphocreatine/ATP (PCr/ATP) using (31)Phosphorus MR Spectroscopy ((31)P MRS). We hypothesized that cardiac energetics are further impaired acutely during exercise in HCM and that this would have important functional consequences. METHODS AND RESULTS: (31)P MRS was performed in 35 HCM patients and 20 age- and gender-matched normal volunteers at rest and during leg exercise with 2.5 kg ankle weights. Peak left-ventricular filling rates (PFRs) and myocardial perfusion reserve (MPRI) were calculated during adenosine stress. Resting PCr/ATP was significantly reduced in HCM (HCM: 1.71 ± 0.35, normal 2.14 ± 0.35 P < 0.0001). During exercise, there was a further reduction in PCr/ATP in HCM (1.56 ± 0.29, P = 0.02 compared with rest) but not in normals (2.16 ± 0.26, P = 0.98 compared with rest). There was no correlation between PCr/ATP reduction and cardiac mass, wall thickness, MPRI, or late-gadolinium enhancement. PFR and PCr/ATP were significantly correlated at rest (r = 0.48, P = 0.02) and stress (r = 0.53, P = 0.01). CONCLUSION: During exercise, the pre-existing energetic deficit in HCM is further exacerbated independent of hypertrophy, perfusion reserve, or degree of fibrosis. This is in keeping with the change at the myofilament level. We offer a potential explanation for exercise-related diastolic dysfunction in HCM.

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.

Emergence of a distinct HIV-specific IL-10-producing CD8+ T-cell subset with immunomodulatory functions during chronic HIV-1 infection.

Interleukin-10 (IL-10) plays a key role in regulating proinflammatory immune responses to infection but can interfere with pathogen clearance. Although IL-10 is upregulated throughout HIV-1 infection in multiple cell subsets, whether this is a viral immune evasion strategy or an appropriate response to immune activation is unresolved. Analysis of IL-10 production at the single cell level in 51 chronically infected subjects (31 antiretroviral (ART) naïve and 20 ART treated) showed that a subset of CD8(+) T cells with a CD25(neg) FoxP3(neg) phenotype contributes substantially to IL-10 production in response to HIV-1 gag stimulation. The frequencies of gag-specific IL-10- and IFN-γ-producing T cells in ART-naïve subjects were strongly correlated and the majority of these IL-10(+) CD8(+) T cells co-produced IFN-γ; however, patients with a predominant IL-10(+) /IFN-γ(neg) profile showed better control of viraemia. Depletion of HIV-specific CD8(+) IL-10(+) cells from PBMCs led to upregulation of CD38 on CD14(+) monocytes together with increased IL-6 production, in response to gag stimulation. Increased CD38 expression was positively correlated with the frequency of the IL-10(+) population and was also induced by exposure of monocytes to HIV-1 in vitro. Production of IL-10 by HIV-specific CD8(+) T cells may represent an adaptive regulatory response to monocyte activation during chronic infection.

Cerebral venous system and anatomical predisposition to high-altitude headache.

OBJECTIVE: As inspired oxygen availability falls with ascent to altitude, some individuals develop high-altitude headache (HAH). We postulated that HAH results when hypoxia-associated increases in cerebral blood flow occur in the context of restricted venous drainage, and is worsened when cerebral compliance is reduced. We explored this hypothesis in 3 studies. METHODS: In high-altitude studies, retinal venous distension (RVD) was ophthalmoscopically assessed in 24 subjects (6 female) and sea-level cranial magnetic resonance imaging was performed in 12 subjects ascending to 5,300m. Correlation of headache burden (summed severity scores [0-4]≤24 hours from arrival at each altitude) with RVD, and with cerebral/cerebrospinal fluid (CSF)/venous compartment volumes, was sought. In a sea-level hypoxic study, 11 subjects underwent gadolinium-enhanced magnetic resonance venography before and during hypoxic challenge (fraction of inspired oxygen=0.11, 1 hour). RESULTS: In the high-altitude studies, headache burden correlated with both RVD (Spearman rho=0.55, p=0.005) and with the degree of narrowing of 1 or both transverse venous sinuses (r=-0.56, p=0.03). It also related inversely to both the lateral+third ventricle summed volumes (Spearman rho=-0.5, p=0.05) and pericerebellar CSF volume (r=-0.56, p=0.03). In the hypoxic study, cerebral and retinal vein engorgement were correlated, and rose as the combined conduit score fell (a measure of venous outflow restriction; r=-0.66, p<0.05 and r=-0.75, p<0.05, respectively). INTERPRETATION: Arterial hypoxemia is associated with cerebral and retinal venous distension, whose magnitude correlates with HAH burden. Restriction in cerebral venous outflow is associated with retinal distension and HAH. Limitations in cerebral venous efferent flow may predispose to headache when hypoxia-related increases in cerebral arterial flow occur.

HIV is an independent predictor of aortic stiffness.

BACKGROUND: Patients with treated Human Immunodeficiency Virus-1 (HIV) infection are at increased risk of cardiovascular events. Traditionally much of this risk has been attributed to metabolic and anthropometric abnormalities associated with HIV, which are similar to the metabolic syndrome (MS), an established risk factor for cardiovascular mortality. It remains unclear whether treated HIV infection is itself associated with increased risk, via increase vascular stiffness. METHODS: 226 subjects (90 with HIV) were divided into 4 groups based on HIV and MS status: 1) HIV-ve/MS-ve, 2) HIV-ve/MS + ve, 3) HIV + ve/MS-ve and 4)HIV + ve/MS + ve. CMR was used to determine aortic pulse wave velocity (PWV) and regional aortic distensibility (AD). RESULTS: PWV was 11% higher and regional AD up to 14% lower in the HIV + ve/MS-ve group when compared to HIV-ve/MS-ve (p < 0.01 all analyses). PWV and AD in the HIV + ve/MS-ve group was similar to that observed in the HIV-ve/MS + ve group (p > 0.99 all analyses). The HIV + ve/MS + ve group had 32% higher PWV and 30-34% lower AD than the HIV-ve/MS-ve group (all p < 0.001), and 19% higher PWV and up to 31% lower AD than HIV + ve/MS-ve subjects (all p < 0.05). On multivariable regression, age, systolic blood pressure and treated HIV infection were all independent predictors of both PWV and regional AD. CONCLUSION: Across multiple measures, treated HIV infection is associated with increased aortic stiffness and is also an independent predictor of both PWV and regional AD. The magnitude of the effect of treated HIV and MS are similar, with additive detrimental effects on central vascular elasticity.

Native T1-mapping detects the location, extent and patterns of acute myocarditis without the need for gadolinium contrast agents.

BACKGROUND: Acute myocarditis can be diagnosed on cardiovascular magnetic resonance (CMR) using multiple techniques, including late gadolinium enhancement (LGE) imaging, which requires contrast administration. Native T1-mapping is significantly more sensitive than LGE and conventional T2-weighted (T2W) imaging in detecting myocarditis. The aims of this study were to demonstrate how to display the non-ischemic patterns of injury and to quantify myocardial involvement in acute myocarditis without the need for contrast agents, using topographic T1-maps and incremental T1 thresholds. METHODS: We studied 60 patients with suspected acute myocarditis (median 3 days from presentation) and 50 controls using CMR (1.5 T), including: (1) dark-blood T2W imaging; >(2) native T1-mapping (ShMOLLI); (3) LGE. Analysis included: (1) global myocardial T2 signal intensity (SI) ratio compared to skeletal muscle; (2) myocardial T1 times; (3) areas of injury by T2W, T1-mapping and LGE. RESULTS: Compared to controls, patients had more edema (global myocardial T2 SI ratio 1.71 ± 0.27 vs.1.56 ± 0.15), higher mean myocardial T1 (1011 ± 64 ms vs. 946 ± 23 ms) and more areas of injury as detected by T2W (median 5% vs. 0%), T1 (median 32% vs. 0.7%) and LGE (median 11% vs. 0%); all p < 0.001. A threshold of T1 > 990 ms (sensitivity 90%, specificity 88%) detected significantly larger areas of involvement than T2W and LGE imaging in patients, and additional areas of injury when T2W and LGE were negative. T1-mapping significantly improved the diagnostic confidence in an additional 30% of cases when at least one of the conventional methods (T2W, LGE) failed to identify any areas of abnormality. Using incremental thresholds, T1-mapping can display the non-ischemic patterns of injury typical of myocarditis. CONCLUSION: Native T1-mapping can display the typical non-ischemic patterns in acute myocarditis, similar to LGE imaging but without the need for contrast agents. In addition, T1-mapping offers significant incremental diagnostic value, detecting additional areas of myocardial involvement beyond T2W and LGE imaging and identified extra cases when these conventional methods failed to identify abnormalities. In the future, it may be possible to perform gadolinium-free CMR using cine and T1-mapping for tissue characterization and may be particularly useful for patients in whom gadolinium contrast is contraindicated.

Observational study of regional aortic size referenced to body size: production of a cardiovascular magnetic resonance nomogram.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is regarded as the gold standard for clinical assessment of the aorta, but normal dimensions are usually referenced to echocardiographic and computed tomography data and no large CMR normal reference range exists. As a result we aimed to 1) produce a normal CMR reference range of aortic diameters and 2) investigate the relationship between regional aortic size and body surface area (BSA) in a large group of healthy subjects with no vascular risk factors. METHODS: 447 subjects (208 male, aged 19-70 years) without identifiable cardiac risk factors (BMI range 15.7-52.6 kg/m2) underwent CMR at 1.5 T to determine aortic diameter at three levels: the ascending aorta (Ao) and proximal descending aorta (PDA) at the level of the pulmonary artery, and the abdominal aorta (DDA), at a level 12 cm distal to the PDA. In addition, 201 of these subjects had aortic root imaging, allowing for measurements at the level of the aortic valve annulus (AV), aortic sinuses and sinotubular junction (STJ). RESULTS: Normal diameters (mean ±2 SD) were; AV annulus male(♂) 24.4 ± 5.4, female (♀) 21.0 ± 3.6 mm, aortic sinus♂ 32.4 ± 7.7, ♀27.6 ± 5.8 mm, ST-junction ♂25.0 ± 7.4, ♀21.8 ± 5.4 mm, Ao ♂26.7 ± 7.7, ♀25.5 ± 7.4 mm, PDA ♂20.6 ± 5.6, +18.9 ± 4.0 mm, DDA ♂17.6 ± 5.1, ♀16.4 ± 4.0 mm. Aortic root and thoracic aortic diameters increased at all levels measured with BSA. No gender difference was seen in the degree of dilatation with increasing BSA (p>0.5 for all analyses). CONCLUSION: Across both genders, increasing body size is characterized by a modest degree of aortic dilatation, even in the absence of traditional cardiovascular risk factors.

Gender-specific differences in left ventricular remodelling in obesity: insights from cardiovascular magnetic resonance imaging.

AIMS: As obesity-related cardiovascular mortality, although elevated when compared with normal weight, is lower in females than in males at every body mass index (BMI) level, we aimed to investigate gender-specific differences in left ventricular (LV) hypertrophy in obesity, which themselves have been shown to have varying prognostic value. METHOD AND RESULTS: In total, 741 subjects (female, n = 399) without identifiable cardiovascular risk factors (BMI 15.7-59.2 kg/m(2)) underwent cardiovascular magnetic resonance (1.5 T) to determine LV mass, end-diastolic volume (EDV, mL), and LV mass/volume ratio (LVM/VR). Across both sexes, there was a strong positive correlation between BMI and LV mass (male r = 0.44, female r = 0.57, both P < 0.001), with males showing a greater LV hypertrophic response (male +2.3 vs. female +1.6 g per BMI point increase, P = 0.001). Concentric hypertrophy was present in both sexes and LVM/VR positively correlated to BMI (male r = 0.45, female r = 0.29, both P < 0.001) on linear regression analysis. However, the degree of concentric hypertrophy was greater in males (male +0.13 vs. female +0.06 LVM/VR increase per BMI point increase, P = 0.001). On the other hand, females showed a greater LV cavity dilatory response (female +1.1 vs. male +0.3 mL per BMI point increase, P < 0.001). Indeed, in contrast to females, where BMI and LV-EDV were positively correlated (r = 0.38, P < 0.001), BMI did not correlate with EDV in men (r = 0.03, P = 0.62). CONCLUSION: In the absence of traditional cardiovascular risk factors, obese men show predominantly concentric hypertrophy, whereas obese women exhibit both eccentric and concentric hypertrophy. As concentric hypertrophy is more strongly related to cardiovascular mortality than eccentric hypertrophy, our observations may explain the observed gender difference in obesity-related mortality.

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/m(2); n=9-17) and obese (body mass index, 39±7 kg/m(2); 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; (31)P-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 (ß=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.

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

BACKGROUND: Quantitative 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. METHODS: A 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. RESULTS: Native 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. CONCLUSION: Native 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.

Normobaric hypoxia impairs human cardiac energetics.

Hypoxia causes left ventricular dysfunction in the human heart, but the biochemical mechanism is poorly understood. Here, we tested whether short-term normobaric hypoxia leads to changes in cardiac energetics and early cardiac dysfunction. Healthy male volunteers (n=12, age 24 ± 2 yr) were exposed to normobaric hypoxia in a purpose-built hypoxic chamber. The partial pressure of oxygen during end-tidal expiration (P(ET)o2) was kept between 50 and 60 mmHg, and peripheral oxygen saturation (Sao2) was kept above 80%. Cardiac morphology and function were assessed using magnetic resonance imaging and echocardiography, both before and after 20 h of hypoxic exposure, and high-energy phosphate metabolism [measured as the phosphocreatine (PCr)/ATP ratio] was measured using ³¹P magnetic resonance spectroscopy. During hypoxia, P(ET)o2 and Sao2 averaged 55 ± 1 mmHg and 83.6 ± 0.4%, respectively. Hypoxia caused a 15% reduction in cardiac PCr/ATP (from 2.0 ± 0.1 to 1.7 ± 0.1, P<0.01) and reduced diastolic function (measured as E/E', rising from 6.1 ± 0.4 to 7.5 ± 0.7, P<0.01). Normobaric hypoxia causes a rapid decrease in high-energy phosphate metabolism in the human cardiac left ventricle, which may lead to a decline in diastolic function. These findings are important in understanding the response of normal individuals to environmental hypoxia, and to situations in which disease reduces cardiac oxygen delivery.

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 after 7 d of 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 (31)P 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.