Kelvin Chow

Saturation recovery single-shot acquisition (SASHA) for myocardial T1 mapping

To validate a new saturation recovery single‐shot acquisition (SASHA) pulse sequence for T1 mapping and to compare SASHA T1 values in heart failure patients and healthy controls.

Accuracy, Precision, and Reproducibility of Four T1 Mapping Sequences: A Head-to-Head Comparison of MOLLI, ShMOLLI, SASHA, and SAPPHIRE

PURPOSE To compare accuracy, precision, and reproducibility of four commonly used myocardial T1 mapping sequences: modified Look-Locker inversion recovery (MOLLI), shortened MOLLI (ShMOLLI), saturation recovery single-shot acquisition (SASHA), and saturation pulse prepared heart rate independent inversion recovery (SAPPHIRE). MATERIALS AND METHODS This HIPAA-compliant study was approved by the institutional review board. All subjects provided written informed consent. Accuracy, precision, and reproducibility of the four T1 mapping sequences were first compared in phantom experiments. In vivo analysis was performed in seven healthy subjects (mean age ± standard deviation, 38 years ± 19; four men, three women) who were imaged twice on two separate days. In vivo reproducibility of native T1 mapping and extracellular volume (ECV) were measured. Differences between the sequences were assessed by using Kruskal-Wallis and Wilcoxon rank sum tests (phantom data) and mixed-effect models (in vivo data). RESULTS T1 mapping accuracy in phantoms was lower with ShMOLLI (62 msec) and MOLLI (44 msec) than with SASHA (13 msec; P < .05) and SAPPHIRE (12 msec; P < .05). MOLLI had similar precision to ShMOLLI (4.0 msec vs 5.6 msec; P = .07) but higher precision than SAPPHIRE (6.8 msec; P = .002) and SASHA (8.7 msec; P < .001). All sequences had similar reproducibility in phantoms (P = .1). The four sequences had similar in vivo reproducibility for native T1 mapping (∼25-50 msec; P > .05) and ECV quantification (∼0.01-0.02; P > .05). CONCLUSION SASHA and SAPPHIRE yield higher accuracy, lower precision, and similar reproducibility compared with MOLLI and ShMOLLI for T1 measurement. Different sequences yield different ECV values; however, all sequences have similar reproducibility for ECV quantification.

Diffuse myocardial fibrosis by T1-mapping in children with subclinical anthracycline cardiotoxicity: relationship to exercise capacity, cumulative dose and remodeling

BackgroundThe late cardiotoxic effects of anthracycline chemotherapy influence morbidity and mortality in the growing population of childhood cancer survivors. Even with lower anthracycline doses, evidence of adverse cardiac remodeling and reduced exercise capacity exist. We aim to examine the relationship between cardiac structure, function and cardiovascular magnetic resonance (CMR) tissue characteristics with chemotherapy dose and exercise capacity in childhood cancer survivors.MethodsThirty patients (15 ± 3 years), at least 2 years following anthracycline treatment, underwent CMR, echocardiography, and cardiopulmonary exercise testing (peak VO2). CMR measured ventricular function, mass, T1 and T2 values, and myocardial extracellular volume fraction, ECV, a measure of diffuse fibrosis based on changes in myocardial T1 values pre- and post-gadolinium. Cardiac function was also assessed with conventional and speckle tracking echocardiography.ResultsPatients had normal LVEF (59 ± 7%) but peak VO2 was 17% lower than age-predicted normal values and were correlated with anthracycline dose (r = −0.49). Increased ECV correlated with decreased mass/volume ratio (r = −0.64), decreased LV wall thickness/height ratio (r = −0.72), lower peak VO2(r = −0.52), and higher cumulative dose (r = 0.40). Echocardiographic measures of systolic and diastolic function were reduced compared to normal values (p < 0.01), but had no relation to ECV, peak VO2 or cumulative dose.ConclusionsMyocardial T1 and ECV were found to be early tissue markers of ventricular remodeling that may represent diffuse fibrosis in children with normal ejection fraction post anthracycline therapy, and are related to cumulative dose, exercise capacity and myocardial wall thinning.

T1 Mapping With Cardiovascular MRI Is Highly Sensitive for Fabry Disease Independent of Hypertrophy and Sex

Background— Fabry disease (FD) is an X-linked disorder of lysosomal metabolism affecting multiple organs with cardiac disease being the leading cause of death. Current imaging evaluations of the heart are suboptimal. The goals of the current study are to evaluate the potential of quantitative T1 mapping with cardiovascular MRI as a disease-specific imaging biomarker. Methods and Results— A total of 31 patients with FD, 23 healthy controls, and 21 subjects with concentric remodeling or hypertrophy underwent cardiovascular MRI to measure left ventricular (LV) morphology, function, delayed enhancement, as well as myocardial T1 values, and derived parameters (extracellular volume). All subjects had LV ejection fraction >50% and similar volumes. FD and concentric remodeling or hypertrophy had similarly increased mass, wall thickness, and mass/volume as compared with controls. A total of 16 of 31 FD subjects and 10 of 21 concentric remodeling or hypertrophy subjects had LV hypertrophy. Noncontrast myocardial T1 values were substantially lower in FD as compared with controls and concentric remodeling or hypertrophy (1070±50, 1177±27, and 1207±33 ms, respectively; P<0.001), but extracellular volume was similar in all groups (21.7±2.4%, 22.2±3.1%, and 21.8±3.9%, respectively). Single-voxel NMR spectroscopy in 4 FD and 4 healthy control subjects showed a significant negative linear relationship between lipid content and noncontrast T1 values (r=−0.9; P=0.002). Female subjects had lower LV mass and wall thickness, longer myocardial T1 values and larger extracellular volume suggesting a key sex difference in cardiac remodeling. Conclusions— Reduced noncontrast myocardial T1 values are the most sensitive and specific cardiovascular MRI parameter in patients with FD irrespective of sex and LV morphology and function.

T1 Mapping with CMR Is Highly Sensitive for Fabry Disease Independent of Hypertrophy and Gender

Background— Fabry disease (FD) is an X-linked disorder of lysosomal metabolism affecting multiple organs with cardiac disease being the leading cause of death. Current imaging evaluations of the heart are suboptimal. The goals of the current study are to evaluate the potential of quantitative T1 mapping with cardiovascular MRI as a disease-specific imaging biomarker. Methods and Results— A total of 31 patients with FD, 23 healthy controls, and 21 subjects with concentric remodeling or hypertrophy underwent cardiovascular MRI to measure left ventricular (LV) morphology, function, delayed enhancement, as well as myocardial T1 values, and derived parameters (extracellular volume). All subjects had LV ejection fraction >50% and similar volumes. FD and concentric remodeling or hypertrophy had similarly increased mass, wall thickness, and mass/volume as compared with controls. A total of 16 of 31 FD subjects and 10 of 21 concentric remodeling or hypertrophy subjects had LV hypertrophy. Noncontrast myocardial T1 values were substantially lower in FD as compared with controls and concentric remodeling or hypertrophy (1070±50, 1177±27, and 1207±33 ms, respectively; P<0.001), but extracellular volume was similar in all groups (21.7±2.4%, 22.2±3.1%, and 21.8±3.9%, respectively). Single-voxel NMR spectroscopy in 4 FD and 4 healthy control subjects showed a significant negative linear relationship between lipid content and noncontrast T1 values (r=−0.9; P=0.002). Female subjects had lower LV mass and wall thickness, longer myocardial T1 values and larger extracellular volume suggesting a key sex difference in cardiac remodeling. Conclusions— Reduced noncontrast myocardial T1 values are the most sensitive and specific cardiovascular MRI parameter in patients with FD irrespective of sex and LV morphology and function.

Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE 101–Breast): A Randomized Trial for the Prevention of Trastuzumab-Associated Cardiotoxicity

Purpose The primary toxicity of trastuzumab therapy for human epidermal growth factor receptor 2-overexpressing (HER2-positive) breast cancer is dose-independent cardiac dysfunction. Angiotensin-converting enzyme inhibitors and β-blockers are recommended first-line agents for heart failure. We hypothesized that angiotensin-converting enzyme inhibitors and β-blockers could prevent trastuzumab-related cardiotoxicity. Patients and Methods In this double-blinded, placebo-controlled trial, patients with HER2-positive early breast cancer were randomly assigned to receive treatment with perindopril, bisoprolol, or placebo (1:1:1) for the duration of trastuzumab adjuvant therapy. Patients underwent cardiac magnetic resonance imaging at baseline and post-cycle 17 for the determination of left ventricular volumes and left ventricular ejection fraction (LVEF). Cardiotoxicity was evaluated as the change in indexed left ventricular end diastolic volume and LVEF. Results Thirty-three patients received perindopril, 31 received bisoprolol, and 30 received placebo. Baseline demographic, cancer, and cardiovascular profiles were similar between groups. Study drugs were well tolerated with no serious adverse events. After 17 cycles of trastuzumab, indexed left ventricular end diastolic volume increased in patients treated with perindopril (+7 ± 14 mL/m2), bisoprolol (+8 mL ± 9 mL/m2), and placebo (+4 ± 11 mL/m2; P = .36). In secondary analyses, trastuzumab-mediated decline in LVEF was attenuated in bisoprolol-treated patients (-1 ± 5%) relative to the perindopril (-3 ± 4%) and placebo (-5 ± 5%) groups ( P = .001). Perindopril and bisoprolol use were independent predictors of maintained LVEF on multivariable analysis. Conclusion Perindopril and bisoprolol were well tolerated in patients with HER2-positive early breast cancer who received trastuzumab and protected against cancer therapy-related declines in LVEF; however, trastuzumab-mediated left ventricular remodeling-the primary outcome-was not prevented by these pharmacotherapies.

Correlation of cardiovascular magnetic resonance imaging findings and endomyocardial biopsy results in patients undergoing screening for heart transplant rejection.

BACKGROUND Endomyocardial biopsy (EMB) is the current gold standard to screen for heart transplant rejection but has important risks and limitations. Cardiovascular magnetic resonance imaging (CMRI) is increasingly used to characterize cardiac function and myocardial tissue. We evaluated the diagnostic accuracy of CMRI compared with EMB and clinically diagnosed heart transplant rejection. METHODS Comprehensive CMRI scans were performed on adult heart transplant recipients within 24 hours of EMB (routine or clinically indicated), before initiation of any anti-rejection therapy, and blinded to EMB results. Multivariable analysis was used to create CMRI diagnostic criteria for comparison with a positive EMB (Grade ≥ 2R or antibody-mediated rejection) and clinical rejection (change in medical therapy to treat rejection). RESULTS Sixty participants (75% male; mean age, 51 ± 14 years) were recruited, providing 73 comparisons between CMRI and EMB for the diagnosis of rejection. Multivariable logistic regression identified myocardial edema (T2 relaxation time) and right ventricular end-diastolic volume index as independent predictors of a positive EMB. Combining threshold right ventricular end-diastolic volume index and edema values predicted a positive EMB with very good accuracy: sensitivity, 93%; specificity, 78%; positive predictive value, 52%; and negative predictive valve, 98%. CMRI was more sensitive than EMB at predicting clinical rejection (sensitivity of 67% vs 58%). CONCLUSIONS CMRI has high sensitivity and high negative predictive value in predicting biopsy-positive heart transplant rejection and may be useful as a screening test before routine EMB. CMRI also has better sensitivity for clinically diagnosed heart transplant rejection and could be helpful in cases of negative rejection on the biopsy specimen.

Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients

Metabolic modulation with dichloroacetate improves hemodynamics in genetically susceptible patients with idiopathic pulmonary arterial hypertension. Progress for PAH In addition to thickening and occlusion of the pulmonary arteries, mitochondrial respiration is suppressed in pulmonary arterial hypertension (PAH). Michelakis et al. treated lungs from patients with PAH with dichloroacetate (DCA), a drug used to treat cancer and congenital mitochondrial disease that inhibits the mitochondrial enzyme pyruvate dehydrogenase kinase. DCA increased mitochondrial function; however, the response was variable, and this variable response was mirrored in a phase 1 trial, with some patients showing improved hemodynamics and functional capacity. The authors determined that patients with inactivating mutations in two genes encoding mitochondrial proteins were less responsive to DCA. This work highlights the importance of considering patient genotype in clinical trial design and identifies a drug target for PAH. Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.

Optimized saturation recovery protocols for T1-mapping in the heart: influence of sampling strategies on precision

BackgroundT1-mapping has the potential to detect and quantify diffuse processes such as interstitial fibrosis. Detection of disease at an early stage by measurement of subtle changes requires a high degree of reproducibility. Initial implementation of saturation recovery (SR) T1-mapping employed 3-parameter fitting which was highly accurate but was quite sensitive to noise; 2-parameter fitting greatly reduced the sensitivity to noise at the expense of a small degree of systematic bias. A recently introduced implementation that uses a variable readout flip angle greatly reduces systematic errors in T1-measurement thereby making it feasible to use SR methods with 2-parameter fitting with improved accuracy and precision. SR T1 mapping techniques with multi-heartbeat recovery times have been proposed to better sample the T1 recovery curve, but have not been evaluated for 2-parameter fitting.MethodsAn analytic formulation for calculating the standard deviation (SD) for SR T1-mapping with 2-parameter fitting is developed and validated using Monte-Carlo simulation. The coefficient of variation is compared for a brute force optimization of sampling and for several previously described sampling schemes for T1 measurement over several uncertainty ranges. Experimental validation is performed in phantoms over a range of T1, and in-vivo both native and post-contrast. Pixel-wise SD maps are calculated for SR T1-mapping.ResultsSampling schemes that use a non-saturated anchor image and multiple (N) measurements at a single fixed saturation delay are found to be near optimum for the case of known T1 and are close to the brute force optimized solution over wide ranges of native and post-contrast T1 values. The fixed delay sampling scheme is simple to implement and provides an improvement over uniformly distributed schemes.ConclusionsSampling strategies for saturation recovery methods for myocardial T1-mapping have been optimized and validated experimentally. Reduced SD, or improved precision, may be achieved by using fixed saturation delays when considering native myocardium and post-contrast T1 ranges. Pixel-wise estimates of T1 mapping errors have been formulated and validated for SR fitting methods.

Changes in ventricular twist and untwisting with orthostatic stress: endurance athletes versus normally active individuals

Endurance-trained individuals exhibit larger reductions in left ventricular (LV) end-diastolic volume in response to lower body negative pressure (LBNP) compared with normally active individuals. However, the relationship between LV torsion and untwisting and the LV volume response to LBNP in endurance athletes is unknown. Eight endurance-trained athletes [maximal oxygen consumption (VO2max): 66.4+/-7.2 ml.kg(-1).min(-1)] and eight normally active individuals (VO2max: 41.9+/-9.0 ml.kg(-1).min(-1)) (all men) underwent two cardiac magnetic resonance imaging (MRI) assessments, the first during supine rest and the second during -30 mmHg LBNP. Right ventricular (RV) and LV volumes were assessed, myocardial tagging was applied in order to quantify LV peak torsion and peak untwisting rate, and filling rates were measured with phase-contrast MRI. In response to LBNP, endurance-trained individuals had greater reductions in RV and LV end-diastolic volume and stroke volume (P<0.05). Endurance athletes had reduced untwisting rates (20.3+/-8.7 degrees/s), while normally active individuals had increased untwisting rates (-16.2+/-32.1 degrees/s) in response to LBNP (P<0.05). Changes in peak untwisting rate were significantly correlated with change in peak torsion (R=-0.87, P<0.05), with the change in early filling rate and VO2max, but not with changes in end-diastolic or end-systolic volume (P>0.05). We conclude that increased untwisting rates in normally active subjects may mitigate the drop in early filling rate with LBNP and thus may be a compensatory mechanism for the reduction in stroke volume with volume unloading. The opposite response in athletes, who showed a decreased untwisting rate, may contribute to their larger reductions in LV end-diastolic and stroke volumes with volume unloading and their orthostatic intolerance.