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1.  The Role of Cardiovascular Magnetic Resonance (CMR) and Computed Tomography (CCT) in Facilitating Heart Failure Management 
Opinion Statement
Cardiovascular magnetic resonance (CMR) and cardiac computed tomography (CCT) offer advantages for detecting left or right ventricular dysfunction in patients with or suspected of heart failure. CMR does not expose patients to ionizing radiation, and thus is well-suited for functional assessments and serial studies. CCT provides high spatial resolution, making it useful for the identification of coronary arteriosclerosis associated with ischemic cardiomyopathy. In this review, the clinical applications of CMR and CCT are individually discussed, with comparisons made between them to examine the strengths of each modality. The major techniques for each modality are outlined, as well as their uses for the evaluation of cardiomyopathy in heart failure patients with reduced left ventricular ejection fraction, preserved left ventricular ejection fraction, and valvular heart disease. Finally, we review the utility of CMR and CCT in determining which patients will benefit from cardiac resynchronization therapy.
doi:10.1007/s11936-013-0253-6
PMCID: PMC3767383  PMID: 23817725
Cardiovascular Magnetic Resonance; Cardiac Computed Tomography; Heart Failure; Cardiomyopathy; Valvular Heart Disease
2.  Low to Moderate Dose Anthracycline-Based Chemotherapy is Associated with Early Noninvasive Imaging Evidence of Subclinical Cardiovascular Disease 
JACC. Cardiovascular imaging  2013;6(8):877-885.
Objective
To determine if low to moderate doses of anthracycline-based chemotherapy (Anth-bC) are associated with subclinical cardiovascular (CV) injury.
Background
Cancer survivors that receive Anth-bC experience premature CV events. It is unknown whether low to moderate doses of anthracyclines a) promote early subclinical CV disease manifested by deteriorations in left ventricular ejection fraction (LVEF) or increases in aortic stiffness, or b) are associated with change in quality of life (QOL).
Methods
In 53 men and women with breast cancer, leukemia, or lymphoma, we assessed left ventricular volumes, LVEF, circumferential strain, aortic pulse wave velocity (PWV), late gadolinium enhancement, serum B-type natriuretic peptide (BNP), troponin I (TnI), and the impact of treatment on QOL before, and 1, 3, and 6 months after receipt of Anth-bC.
Results
Participants averaged 50±2 (range 19–80) years in age, 58% were women, 17% were black, and they each received a range of 50 to 375 mg/m2 of doxorubicin equivalent chemotherapy. Left ventricular end systolic volume (LVESV; 48±3 to 54±3 ml; p=0.02), left ventricular strain (−17.7±0.4 to −15.1±0.4; p=0.0003), PWV (6.7±0.5 to 10.1±1 m/sec; p=0.0006), and QOL deterioration (15.4±3.3 to 28.5±3.9; p=0.008) increased, while LVEF (58±1 to 53±1%; p=0.0002) decreased within 6 months after low to moderate doses of Anth-bC. All findings persisted after accounting for age, gender, race (white/black), doxorubicin equivalent dose, doxorubicin administration technique, comorbidities associated with CV events, and cancer diagnosis (p=0.02 to 0.0001 for all). There were no new late gadolinium enhancement findings after 6 months.
Conclusions
Low to moderate doses of Anth-bC are associated with the early development of subclinical abnormalities of cardiac and vascular function that in other populations are associated with the future occurrence of CV events.
doi:10.1016/j.jcmg.2012.11.017
PMCID: PMC3745801  PMID: 23643285
Cardio-oncology; chemotherapy; cardiotoxicity
3.  Steadily Straining Toward Clinical Utility 
JACC. Cardiovascular imaging  2010;3(4):372-374.
doi:10.1016/j.jcmg.2009.12.009
PMCID: PMC4316662  PMID: 20394898
cardiac magnetic resonance; strain; dobutamine; ischemia; stress testing
4.  Relation of Thoracic Aortic Distensibility to Left Ventricular Area (From the Multi-ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2013;113(1):178-182.
Decreased arterial compliance is an early manifestation of adverse structural and functional changes within the vessel wall. Its correlation with left ventricular (LV) area on computed tomography (CT), a marker of LV remodeling, has not been well demonstrated. We tested the hypothesis that decreasing aortic compliance and increasing arterial stiffness is independently associated with increased LV area. The study population consisted of 3,540 (61±10 years, 46% men) from the MESA study who underwent aortic distensibility (AD) assessment on magnetic resonance imaging (MRI) and LV area measurement on CT (adjusted to body surface area). Multivariable logistic regression was performed to assess the association between body surface area (BSA) normalized LV area >75th percentile and AD after adjusting for baseline clinical, historical and imaging covariates. The mean LV area /BSA was 2,153 cm2 and mean AD was 1.84 mm Hg−1 x103. Subjects in the lowest AD quartile were older with higher prevalence of hypertension, diabetes, and hypercholesterolemia (p<0.05 for all comparisons). Using multivariate linear regression adjusting for demographics, traditional risk factors, coronary artery calcium and C-reactive protein, each standard deviation decrease was associated with 18 cm2 increase in the LV area. In addition, decreasing AD quartiles were independently associated with increased BSA LV area defined as >75th percentile. In this multi-ethnic cohort, reduced AD was associated with increased LV area. Longitudinal studies are needed to determine if decreased distensibility precedes and directly influences increased LV area.
doi:10.1016/j.amjcard.2013.09.039
PMCID: PMC3912190  PMID: 24210674
Arterial compliance; Left ventricular area; Computed tomography; Aortic Distensibility
5.  Intraperitoneal Fat Is Associated With Thickening of the Thoracic Aorta in Individuals at High Risk for Cardiovascular Events 
Obesity (Silver Spring, Md.)  2011;19(9):10.1038/oby.2011.188.
Increased intraperitoneal (IP) fat is associated with increased cardiovascular (CV) risk, but mechanisms for this increase in risk are not completely established. We performed this study to assess whether IP fat is associated with ascending aortic wall thickness (AOWT), a risk factor for CV events. Four hundred and forty-one consecutive participants, aged 55–85 years, with risk factors for CV events underwent magnetic resonance measures of AOWT and abdominal fat (subcutaneous (SC) fat + IP fat). For the ascending aorta, mean wall thickness of the 4th quartile of the IP fat was higher relative to the 1st quartile (P ≤ 0.001). This difference persisted after accounting for SC fat (P ≤ 0.001), as well as age, gender, height, weight, smoking, diabetes, hypertension, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and C-reactive protein (CRP) (P < 0.03). Elevated IP fat volume is associated with an increase in ascending AOWT, a condition that promotes CV events in middle aged and elderly adults.
doi:10.1038/oby.2011.188
PMCID: PMC3814164  PMID: 21720433
6.  Aging reduces left atrial performance during adrenergic stress in middle aged and older patients 
Cardiology journal  2012;19(1):45-52.
Background
During adrenergic stress, the influence of age on left atrial (LA) function is unknown. We hypothesized that aging decreases LA total emptying fraction (LAEF) during maximal adrenergic stress. The aim of the study was to determine the influence of aging on LA function during adrenergic stress in middle aged and older patients.
Methods
We enrolled 167 middle aged and elderly participants, and measured LA and left ventricular (LV) volumes using a multi-slice three-dimensional cine white blood cardiovascular magnetic resonance (CMR) technique before and during intravenous dobutamine infused to achieve 80% of the maximum heart rate response for age. Paired sample t-test was used to detect differences in LA and LV volumes between baseline and peak dose stage of dobutamine stress CMR, and multivariable linear regression was used to identify predictors of LA function.
Results
Participants averaged 68 ± 8 years in age, 53% were men, 25% exhibited coronary artery disease, 35% had diabetes, 9% had a remote history of atrial fibrillation, 90% had hypertension, and 11% had inducible LV wall motion abnormalities indicative of ischemia during dobutamine CMR. Increasing age correlated with LA volumes (maximal and minimal) and inversely correlated with LAEF at rest and after peak adrenergic stress. Age was an independent predictor of LAEF during adrenergic stress, even after accounting for gender, LV volumes, and other co-morbidities including inducible ischemia.
Conclusions
Age is associated with a decrease in LA function during adrenergic stress even after adjusting for co-morbidities associated with cardiovascular disease and LV function.
PMCID: PMC3767009  PMID: 22298167
aging; left atrial function; adrenergic stress; cardiac MRI
7.  Pharmacological Stress Cardiovascular Magnetic Resonance 
Postgraduate medicine  2011;123(3):162-170.
Over the past decade, cardiovascular magnetic resonance (CMR) has evolved into a cardiac stress testing modality that can be used to diagnose myocardial ischemia using intravenous dobutamine or vasodilator perfusion agents such as adenosine or dipyridamole. Because CMR produces high-resolution tomographic images of the human heart in multiple imaging planes, it has become a highly attractive noninvasive testing modality for those suspected of having myocardial ischemia. The purpose of this article is to review the clinical, diagnostic, and prognostic utility of stress CMR testing for patients with (or suspected of having) coronary artery disease.
doi:10.3810/pgm.2011.05.2295
PMCID: PMC3767031  PMID: 21566427
stress CMR; dobutamine; adenosine; myocardial ischemia
8.  Prediction of Cardiac Events in Patients with Reduced Left Ventricular Ejection Fraction Using Dobutamine Cardiovascular Magnetic Resonance Assessment of Wall Motion Score Index 
Objectives
To assess the utility of dobutamine cardiovascular magnetic resonance (DCMR) results for predicting cardiac events in individuals with reduced left ventricular ejection fraction (LVEF).
Background
It is unknown whether DCMR results identify a poor cardiac prognosis when the resting LVEF is moderately to severely reduced.
Methods
Two-hundred consecutive patients aged 30 to 88 (average 64) years with a LVEF ≤55% that were poorly suited for stress echocardiography, underwent DCMR in which LV wall motion score index (WMSI), defined as the average wall motion of the number of segments scored, was assessed at rest, during low dose, and after peak intravenous infusion of dobutamine/atropine. All participants were followed for an average of 5 years after DCMR to ascertain the post testing occurrence of cardiac death, myocardial infarction (MI), and unstable angina or congestive heart failure warranting hospitalization.
Results
After accounting for risk factors associated with coronary arteriosclerosis and MI, a stress induced increase in WMSI during DCMR was associated with future cardiac events (p< 0.001). After accounting for resting LVEF, a DCMR stress induced change in WMSI added significantly to predicting future cardiac events (p=0.003), but this predictive value was confined primarily to those with a LVEF >40%.
Conclusions
In individuals with mild to moderate reductions in LVEF (40% to 55%), dobutamine induced increases in WMSI forecast MI and cardiac death to a greater extent than an assessment of resting LVEF. In those with a LVEF < 40%, a dobutamine induced increase in WMSI does not predict MI and cardiac death beyond the assessment of resting LVEF.
doi:10.1016/j.jacc.2008.04.025
PMCID: PMC3666037  PMID: 18634983
magnetic resonance imaging; cardiac prognosis; myocardial ischemia; dobutamine stress imaging
9.  Simultaneous Measurement of Left and Right Ventricular Volumes and Ejection Fraction During Dobutamine Stress Cardiovascular Magnetic Resonance 
Objective
During cardiovascular stress, if right ventricular (RV) exceeds left ventricular (LV) stroke volume, then a large volume of blood is displaced into the pulmonary circulation that may precipitate pulmonary edema. We sought to determine the metrics by which cardiovascular magnetic resonance (CMR) could measure simultaneous displacement of right and LV stroke volume during dobutamine stress.
Methods
Thirteen healthy subjects (5 women) aged 53±10 years without medical conditions and taking no medications underwent 2 CMR exams at 1.5 T separated by 4 to 8 weeks in which right and LV stroke volume were determined during intravenous dobutamine and atropine infused to achieve 80% of the maximum predicted heart rate response (MPHRR) for age.
Results
The right and LV stroke volume were highly correlated at each level of stress (rest, r=0.98, p=0.007; low stress, r=0.87, p=0.001; and peak stress, r=0.88, p=0.001), and the mean difference in SV at each level of stress (rest, low stress, and peak stress was 0 to 2 ml on both exam 1 and 2.
Conclusions
Simultaneous change in right and left ventricular stroke volume can be assessed in a highly reproducible manner throughout the course of dobutamine CMR stress administered to achieve 80% of MPHRR for age. This technology may help identify discrepancies in right and LV stroke volume during cardiovascular stress that are associated with the development of pulmonary edema.
doi:10.1097/RCT.0b013e31822abbcd
PMCID: PMC3666038  PMID: 21926858
10.  RENAL SINUS FAT AND POOR BLOOD PRESSURE CONTROL IN MIDDLE-AGED AND ELDERLY INDIVIDUALS AT RISK FOR CARDIOVASCULAR EVENTS 
Hypertension  2010;56(5):901-906.
Fat in the renal sinus (RS), a region of the kidney in which low pressure venous and lymphatic vessels are present, may indirectly influence blood pressure (BP). The purpose of this study was to assess the association between RS fat and control of BP upon receipt of antihypertensive medications.
Two hundred-five (205) participants aged 55 to 85 years at risk for cardiovascular (CV) events underwent magnetic resonance imaging assessments of abdominal and RS fat, measurement of blood pressure, and determination of the number of prescribed antihypertensive medications. Multivariable linear regression was used to determine associations between RS fat, blood pressure, and the number of prescribed antihypertensive medications.
Abdominal fat averaged (416 ± 160 cm3, median and interquartile range (IQR) of 396 cm3 and 308 to 518 cm3); intraperitoneal (IP) fat averaged (141 ± 73 cm3, median and IQR of 129 cm3 and 86 to 194 cm3); and RS fat averaged (4.6 ± 3.2 cm3, median and IQR of 4.2 cm3 and 2.2 to 6.6 cm3). After accounting for age, gender, height, body mass index (BMI), and IP fat, RS fat correlated with the number of prescribed antihypertensive medications (p=0.010), stage II hypertension (p=0.02), and renal size (p=<0.001).
In conclusion, after accounting for other body fat depots and risk factors for hypertension, renal sinus fat volume is associated with the number of prescribed antihypertensive medications and stage II hypertension. These results indicate that further studies are warranted to determine if fat accumulation in the renal sinus promotes hypertension.
doi:10.1161/HYPERTENSIONAHA.110.157370
PMCID: PMC3634339  PMID: 20837881
Renal sinus; intraperitoneal fat; hypertension; blood pressure; body mass index
11.  The use of cardiovascular magnetic resonance to identify adverse cardiac prognosis: An important step in reducing image related heathcare expenditures 
doi:10.1016/j.jacc.2010.07.011
PMCID: PMC3634341  PMID: 20883931
coronary artery disease; cardiovascular magnetic resonance; adverse cardiac prognosis; cardiovascular computer tomography
12.  Impaired Left Ventricular Stroke Volume Reserve During Clinical Dobutamine Stress 
Objective
To determine if dobutamine induced abnormal stress induce changes in left ventricular (LV) stroke volume (SV) and aortic stiffness predict future pulmonary edema.
Background
Heightened aortic stiffness that reduces LV stroke volume during adrenergic stress may serve as a marker for future pulmonary edema (P edema).
Methods
We measured LVSV, ventriculo-vascular stiffness (pulse pressure/LVSVi), and aortic distensibility (AoD) at rest and during intravenous dobutamine using cardiovascular magnetic resonance (DCMR). Personnel blinded to DCMR followed participants longitudinally over time to identify those admitted to the hospital with P edema. Data from 44 participants who experienced a hospital admission for P edema were compared to data from 72 participants of similar age, gender, and resting LV ejection fraction who remained free of P edema.
Results
Expressed as median and interquartile range, participants with versus without P edema exhibited a reduced ratio of stress/rest LVSV (0.9 [0.7,1.1] versus 1.0 [0.9,1.2], respectively, p= 0.002); an increased ventriculo-vascular stiffness stress/rest ratio (1.4 [1.0,1.6] versus 1.0 [0.8,1.3], respectively, p= ≤ 0.001); and a reduced stress induced measure of AoD (0.8 [0.3,1.3] versus 1.6 [1.2,3.2] mmHg−3, respectively, p=0.002). After accounting for age, gender, LVEF, risk factors for P edema and the presence of dobutamine induced ischemia, LVSV reserve and the stress/rest ventriculo-vascular stiffness ratio remained different (p<0.008 for both) between those with and without P edema.
Conclusions
In patients without inducible ischemia during dobutamine stress, in whom one might otherwise assume a favorable prognosis, the failure to increase LV stroke volume, or an increase in ventriculo-vascular stiffness indicates patients at risk for subsequent P edema.
doi:10.1016/j.jacc.2010.10.019
PMCID: PMC3634344  PMID: 21310321
Stroke volume; heart failure; dobutamine cardiovascular magnetic resonance
13.  Relationship of CRP, IL-6, and Fibrinogen with Right Ventricular Structure and Function: The MESA-Right Ventricle Study 
International journal of cardiology  2013;168(4):3818-3824.
Background/objectives
Inflammation contributes to the pathogenesis of disease associated with the left ventricle (LV); yet, our understanding of the effect of inflammation on the right ventricle (RV) is quite limited.
Methods and results
The relationships of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with RV morphology and function (from cardiac MRI) were examined in participants free of clinical cardiovascular disease (n=4,009) from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of CRP, IL-6 and fibrinogen with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF). Unadjusted and adjusted analyses revealed strong inverse associations between both CRP and IL-6 with RV mass, RVEDV, RVESV and RVSV (all p<0.01); there were no associations with RVEF. These relationships remained significant after adjustment for the respective LV parameters and lung function. However, GAM models suggested that extreme values of CRP and IL-6 might have positive associations with RV parameters. Fibrinogen showed significant associations in unadjusted models, but no associations after adjustment or in sensitivity analyses.
Conclusion
Levels of CRP and IL-6 are independently associated with RV morphology even after adjustment for the respective LV measure in this multi-ethnic population free of cardiovascular disease. Systemic inflammation may contribute to RV structural changes independent of effects on the LV.
doi:10.1016/j.ijcard.2013.06.028
PMCID: PMC3805818  PMID: 23932860
Systemic inflammation; right ventricle; heart failure; Multi-Ethnic Study of Atherosclerosis
15.  Association of resting heart rate with carotid and aortic arterial stiffness: Multi-Ethnic Study of Atherosclerosis (MESA) 
Hypertension  2013;62(3):10.1161/HYPERTENSIONAHA.113.01605.
Resting heart rate is an easily measured, non-invasive vital sign that is associated with cardiovascular disease events. The pathophysiology of this association is not known. We investigated the relationship between resting heart rate and stiffness of the carotid (a peripheral artery) and the aorta (a central artery) in an asymptomatic multi-ethnic population. Resting heart rate was recorded at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Distensibility was used as a measure of arterial elasticity, with a lower distensibility indicating an increase in arterial stiffness. Carotid distensibility was measured in 6,484 participants (98% of participants) using B-mode ultrasound and aortic distensibility was measured in 3,512 participants (53% of participants) using cardiac MRI. Heart rate was divided into quintiles and we used progressively adjusted models that included terms for physical activity and AV-nodal blocking agents. Mean resting heart rate of participants (mean age 62 years, 47% male) was 63 beats per minute (SD 9.6 beats per minute). In unadjusted and fully adjusted models, carotid distensibility and aortic distensibility decreased monotonically with increasing resting heart rate (p for trend <0.001 and 0.009 respectively). The relationship was stronger for carotid versus aortic distensibility. Similar results were seen using the resting heart rate taken at the time of MRI scanning. Our results suggest that a higher resting heart rate is associated with an increased arterial stiffness independent of AV-nodal blocker use and physical activity level, with a stronger association for a peripheral (carotid) compared to a central (aorta) artery.
doi:10.1161/HYPERTENSIONAHA.113.01605
PMCID: PMC3838105  PMID: 23836802
heart rate; cardiovascular disease; stiffness; ultrasound; cardiac magnetic resonance imaging
16.  Effect of Endurance Exercise Training on Endothelial function and Arterial Stiffness in Older Patients with Heart Failure and Preserved Ejection Fraction: A Randomized, Controlled, Single-Blind Trial 
Objectives
To evaluate the effects of endurance exercise training (ET) on endothelial dependent flow-mediated arterial dilation (FMD) and carotid artery stiffness and their potential contributions to the training-related increase in peak exercise oxygen consumption (VO2) in older patients with heart failure with preserved ejection fraction (HFPEF).
Background
Elderly HFFEF patients have severely reduced peak VO2 which improves with ET, however the mechanisms of this improvement are unclear. FMD and arterial distensibility are critical components of the exercise response and are reduced with aging. However, it's unknown whether these improve with ET in elderly HFPEF or contribute to the training-related improvement in peak VO2.
Methods
63 HFPEF patients (70±7 years) were randomized to 16 weeks of ET (walking, arm and leg ergometry, n=32) or attention control (CT; n=31). Peak VO2, brachial artery FMD in response to cuff ischemia, carotid artery distensibility by high-resolution ultrasound, LV function, and QOL were measured at baseline and follow-up.
Results
ET increased peak VO2 (ET: 15.8±3.3 vs. CT: 13.8±3.1 ml/kg/min, p=0.0001) and QOL. However, brachial artery FMD (ET: 3.8±3.0% vs. CT: 4.3±3.5%, p=0.88), and carotid arterial distensibility (ET: 0.97±0.56 vs. CT: 1.07±0.34 × 10-3mm × mmHg-1 p=0.65) were unchanged. Resting LV systolic and diastolic function were unchanged by ET.
Conclusions
In elderly HFPEF patients, 16 weeks of ET improved peak VO2 without altering endothelial function or arterial stiffness. This suggests that other mechanisms, such as enhanced skeletal muscle perfusion and / or oxygen utilization, may be responsible for the ET-mediated increase in peak VO2 in older HFPEF patients.
doi:10.1016/j.jacc.2013.04.033
PMCID: PMC3740089  PMID: 23665370
Heart Failure; Preserved ejection fraction; exercise; aging
17.  Stress Cardiac Magnetic Resonance Imaging Reduces Revascularization, Hospital Readmission, and Recurrent Cardiac Testing in Intermediate Risk Patients with Acute Chest Pain: A Randomized Trial 
JACC. Cardiovascular imaging  2013;6(7):785-794.
Objectives
To determine the effect of stress cardiac magnetic resonance (CMR) imaging in an observation unit (OU) on revascularization, hospital readmission, and recurrent cardiac testing in intermediate risk patients with possible acute coronary syndrome (ACS).
Background
Intermediate risk patients commonly undergo hospital admission with high rates of coronary revascularization. It is unknown whether OU-based care with CMR is a more efficient alternative.
Methods
We randomized 105 intermediate risk participants with symptoms of ACS but without definite ACS based on the first electrocardiogram and troponin to usual care provided by Cardiologists and Internists (n=53) versus OU care with stress CMR (n=52). We determined the primary composite endpoint of coronary artery revascularization, hospital readmission, and recurrent cardiac testing at 90 days. The secondary endpoint was length of stay from randomization to index visit discharge; safety was measured as ACS after discharge.
Results
The median age of participants was 56 (range 35 to 91) years, 54% were men, and 20% had pre-existing coronary disease. Index hospital admission was avoided in 85% of the OU-CMR participants. The primary outcome occurred in 20 (38%) usual care versus 7 (13%) OU-CMR participants (hazard ratio 3.4, 95% CI 1.4 – 8.0, p = .006). The OU-CMR group experienced significant reductions in all components: revascularizations [15% vs 2%, p=0.03], hospital readmissions [23% vs 8%, p = .03], and recurrent cardiac testing [17% vs 4%, p = .03]. Median length of stay was 26 hours (IQR: 23 – 45) in the usual care group and 21 hours (IQR: 15 – 25) in the OU-CMR group (p < .001). ACS after discharge occurred in 3 (6%) usual care and no OU-CMR participants.
Conclusions
In this single center trial, management of intermediate risk patients with possible ACS in an OU with stress CMR reduced coronary artery revascularization, hospital readmissions, and recurrent cardiac testing without an increase in post-discharge ACS at 90 days.
doi:10.1016/j.jcmg.2012.11.022
PMCID: PMC3710522  PMID: 23664718
chest pain; acute coronary syndrome; angioplasty; balloon; coronary; magnetic resonance imaging
18.  A Novel Approach to Early Detection of Doxorubicin Cardiotoxicity using Gadolinium Enhanced Cardiovascular Magnetic Resonance Imaging in an Experimental Model 
Background
To determine if cardiovascular magnetic resonance (CMR) measures of gadolinium (Gd) signal intensity (SI) within the left ventricular (LV) myocardium are associated with future changes in LV ejection fraction (LVEF) after receipt of doxorubicin (DOX).
Methods and Results
Forty Sprague-Dawley rats were divided into 3 groups scheduled to receive weekly intravenous doses of: normal saline (NS) (n=7), 1.5 mg/kg DOX (n=19), or 2.5 mg/kg DOX (n=14). MR determinations of LVEF and myocardial Gd-SI were performed before and then at 2, 4, 7, and 10 weeks after DOX initiation. During treatment, animals were sacrificed at different time points so that histopathological assessments of the LV myocardium could be obtained. Within group analyses were performed to examine time-dependent relationships between Gd-SI and primary events (a deterioration in LVEF or an unanticipated death). Six of 19 animals receiving 1.5 mg/kg of DOX and 10/14 animals receiving 2.5 mg/kg of DOX experienced a primary event; no NS animals experienced a primary event. In animals with a primary event, histopathological evidence of myocellular vacuolization occurred (p=0.04), and the Gd-SI was elevated relative to baseline at the time of the event (p<0.0001) and during the measurement period prior to the event (p=0.0001). In all animals (including NS) without an event, measures of Gd-SI did not differ from baseline.
Conclusions
After DOX, low serial measures of Gd-SI predict an absence of a LVEF drop or unanticipated death. An increase in Gd-SI after DOX forecasts a subsequent drop in LVEF as well as histopathologic evidence of intracellular vacuolization consistent with DOX cardiotoxicity.
doi:10.1161/CIRCIMAGING.109.918540
PMCID: PMC3068484  PMID: 20622140
cardiotoxicity; chemotherapy; congestive heart failure; doxorubicin
19.  Left Ventricular Hypertrophy Influences Cardiac Prognosis in Patients Undergoing Dobutamine Cardiac Stress Testing 
Background
This study was performed to determine the utility of dobutamine stress test results for predicting myocardial infarction (MI) and cardiac death in patients with chest pain and left ventricular hypertrophy (LVH).
Methods and Results
Three hundred fifty-three (353) participants, aged 64±12 years (54% men) underwent dobutamine cardiovascular magnetic resonance (DCMR) stress testing and then were followed for 6±2 (range 0.5 to 11.5) years to assess the post-DCMR occurrence of MI or cardiac death. Left ventricular mass and the presence or absence of ischemia were determined; LVH was defined as > 96 g/m2 in men and > 77 g/m2 in women. LVH was present in 62 participants (18 % of the men and 17% of the women, p=0.90). Seventy-one (20%) participants experienced a MI or cardiac death during follow-up. The MI and cardiac death rate was more frequent in those with versus without LVH (32% vs. 17%, p=0.009). In multivariable analysis that accounted for the presence of pre-existing coronary artery disease, hypertension, diabetes, stress induced ischemia, and reduced LVEF, LVH was an independent predictor of MI and cardiac death (hazard ratio = 1.99, 95% confidence interval = 1.13-3.50; p=0.02).
Conclusions
Left ventricular hypertrophy is predictive of future MI and cardiac death in patients with or without inducible ischemia during dobutamine cardiac stress testing. As a result, LVH should be reported in those referred for dobutamine cardiac stress tests, particularly those without inducible ischemia, in whom otherwise one would assume a favorable cardiac prognosis.
doi:10.1161/CIRCIMAGING.109.912071
PMCID: PMC3053573  PMID: 20442370
hypertrophy; magnetic resonance imaging; myocardial infarction
20.  Cardiovascular Magnetic Resonance Imaging: Is Only One Shop Worth the Stop? 
JACC. Cardiovascular imaging  2009;2(9):1144-1145.
doi:10.1016/j.jcmg.2009.07.004
PMCID: PMC3053568  PMID: 19761996
21.  Aortic Stiffness Increases Upon Receipt of Anthracycline Chemotherapy 
Journal of Clinical Oncology  2009;28(1):166-172.
Purpose
Cancer survivors exposed to anthracyclines experience an increased risk of cardiovascular (CV) events. We hypothesized that anthracycline use may increase aortic stiffness, a known predictor of CV events.
Patients and Methods
We performed a prospective, case-control study involving 53 patients: 40 individuals who received an anthracycline for the treatment of breast cancer, lymphoma, or leukemia (cases), and 13 age- and sex-matched controls. Each participant underwent phase-contrast cardiovascular magnetic resonance measures of pulse wave velocity (PWV) and aortic distensibility (AoD) in the thoracic aorta at baseline, and 4 months after initiation of chemotherapy. Four one-way analyses of covariance models were fit in which factors known to influence thoracic aortic stiffness were included as covariates in the models.
Results
At the 4-month follow-up visit, aortic stiffness remained similar to baseline in the control participants. However, in the participants receiving anthracyclines, aortic stiffness increased markedly (relative to baseline), as evidenced by a decrease in AoD (P < .0001) and an increase in PWV (P < .0001). These changes in aortic stiffness persisted after accounting for age, sex, cardiac output, administered cardioactive medications, and underlying clinical conditions known to influence aortic stiffness, such as hypertension or diabetes (P < .0001).
Conclusion
A significant increase in aortic stiffness occurs within 4 months of exposure to an anthracycline which was not seen in an untreated control group. These results indicate that previously regarded cardiotoxic cancer therapy adversely increases thoracic aortic stiffness, a known independent predictor of adverse cardiovascular events.
doi:10.1200/JCO.2009.23.8527
PMCID: PMC2799231  PMID: 19901105
22.  Submaximal Exercise Coronary Artery Flow Increases in Postmenopausal Women without Coronary Artery Disease after Estrogen and Atorvastatin 
Menopause (New York, N.Y.)  2010;17(1):114-120.
Objectives
To determine the effect of statins and hormone replacement therapy on submaximal exercise induced coronary artery blood flow in postmenopausal women without a history of coronary artery disease.
Background
Hormone replacement or statin therapy in early postmenopausal women without coronary artery disease have been shown to enhance arterial endothelial function; we hypothesized that these agents would improve submaximal exercise induced coronary artery blood flow.
Methods
Sixty-four postmenopausal women, aged 50–65 years without documented coronary artery disease, were randomized in a double blinded, cross-over fashion to receive 8 weeks of hormone replacement therapy versus placebo, with or without 80 mg/day of atorvastatin. Prior to receipt of any therapy and after each treatment period, each woman underwent measures of coronary artery blood flow at rest and stress.
Results
The combination of hormone replacement therapy and atorvastatin increased submaximal exercise induced coronary artery blood flow (p=0.04). In the subgroups of women compliant with treatment, resting coronary artery blood flow increased in those receiving hormone replacement therapy (p=0.03) or statin therapy (p=0.02).
Conclusion
In postmenopausal women aged 50–65 years without documented coronary artery disease, rest and submaximal exercise induced coronary artery blood flow improve after receipt of high dose atorvastatin and conjugated estrogen therapy.
doi:10.1097/gme.0b013e3181b63c4d
PMCID: PMC2806513  PMID: 19752761
estrogen; statins; exercise; magnetic resonance imaging; coronary artery flow
23.  Dobutamine Cardiovascular Magnetic Resonance Results Predict Cardiac Prognosis in Women with Known or Suspected Ischemic Heart Disease 
JACC. Cardiovascular imaging  2009;2(3):299-307.
Objective
To determine the prognostic utility of dobutamine cardiovascular magnetic resonance (DCMR) stress test results in women.
Background
To date, the preponderance of studies reporting the utility of DCMR stress results for predicting cardiac prognosis have been performed in men. We sought to determine the utility of DCMR results for predicting cardiac prognosis in women.
Methods
Two hundred sixty-six consecutively referred women underwent DCMR in which left ventricular wall motion (LVWM) was assessed at rest and after intravenous dobutamine and atropine. Inducible LVWM abnormalities were identified during testing. Women were contacted to determine the post DCMR occurrence of a cardiac event. All events were substantiated according to defined criteria, and then verified after a thorough medical record review by individuals blinded to testing data.
Results
Women were contacted an average of 6.2 ± 1.6 (median 6.2, range 0.8 to 10.4) years after DCMR; 27% of the women experienced an inducible LVWM abnormality during testing. In those with and without inducible LVWM abnormalities, the proportion of women with cardiac events were 63% versus 30%, respectively, (hazard ratio [HR] of 2.7 [CI 1.8 – 4.3] for the presence of inducible LVWM abnormalities p<0.0001). The proportion of women with myocardial infarction (MI) and cardiac death were 33.3% and 7.5%, respectively. This resulted in a HR for MI and cardiac death of 4.1 [CI 2.2 – 9.4] for those with versus without inducible LVWM abnormalities; p<0.0001. A subgroup analysis was performed in women without a history of coronary artery disease and in those with LVWM abnormalities, DCMR remained an adverse predictor of cardiac events (HR 4.0, CI 1.8 – 9.0, p=0.003).
Conclusions
Inducible LVWM abnormalities during DCMR predict cardiac death and MI in women. Similar to men, these results indicate DCMR is a valuable noninvasive stress imaging modality for identifying cardiac risk in women with known or suspected ischemic heart disease.
doi:10.1016/j.jcmg.2008.10.015
PMCID: PMC2920607  PMID: 19356575
Women; Prognosis; Magnetic Resonance
24.  Left Ventricular Infarct Size Assessed with 0.1 mmol/kg Gadobenate Dimeglumine (Gd-BOPTA) Correlates with 0.2 mmol/kg of Gadopentetate Dimeglumine (Gd-DTPA) 
Objective
To determine myocardial infarct (MI) size during cardiovascular magnetic resonance (CMR) at 1.5 Tesla using 0.1 mmol/kg bodyweight of gadobenate dimeglumine (Gd-BOPTA) and 0.2 mmol/kg bodyweight of gadopentetate dimeglumine (Gd-DTPA).
Methods
Twenty participants (16 men, 4 women), aged 58 ± 12 years, with a prior chronic MI were imaged in a cross-over design. Participants received 0.2 mmol/kg bodyweight of Gd-DTPA, and 0.1 mmol/kg bodyweight of Gd-BOPTA on 2 occasions separated by 3 to 7 days
Results
The correlations were high between Gd-DTPA and Gd-BOPTA measures of infarct volume (r=0.93) and the percentage of infarct relative to LV myocardial volume (r=0.85). The size and location of the infarcts were similar (p=0.9) for the 2 contrast agents. Interobserver correlation of infarct volume (r=0.91) was high.
Conclusions
In chronic myocardial infarction, late gadolinium enhancement identified with a single 0.1 mmol/kg bodyweight dose of Gd-BOPTA is associated in volume and location to a double (0.2 mmol/kg body weight) dose of Gd-DTPA. Lower doses of higher relaxivity contrast agents should be considered for determining LV myocardial infarct size.
doi:10.1097/RCT.0b013e318187fed0
PMCID: PMC2705952  PMID: 19478622
myocardial infarction; contrast; ischemic heart disease
25.  Location of Arterial Stiffening Differs in Those With Impaired Fasting Glucose Versus Diabetes 
Diabetes  2009;58(4):946-953.
OBJECTIVE
To determine whether middle-aged and older individuals with impaired fasting glucose (IFG), but no clinical evidence of cardiovascular disease, exhibit abnormal changes in proximal thoracic aortic stiffness or left ventricular (LV) mass when compared with healthy counterparts.
RESEARCH DESIGN AND METHODS
From the Multi-Ethnic Study of Atherosclerosis, 2,240 subjects with normal fasting glucose (NFG), 845 with IFG, and 414 with diabetes, all aged 45 to 85 years and without preexisting coronary artery disease, underwent MRI determinations of total arterial and proximal thoracic aortic stiffness and LV mass. The presence or absence of other factors known to influence arterial stiffness was assessed.
RESULTS
After adjustment for clinical factors known to modify arterial stiffness, proximal thoracic aortic stiffness was not increased in those with IFG compared with those with NFG (1.90 ± 0.05 versus 1.91 ± 0.04 10−3 mmHg−1, respectively, P = 0.83). After accounting for clinical factors known to influence LV mass, LV mass was increased in those with diabetes relative to those with NFG (150.6 ± 1.4 versus 145.8 ± 0.81 g, P < 0.0009) but not in those with IFG in comparison with NFG (145.2 ± 1.03 versus 145.8 ± 0.81 g, P = 0.56).
CONCLUSIONS
Middle-aged and older individuals with the pre-diabetes state of IFG do not exhibit abnormal proximal thoracic distensibility or LV hypertrophy relative to individuals with NFG. For this reason, an opportunity may exist in those with IFG to prevent LV hypertrophy and abnormal aortic stiffness that is observed in middle-aged and older individuals with diabetes.
doi:10.2337/db08-1192
PMCID: PMC2661581  PMID: 19136657

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