The role of renin angiotensin system antagonists in the prevention of doxorubicin and trastuzumab induced cardiotoxicity.

BACKGROUND: Cardio-Oncology is an evolving discipline that focuses on the management of cancer patients who develop cardiovascular complications as a result of their treatment. Although the current combination of surgical resection, radiation, and chemotherapy may lead to a cure in cancer patients, the administration of anti-cancer drugs, in particular Doxorubicin (DOX) and Trastuzumab (TRZ), is associated with an increased risk of cardiotoxicity. Little is known on the potential cardioprotective role of renin angiotensin system (RAS) antagonists in the prevention of DOX+TRZ mediated cardiotoxicity. OBJECTIVE: The aim of the study was to determine whether RAS antagonists would be useful in attenuating DOX+TRZ induced cardiotoxicity. METHODS: A total of 240 C57Bl/6 mice were randomized to prophylactic treatment with placebo, Aliskiren, Perindopril, or Valsartan for a total of 13 weeks. Within each arm, mice received treatment with either DOX, TRZ, or the combination of both drugs. Serial murine echocardiography was performed weekly to characterize the degree of cardiovascular remodeling within each group. RESULTS: In wild-type (WT) mice treated with DOX+TRZ, LV end diastolic internal diameter (LVID) increased from 3.1 ± 0.2 mm at baseline to 4.6 ± 0.3 mm at week 13 (p < 0.05) and the LV fractional shortening (FS) decreased from 52 ± 2% at baseline to 26 ± 2% at week 13 (p < 0.05). Prophylactic treatment with Aliskiren, Perindopril, or Valsartan attenuated the degree of LV cavity dilatation with LVID dimensions of 3.9 ± 0.2 mm, 4.1 ± 0.2 mm, and 4.2 ± 0.1 mm at week 13, respectively (p < 0.05). Similarly, prophylactic treatment with Aliskiren, Perindopril, or Valsartan was partially cardioprotective with FS of 40 ± 1%, 32 ± 1%, and 33 ± 2% at week 13, respectively (p < 0.05). As compared to WT mice receiving DOX+TRZ, prophylactic treatment with RAS inhibition was also associated with improved survival, corroborating the echocardiographic findings. CONCLUSION: The cardiotoxic effects of DOX+TRZ were partially attenuated by the prophylactic administration of RAS antagonists in a chronic murine model of chemotherapy induced cardiac dysfunction.

The impact of repeated marathon running on cardiovascular function in the aging population.

BACKGROUND: Several studies have correlated elevations in cardiac biomarkers of injury post marathon with transient and reversible right ventricular (RV) systolic dysfunction as assessed by both transthoracic echocardiography (TTE) and cardiovascular magnetic resonance (CMR). Whether or not permanent myocardial injury occurs due to repeated marathon running in the aging population remains controversial. OBJECTIVES: To assess the extent and severity of cardiac dysfunction after the completion of full marathon running in individuals greater than 50 years of age using cardiac biomarkers, TTE, cardiac computed tomography (CCT), and CMR. METHODS: A total of 25 healthy volunteers (21 males, 55 ± 4 years old) from the 2010 and 2011 Manitoba Full Marathons (26.2 miles) were included in the study. Cardiac biomarkers and TTE were performed one week prior to the marathon, immediately after completing the race and at one-week follow-up. CMR was performed at baseline and within 24 hours of completion of the marathon, followed by CCT within 3 months of the marathon. RESULTS: All participants demonstrated an elevated cTnT post marathon. Right atrial and ventricular volumes increased, while RV systolic function decreased significantly immediately post marathon, returning to baseline values one week later. Of the entire study population, only two individuals demonstrated late gadolinium enhancement of the subendocardium in the anterior wall of the left ventricle, with evidence of stenosis of the left anterior descending artery on CCT. CONCLUSIONS: Marathon running in individuals over the age of 50 is associated with a transient, yet reversible increase in cardiac biomarkers and RV systolic dysfunction. The presence of myocardial fibrosis in older marathon athletes is infrequent, but when present, may be due to underlying occult coronary artery disease.

Probabilistic White Matter Atlases of Human Auditory, Basal Ganglia, Language, Precuneus, Sensorimotor, Visual and Visuospatial Networks.

Background: Despite the popularity of functional connectivity analyses and the well-known topology of several intrinsic cortical networks, relatively little is known about the white matter regions (i.e., structural connectivity) underlying these networks. In the current study, we have therefore performed fMRI-guided diffusion tensor imaging (DTI) tractography to create probabilistic white matter atlases for eight previously identified functional brain networks, including the Auditory, Basal Ganglia, Language, Precuneus, Sensorimotor, Primary Visual, Higher Visual and Visuospatial Networks. Methods: Whole-brain diffusion imaging data were acquired from a cohort of 32 healthy volunteers, and were warped to the ICBM template using a two-stage, high-dimensional, non-linear spatial normalization procedure. Deterministic tractography, with fractional anisotropy (FA) ≥0.15 and deviation angle <50°, was then performed using the Fiber Association by Continuous Tracking (FACT) algorithm, and a multi-ROI approach to identify tracts of interest. Regions-of-interest (ROIs) for each of the eight networks were taken from a pre-existing atlas of functionally defined regions to explore all ROI-to-ROI connections within each network, and all resulting streamlines were saved as binary masks to create probabilistic atlases (across participants) for tracts between each ROI-to-ROI pair. Results: The resulting functionally-defined white matter atlases (i.e., for each tract and each network as a whole) were saved as NIFTI images in stereotaxic ICBM coordinates, and have been added to the UManitoba-JHU Functionally-Defined Human White Matter Atlas (http://www.nitrc.org/projects/uofm_jhu_atlas/). Conclusion: To the best of our knowledge, this work represents the first attempt to comprehensively identify and map white matter connectomes for the Auditory, Basal Ganglia, Language, Precuneus, Sensorimotor, Primary Visual, Higher Visual and Visuospatial Networks. Therefore, the resulting probabilistic atlases represent a unique tool for future neuroimaging studies wishing to ascribe voxel-wise or ROI-based changes (i.e., in DTI or other quantitative white matter imaging signals) to these functional brain networks.

Probabilistic atlases of default mode, executive control and salience network white matter tracts: an fMRI-guided diffusion tensor imaging and tractography study.

Diffusion tensor imaging (DTI) is a powerful MRI technique that can be used to estimate both the microstructural integrity and the trajectories of white matter pathways throughout the central nervous system. This fiber tracking (aka, "tractography") approach is often carried out using anatomically-defined seed points to identify white matter tracts that pass through one or more structures, but can also be performed using functionally-defined regions of interest (ROIs) that have been determined using functional MRI (fMRI) or other methods. In this study, we performed fMRI-guided DTI tractography between all of the previously defined nodes within each of six common resting-state brain networks, including the: dorsal Default Mode Network (dDMN), ventral Default Mode Network (vDMN), left Executive Control Network (lECN), right Executive Control Network (rECN), anterior Salience Network (aSN), and posterior Salience Network (pSN). By normalizing the data from 32 healthy control subjects to a standard template-using high-dimensional, non-linear warping methods-we were able to create probabilistic white matter atlases for each tract in stereotaxic coordinates. By investigating all 198 ROI-to-ROI combinations within the aforementioned resting-state networks (for a total of 6336 independent DTI tractography analyses), the resulting probabilistic atlases represent a comprehensive cohort of functionally-defined white matter regions that can be used in future brain imaging studies to: (1) ascribe DTI or other white matter changes to particular functional brain networks, and (2) compliment resting state fMRI or other functional connectivity analyses.

The role of three-dimensional echocardiography in the assessment of right ventricular dysfunction after a half marathon: comparison with cardiac magnetic resonance imaging.

BACKGROUND: Although marathon running is associated with transient right ventricular (RV) systolic dysfunction as detected by two-dimensional transthoracic echocardiography, quantitative assessment of the right ventricle is difficult because of its complex geometry. Little is known about the use of real-time three-dimensional echocardiography (RT3DE) in the detection of cardiac dysfunction after a half marathon. The aim of this study was to assess the extent of RV dysfunction after the completion of a half marathon using cardiac biomarkers, RT3DE, and cardiac magnetic resonance imaging (CMR). METHODS: A prospective study was performed in 15 individuals in 2009 participating in the Manitoba Half Marathon. Cardiac biomarkers (myoglobin, creatine kinase-MB and cardiac troponin T) were assessed and RT3DE and CMR were performed 1 week before, immediately after, and 1 week after the race. RESULTS: At baseline, cardiac biomarkers and ventricular function were within normal limits. Immediately following the half marathon, all patients demonstrated elevated cardiac troponin T levels, with a median value of 0.37 ng/mL. RV ejection fraction, as assessed by RT3DE, decreased from 59 ± 4% at baseline to 45 ± 5% immediately following the race (P < .05). On CMR, RV end-diastolic volume increased after the half marathon, and the RV ejection fraction was reduced, at 47 ± 5% compared with 60 ± 2% at baseline (P < .05). There were strong linear correlations between RV ejection fraction assessed by RT3DE and CMR at baseline and after the half marathon (r = 0.69 and r = 0.87, P < .01, respectively). CONCLUSIONS: Compared with CMR, RT3DE is a feasible and reproducible method of assessing transient RV dysfunction in athletes completing a half marathon.

Role of three-dimensional echocardiography in breast cancer: comparison with two-dimensional echocardiography, multiple-gated acquisition scans, and cardiac magnetic resonance imaging.

PURPOSE: In patients with breast cancer, the administration of doxorubicin and trastuzumab is associated with an increased risk of cardiotoxicity. Although multiple-gated acquisition (MUGA) scans and two-dimensional transthoracic echocardiography (TTE) are conventional methods for baseline and serial assessment of left ventricular ejection fraction (LVEF) in these patients, little is known about the use of real-time three-dimensional TTE (RT3D TTE) in this clinical setting. The aim of this study was to assess the accuracy of MUGA, 2D TTE, and RT3D TTE for determining LVEF in comparison to cardiac magnetic resonance imaging (CMR). METHODS: Between 2007 and 2009 inclusive, 50 female patients with human epidermal growth factor receptor 2-positive breast cancer received adjuvant trastuzumab after doxorubicin. Serial MUGA, 2D TTE, RT3D TTE, and CMR were performed at baseline, 6, and 12 months after the initiation of trastuzumab. RESULTS: A comparison of left ventricular end diastolic volume (LVEDV) demonstrated a modest correlation between 2D TTE and CMR (r = 0.64 at baseline; r = 0.69 at 12 months, respectively). A comparison of LVEDV between RT3D TTE and CMR demonstrated a stronger correlation (r = 0.87 at baseline; r = 0.95 at 12 months, respectively). Although 2D TTE demonstrated a weak correlation with CMR for LVEF assessment (r = 0.31 at baseline, r = 0.42 at 12 months, respectively), both RT3D TTE and MUGA showed a strong correlation when compared with CMR (r = 0.91 at baseline; r = 0.90 at 12 months, respectively). CONCLUSION: As compared with conventional MUGA, RT3D TTE is a feasible, accurate, and reproducible alternate imaging modality for the serial monitoring of LVEF in patients with breast cancer.