Evaluation of left atrial remodeling using cardiovascular magnetic resonance imaging in breast cancer patients treated with adjuvant trastuzumab.

OBJECTIVES: We evaluated left atrial (LA) remodeling using cardiac MRI (CMR) in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer during and after trastuzumab therapy. METHODS: In this prospective 2-center longitudinal study, 41 women with HER2-positive breast cancer received adjuvant trastuzumab for 12 months, in addition to standard chemotherapy. Serial CMRs were performed at baseline, 6, 12, and 18 months after initiation of trastuzumab. LA volumes were measured by a blinded reader. Linear mixed model was used to evaluate longitudinal changes. RESULTS: Of 41 women (mean age 52 ± 11 [SD] years; 56% received anthracycline), one patient experienced trastuzumab-induced cardiotoxicity (TIC) for which trastuzumab was interrupted for one cycle. Mean baseline left ventricular ejection fraction (LVEF) was 68.0 ± 5.9% and LA ejection fraction (LAEF) was 66.0 ± 6.6%. Compared to baseline, LAEF decreased significantly at 6 months (62.7 ± 5.7%, p = 0.027) and 12 months (62.2 ± 6.1%, p = 0.003), while indexed LA minimum volume (LAmin) significantly increased at 12 months (11.6 ± 4.9 ml/m2 vs 13.8 ± 4.5 ml/m2, p = 0.002). At 18 months, all changes from baseline were no longer significant. From baseline to 6 months, change in LAEF correlated with change in LVEF (Spearman's r = 0.41, p = 0.014). No significant interactions (all p > 0.10) were detected between time and anthracycline use for LA parameters. CONCLUSIONS: Among trastuzumab-treated patients with low incidence of TIC, we observed a small but significant decline in LAEF and increase in LAmin that persisted for the duration of therapy and recovered 6 months after therapy cessation. These findings suggest that trastuzumab has concurrent detrimental effects on atrial and ventricular remodeling. KEY POINTS: • In trastuzumab-treated breast cancer patients evaluated by cardiac MRI, left atrial ejection fraction declined and minimum volume increased during treatment and recovered to baseline after trastuzumab cessation. • Changes in left atrial ejection fraction correlated with changes in left ventricular ejection fraction in the first 6 months of trastuzumab treatment. • Trastuzumab therapy is associated with concurrent detrimental effects on left atrial and ventricular remodeling.

Association Between Neuropsychiatric Symptom Trajectory and Conversion to Alzheimer Disease.

INTRODUCTION: Neuropsychiatric symptoms (NPS) are both common in mild cognitive impairment and Alzheimer disease (AD). Studies have shown that some NPS such as apathy and depression are a key indicator for progression to AD. METHODS: We compared Neuropsychiatric Inventory (NPI) total score and NPI subdomain score between mild cognitive impairment-converters (MCI-C) and mild cognitive impairment-nonconverters (MCI-NC) longitudinally for 6 years using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. In addition to the NPI, Mini-Mental State Examination (MMSE) scores were also compared to find out if MMSE scores would differ between different NPI groups. Lastly, a linear regression model was done on MMSE and NPI total score to establish a relationship between MMSE and NPI total score. RESULTS: The results in this study showed that NPI total scores between MCI-C and MCI-NC differed significantly throughout 6 years. MCI-C subjects had a higher mean NPI total score and lower MMSE score compared with MCI-NC subjects. In addition, MMSE scores were significantly different between the 3 groups of NPI total score. Subjects who have a high NPI score have the lowest mean MMSE score, thus demonstrating that NPI scores do indeed affect MMSE scores. Further analyses using a regression model revealed that a unit change in NPI total score lead to 0.1 to 0.3 decrease in MMSE. DISCUSSION: On the basis of the findings, this study showed evidence that increase in NPS burden (reflected by increase in NPI) over time predicts conversion to AD, whereas stability of symptoms (reflected by stable NPI score) favors nonconversion. Further study should investigate the underlying mechanisms that drive both NPS burden and cognitive decline.

Cerebrospinal Fluid Correlates of Neuropsychiatric Symptoms in Patients with Alzheimer's Disease/Mild Cognitive Impairment: A Systematic Review.

BACKGROUND: Neuropsychiatric symptoms (NPS) are common, accelerate the conversion to dementia, and are associated with increased caregiver burden in Alzheimer's disease (AD) and mild cognitive impairment (MCI). OBJECTIVE: The aim of this study is to identify potential associations between the core cerebrospinal fluid (CSF) biomarkers (amyloid/tau) and NPS in AD/MCI. METHODS: For this systematic review, four databases, PubMed (1946-2018), Cochrane (2005-2018), EMBASE (1947-2018), and PsycINFO (1806-2018) were searched for relevant observational studies using an extensive list of keywords. English studies were selected for critical appraisal based on our inclusion/exclusion criteria. Inclusion criteria were defined as 1) at least one AD CSF biomarker has been measured; 2) at least one NPS has been assessed; and 3) analysis has been done to examine the association between core AD CSF biomarker and NPS (main outcome). Animal, postmortem, and review studies were excluded. RESULTS: In total, 21 studies qualified for the systematic review. The overall picture regarding the association between NPS and AD CSF biomarkers is conflicting. However, agitation/aggression was significantly and consistently related to core AD CSF biomarkers. Moreover, depression was the only NPS to occasionally be associated with lower core AD CSF pathology. CONCLUSION: Our study has revealed agitation/aggression as the most consistent NPS related to core AD CSF biomarkers. Future studies are required to focus on other neglected NPS domains such as disinhibition. Moreover, why depression was the only NPS inversely associated with core AD CSF pathology remains to be elucidated. Our study also revealed a great degree of heterogeneity, hence calling for a more standardized "objective" approach for the evaluation of NPS.

Serial Measurements of Left Ventricular Systolic and Diastolic Function by Cardiac Magnetic Resonance Imaging in Patients with Early Stage Breast Cancer on Trastuzumab.

Our aim was to evaluate the temporal changes in left ventricular (LV) diastolic filling in relation to other LV parameters using cardiac MRI (CMR) in patients with HER2 positive breast cancer receiving trastuzumab therapy. Fourty-one women with early stage HER2+ breast cancer underwent serial CMR (baseline, 6, 12, and 18 months) after initiation of trastuzumab therapy. A single, blinded observer measured LV parameters on de-identified CMRs in random order. Linear mixed models were used to investigate temporal changes. Compared to baseline, there were significant decreases in systolic function as measured by both left ventricular ejection fraction (LVEF) (p <0.001 at 6 and 12 months) and peak ejection rate corrected for end-diastolic volume (PER/LVEDV) (p = 0.008 at 6 months, p = 0.01 at 12 months). However, these differences were no longer significant at 18 months. In contrast, significant reductions in diastolic function as measured by LV peak filling rate corrected for end-diastolic volume (PFR/LVEDV) were observed at 6 months (p = 0.012), 12 months (p = 0.031), and up to 18 months (p = 0.034). There were no significant temporal changes in the time to peak filling rate corrected for cardiac cycle (TPF/RR). The reduction in PFR/LVEDV at 18 months was no longer significant when corrected for heart rate. In conclusion, there were significant subclinical deleterious effects on both LV systolic and diastolic function among patients receiving trastuzumab. While there was recovery in LV systolic function after therapy cessation at 18 months, reduction in PFR/LVEDV appeared to persist. Thus, diastolic dysfunction may serve as a marker of trastuzumab-induced cardiotoxicity that needs to be confirmed in a larger study.

Gray Matter Changes Associated With the Development of Delusions in Alzheimer Disease.

OBJECTIVE: Delusions affect approximately a third of Alzheimer disease (AD) patients and are associated with poor outcomes. Previous studies investigating the neuroanatomic correlates of delusions have yet to reach a consensus, with findings of reduced volume across all lobes, particularly in frontal regions. The current study examined the gray matter (GM) differences associated with delusions in AD. METHODS: Using voxel-based morphometry, we assessed GM in 23 AD patients who developed delusions (AD+D) and 36 comparable AD patients who did not (AD-D) at baseline and follow-up. Analysis of variance was used to identify consistent differences between AD+D and AD-D patients across time points (main effect of group), consistent changes from baseline to follow-up (main effect of time), and differential changes between AD+D and AD-D over time (interaction of group and time). All data were obtained from the National Alzheimer's Coordinating Center database. RESULTS: The AD+D group had consistently lower frontal GM volume, although both groups showed decreased GM in frontotemporal brain regions over time. An interaction was observed between delusions and longitudinal change, with AD+D patients having significantly elevated GM in predominantly temporal areas at baseline assessment, becoming significantly lower than the AD-D group at follow-up. CONCLUSION: These findings suggest that, there are specific volumetric markers that distinguish patients with delusions from those without, before, and after the onset of delusions. Specifically, the decline of GM in temporal areas that had elevated levels prior to the onset of delusions may be involved in the manifestation of delusions.

Early diastolic strain rate measurements by cardiac MRI in breast cancer patients treated with trastuzumab: a longitudinal study.

We evaluated temporal changes in early diastolic strain rates by cardiovascular magnetic resonance (CMR) as an early detector of trastuzumab-induced ventricular dysfunction. We conducted a prospective, multi-centre, longitudinal observational study of 41 trastuzumab-treated breast cancer women who underwent serial CMR (baseline, 6, 12, and 18 months). Two blinded readers independently measured left ventricular ejection fraction (LVEF), peak systolic strain parameters (global longitudinal strain [GLS] and global circumferential strain [GCS]), and early diastolic strain rate parameters (global longitudinal diastolic strain rate [GLSR-E], global circumferential diastolic strain rate [GCSR-E], and global radial diastolic strain rate [GRSR-E]), by feature tracking (FT-CMR) using CMR42. There was a significant decline in peak systolic strain GLS and GCS at 6 months (p = 0.024 and p < 0.001, respectively) and 12 months (p = 0.002 and p < 0.001, respectively), followed by recovery at 18 months, which paralleled decline in LVEF at 6 months (p = 0.034) and 12 months (p = 0.012). Conversely, early diastolic strain rates GLSR-E and GCSR-E did not significantly change over 18 months (p > 0.10), while GRSR-E was marginally significant at 12 months (p = 0.021). There was no significant correlation between changes at 6 months in LVEF and GLSR-E or GRSR-E (p > 0.10), and a marginally significant weak correlation between LVEF and GCSR-E (p = 0.046). Among trastuzumab-treated patients without overt cardiotoxicity, there was no consistent temporal change in FT-CMR-derived diastolic strain rate parameters up to 18 months, in contrast to decline in systolic strain and LVEF. Systolic strains by FT-CMR are likely more useful than diastolic strain rates for monitoring subclinical trastuzumab-related myocardial dysfunction.ClinicalTrials.gov identifier NCT01022086.

Cardiac MRI and radionuclide ventriculography for measurement of left ventricular ejection fraction in ICD candidates.

OBJECTIVE: Current guidelines provide left ventricular ejection fraction (LVEF) criterion for use of implantable cardioverter defibrillators (ICD) but do not specify which modality to use for measurement. We compared LVEF measurements by radionuclide ventriculography (RNV) vs cardiac MRI (CMR) in ICD candidates to assess impact on clinical decision making. METHODS: This single-centre study included 124 consecutive patients referred for assessment of ICD implantation who underwent RNV and CMR within 30 days for LVEF measurement. RNV and CMR were interpreted independently by experienced readers. RESULTS: Among 124 patients (age 64 ±â€¯11 years, 77% male), median interval between CMR and RNV was 1 day; mean LVEF was 32 ±â€¯12% by CMR and 33 ±â€¯11% by RNV (p = 0.60). LVEF by CMR and RNV showed good correlation, but Bland-Altman analysis showed relatively wide limits of agreement (-12.1 to 11.4). CMR LVEF reclassified 26 (21%) patients compared to RNV LVEF (kappa = 0.58). LVEF by both modalities showed good interobserver reproducibility (ICC 0.96 and 0.94, respectively) (limits of agreement -7.27 to 5.75 and -8.63 to 6.34, respectively). CONCLUSION: Although LVEF measurements by CMR and RNV show moderate agreement, there is frequent reclassification of patients for ICD placement based on LVEF between these modalities. Future studies should determine if a particular imaging modality for LVEF measurement may enhance ICD decision making and treatment benefit.

Computed tomography identified factors that preclude living kidney donation.

INTRODUCTION: The purpose of this study was to determine the variety and prevalence of renal and non-renal abnormalities detected on multidetector computed tomography (MDCT) that precluded patients from donating a kidney. METHODS: Institutional review board approval was obtained and the requirement for informed consent was waived. A retrospective, single-centre review of 701 patients (444 female, 257 male; age range 18-86 years; mean age 43.2±11.9 years) that underwent renal donor protocol MDCT was conducted. A systematic review of the CT report, records from multidisciplinary renal transplantation rounds, and electronic medical records was performed to determine which patients were approved or declined as live renal donors. If declined as a donor, CT-identified reasons were categorized as abnormalities of renal vasculature, renal parenchyma, collecting system, or extra-renal. RESULTS: A total of 81 patients were excluded as renal donors on the basis of CT findings. Abnormalities of the collecting system accounted for the most frequent cause of exclusion (n=41), with asymptomatic renal calculi being detected in 39 patients. Complex vascular anatomy and vascular abnormalities resulted in the exclusion of 29 patients. Supernumerary arteries and early arterial branching resulted in the exclusion of 20 patients, while renal vein anomalies leading to exclusion were uncommon (n=2). Abnormalities of renal parenchyma resulted in the exclusion of nine patients. Three patients were diagnosed with autosomal dominant polycystic kidney disease, two patients had renal cell carcinoma, and two patients had areas of cortical scarring. A complex cystic lesion requiring surveillance imaging was encountered in one patient and a large area of renal infarction related to prior adrenalectomy was demonstrated in one patient. Extra-renal abnormalities leading to exclusion were limited to two patients with pulmonary nodules. CONCLUSIONS: MDCT plays a critical role in the preoperative assessment of potential renal donors by identifying contraindications to donor nephrectomy and providing accurate vascular mapping. This study is anticipated to be informative for those involved in the workup of potential living renal donors by quantifying the incidence and reasons for donor exclusion identified on CT.

Myocardial strain imaging by cardiac magnetic resonance for detection of subclinical myocardial dysfunction in breast cancer patients receiving trastuzumab and chemotherapy.

BACKGROUND: Our objectives were to evaluate the temporal changes in CMR-based strain imaging, and examine their relationship with left ventricular ejection fraction (LVEF), in patients treated with trastuzumab. PATIENTS AND METHODS: In this prospective longitudinal observational study, 41 women with HER2+ breast cancer treated with chemotherapy underwent serial CMR (baseline, 6, 12, and 18 months) after initiation of trastuzumab (treatment duration 12 months). LVEF and LV strain (global longitudinal[GLS] and circumferential[GCS]) measurements were independently measured by 2 blinded readers. RESULTS: Of the 41 patients, 56% received anthracycline-based chemotherapy. Compared to baseline (60.4%, 95%CI 59.2-61.7%), there was a small but significant reduction in LVEF at 6 months (58.4%, 95%CI 56.7-60.0%, p = 0.034) and 12 months (57.9%, 95%CI 56.4-59.7%, p = 0.012), but not at 18 months (60.2%, 95%CI 58.2-62.2%, p = 0.93). Similarly, compared to baseline, GLS and GCS decreased significantly at 6 months (p = 0.024 and < 0.001, respectively) and 12 months (p = 0.002 and < 0.001, respectively) with an increase in LV end-diastolic volume, but not at 18 months. There were significant correlations between the temporal (6 month-baseline) changes in LVEF, and all global strain measurements (Pearson's r = -0.60 and r = -0.75 for GLS and GCS, respectively, all p < 0.001). CONCLUSION: There was a significant reduction in LV strain during trastuzumab treatment, which correlated with a concurrent subtle decline in LVEF and was associated with an increase in LV end-diastolic volume. LV strain assessment by CMR may be a promising method to monitor for subclinical myocardial dysfunction in breast cancer patients receiving chemotherapy. Future studies are needed to determine its prognostic and therapeutic implications.

Longitudinal assessment of right ventricular structure and function by cardiovascular magnetic resonance in breast cancer patients treated with trastuzumab: a prospective observational study.

BACKGROUND: There are limited data on the effects of trastuzumab on the right ventricle (RV). Therefore, we sought to evaluate the temporal changes in right ventricular (RV) structure and function as measured by cardiovascular magnetic resonance (CMR), and their relationship with left ventricular (LV) structure and function in breast cancer patients treated with trastuzumab. METHODS: Prospective, longitudinal, observational study involving 41 women with HER2+ breast cancer who underwent serial CMR at baseline, 6, 12, and 18 months after initiation of trastuzumab. A single blinded observer measured RV parameters on de-identified CMRs in a random order. Linear mixed models were used to investigate temporal changes in RV parameters. RESULTS: Of the 41 women (age 52 ± 11 years), only one patient experienced trastuzumab-induced cardiotoxicity. Compared to baseline, there were small but significant increases in the RV end-diastolic volume at 6 months (p = 0.002) and RV end-systolic volume at 6 and 12 months (p < 0.001 for both), but not at 18 months (p = 0.82 and 0.13 respectively). RV ejection fraction (RVEF), when compared to baseline (58.3%, 95% CI 57.1-59.5%), showed corresponding decreases at 6 months (53.9%, 95% CI 52.5-55.4%, p < 0.001) and 12 months (55%, 95% CI 53.8-56.2%, p < 0.001) that recovered at 18 months (56.6%, 95% CI 55.1-58.0%, p = 0.08). Although the temporal pattern of changes in LVEF and RVEF were similar, there was no significant correlation between RVEF and LVEF at baseline (r = 0.29, p = 0.07) or between their changes at 6 months (r = 0.24, p = 0.17). CONCLUSION: In patients receiving trastuzumab without overt cardiotoxicity, there is a subtle but significant deleterious effect on RV structure and function that recover at 18 months, which can be detected by CMR. Furthermore, monitoring of LVEF alone may not be sufficient in detecting early RV injury. These novel findings provide further support for CMR in monitoring early cardiotoxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01022086 . Date of registration: November 27, 2009.

Relationship between changes in blood pressure and left ventricular mass over 1 year in end-stage renal disease.

OBJECTIVE: The optimal timing of blood pressure (BP) measurement is not firmly established for patients undergoing hemodialysis. We sought to assess which BP measurement change best correlates with changes in left ventricular mass index (LVMI) over 1 year in patients with end-stage renal disease. METHODS: Fifty-seven patients were included in a prospective cohort study comparing the cardiovascular impact of conversion to in-center nocturnal hemodialysis versus continuing conventional hemodialysis. BP measurements were recorded at different time points (predialysis, after initiation of dialysis, at the intradialytic nadir, and postdialysis) during dialysis sessions over 12 weeks at baseline and after 1-year follow-up. LVMI was independently measured by a single blinded reader using cardiac magnetic resonance imaging at baseline and 1 year. RESULTS: Overall, the mean LVMI was 69.9 g/m (standard deviation 15.9) at baseline and 69.6 g/m (standard deviation 16.0) at 1 year. The change in initiation mean arterial pressure (MAP) most strongly correlated with the change in LVMI (Pearson correlation coefficient r = 0.71, P < 0.001). The relationship was similar in both dialysis groups and in multivariable analysis. In pairwise comparisons, initiation MAP was more strongly correlated with the change in LVMI than nadir and postdialysis measurements (all P < 0.05). However, the correlation was not stronger than predialysis SBP (P = 0.33). CONCLUSION: The change in initiation MAP correlated best with the change in LVMI over 1 year in patients undergoing hemodialysis. Further studies are needed to determine whether it represents a potentially useful treatment target to prevent adverse ventricular remodeling, thereby improving cardiovascular outcome.ClinicalTrials.gov Identifier: NCT00718848.