Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation.

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

Everolimus for the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy After Heart Transplantation (RADTAC Study).

OBJECTIVES: This study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT). BACKGROUND: Calcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs. METHODS: In this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (ΔLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection. RESULTS: Forty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 ± 3.5 µg/l vs. 8.6 ± 2.8 µg/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 ± 1.7 µg/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (ΔLVM = -13.0 ± 16.8 g vs. 2.1 ± 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Δ circumferential strain = -2.9 ± 2.8 vs. 2.1 ± 2.3; p < 0.001; ΔT1 mapping values = -32.7 ± 51.3 ms vs. 26.3 ± 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Δ mean arterial pressure = 4.2 ± 18.8 mm Hg vs. 2.8 ± 13.8 mm Hg; p = 0.77), renal function (Δ creatinine = 3.1 ± 19.9 µmol/l vs. 9 ± 21.8 µmol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups. CONCLUSIONS: The combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain.

Imaging correlates of the blood-brain barrier disruption in HIV-associated neurocognitive disorder and therapeutic implications.

OBJECTIVE: HIV-associated neurocognitive disorders (HANDs) in the context of suppressive combination antiretroviral therapy (cART) still occur. We explored the role of blood-brain barrier (BBB) disruption in the pathogenesis of HAND in the context of fully suppressive cART using dynamic contrast enhanced perfusion (DCE-P) MRI. DCE-P is a new MRI technique that measures capillary permeability as an indicator for BBB integrity. We hypothesized that virally suppressed incident HAND would be associated with an impaired BBB as determined by DCE-P. DESIGN: A cross sectional study. METHODS: K-trans, a metric derivative of DCE-P, was obtained from different regions of the brain in a cohort of 20 patients with HAND who were virally suppressed in both cerebrospinal fluid (CSF) and blood compared with CSF and blood markers of neuroinflammation as well as with neurometabolites derived from magnetic resonance (MR) spectroscopy. RESULTS: The K-trans data showed significantly impaired BBB in HAND patients when compared with the controls in the regions of the basal ganglia and anterior frontal white matter (both P < 0.0001). CSF neopterin and CSF/serum albumin ratio correlated positively with K-trans but not with blood levels. CONCLUSION: This study indicates that HAND in the context of viral suppression is associated with BBB disruption and the DCE MR derived K-trans metric is a very sensitive parameter to identify the BBB disruption. The finding of region-specific BBB disruption rather than globally and the lack of correlation with blood markers of neuroinflammation suggest that HIV and not systemic inflammation is driving the BBB disturbance and that the BBB disruption is a consequence of HIV already in the brain as opposed to HIV first causing BBB disruption then brain disease.

Native T1 Mapping in the Diagnosis of Cardiac Allograft Rejection: A Prospective Histologically Validated Study.

OBJECTIVES: This study aimed to determine the role of T1 mapping in identifying cardiac allograft rejection. BACKGROUND: Endomyocardial biopsy (EMBx), the current gold standard to diagnose cardiac allograft rejection, is associated with potentially serious complications. Cardiac magnetic resonance (CMR)-based T1 mapping detects interstitial edema and fibrosis, which are important markers of acute and chronic rejection. Therefore, T1 mapping can potentially diagnose cardiac allograft rejection noninvasively. METHODS: Patients underwent CMR within 24 h of EMBx. T1 maps were acquired at 1.5-T. EMBx-determined rejection was graded according to International Society of Heart and Lung Transplant (ISHLT) criteria. RESULTS: Of 112 biopsies with simultaneous CMR, 60 were classified as group 0 (ISHLT grade 0), 35 as group 1 (ISHLT grade 1R), and 17 as group 2 (2R, 3R, clinically diagnosed rejection, antibody-mediated rejection). Native T1 values in patients with grade 0 biopsies and left ventricular ejection fraction >60% (983 ± 42 ms; 95% confidence interval: 972 to 994 ms) were comparable to values in nontransplant healthy control subjects (974 ± 45 ms; 95% confidence interval: 962 to 987 ms). T1 values were significantly higher in group 2 (1,066 ± 78 ms) versus group 0 (984 ± 42 ms; p = 0.0001) and versus group 1 (1,001 ± 54 ms; p = 0.001). After excluding patients with an estimated glomerular filtration rate <50 ml/min/m2, there was a moderate correlation of log-transformed native T1 with high-sensitivity troponin T (r = 0.54, p < 0.0001) and pro-B-type natriuretic peptide (r = 0.67, p < 0.0001). Using a T1 cutoff value of 1,029 ms, the sensitivity, specificity, and negative predictive value were 93%, 79%, and 99%, respectively. CONCLUSIONS: Myocardial tissue characterization with T1 mapping displays excellent negative predictive capacity for the noninvasive detection of cardiac allograft rejection and holds promise to reduce substantially the EMBx requirement in cardiac transplant rejection surveillance.

Atrophic brain signatures of mild forms of neurocognitive impairment in virally suppressed HIV infection.

OBJECTIVE: There is a lack of evidence for the neurobiological underpinning of asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorders (MNDs) in virally suppressed HIV-positive persons. We hypothesized that such mild impairment would be associated with focal brain atrophy. DESIGN: A cross-sectional observational study. METHODS: Eighty-five virally suppressed HIV-positive and 44 geographically, demographically and lifestyle comparable HIV-negative men underwent anatomical MRI, neuropsychological evaluation and HIV laboratory tests. Volumes of interest (VOI) from magnetic resonance (MR) images were extracted using FreeSurfer to yield grey and white matter volumes in regions associated with HIV-related brain injury. HIV-associated neurocognitive disorder (HAND) [ANI = 38%, MND = 13%, HIV-associated dementia (HAD) = 3% vs. neuropsychologically-normal] was classified using Global Deficit Score (GDS ≥0.5) and functional decline. Effects of HIV status on VOI were assessed with multivariate analyses controlling for family-wise error. HAND categories and HIV biomarker effects on VOI were assessed with multiple regression. RESULTS: Relative to the HIV-negative group, the HIV-positive group demonstrated subcortical grey (d = 0.50-0.60) and white matter (d = 0.43-0.69) atrophy, with relative cortical sparing (d = 0.23). ANI showed reduced medial-orbitofrontal white matter compared with NP-normal cases (P = 0.04). MND showed enlarged lateral ventricles (P = 0.02) and reduced caudal-middle-frontal white matter (P = 0.04), caudal-anterior-cingulate white matter (P = 0.006) and inferior-parietal white matter (P = 0.04) compared with neuropsychologically normal. Across the HIV-positive group, lower CD4+/CD8 ratio was the strongest predictor of atrophy in subcortical regions. Across HAND categories, HIV disease duration uniquely predicted greater medial-orbitofrontal white matter atrophy only in ANI (P = 0.002). CONCLUSION: ANI shows specific frontal white matter atrophy to which HIV disease duration is a unique contributor. MND is characterized by more widespread subcortical atrophy.

Covertly active and progressing neurochemical abnormalities in suppressed HIV infection.

OBJECTIVE: To assess whether HIV-related brain injury is progressive in persons with suppressed HIV infection. METHODS: Seventy-three HIV+ virally suppressed men and 35 HIV- men, screened for psychiatric and alcohol/drug use disorders, underwent neuropsychological evaluation and proton magnetic resonance spectroscopy (1H-MRS) at baseline and after and 23 ± 5 months. 1H-MRS included brain regions known to be vulnerable to HIV and aging: frontal white matter (FWM), posterior cingulate cortex (PCC), and caudate area (CA). Major brain metabolites such as creatine (Cr: marker of cellular energy), N-acetyl aspartate (NAA: marker of neuronal integrity), choline (marker of cellular membrane turnover), glutamate/glutamine (excitatory/inhibitory neurotransmitter), and myo-Inositol (mI: marker of neuroinflammation) were calculated with reference to water signal. Neurocognitive decline was corrected for practice effect and baseline HIV-associated neurocognitive disorder (HAND) status. RESULTS: Across the study period, 44% had intact cognition, 42% stable HAND (including the single case that improved), 10% progressing HAND, and 4% incident HAND. When analyzing the neurochemical data per neurocognitive trajectories, we found decreasing PCC Cr in all subgroups compared with controls (p < 0.002). In addition, relative to the HIV- group, stable HAND showed decreasing FWM Cr, incident HAND showed steep FWM Cr reduction, whereas progressing HAND had a sharply decreasing PCC NAA and reduced but stable CA NAA. When analyzing the neurochemical data at the group level (HIV+ vs HIV- groups), we found stable abnormal metabolite concentrations over the study period: decreased FWM and PCC Cr (both p < 0.001), decreased PCC NAA and CA NAA (both p < 0.05) and PCC mI increase (p < 0.05). HIV duration and historical HAND had modest effects on metabolite changes. CONCLUSIONS: Our study reveals covertly active or progressing HIV-related brain injury in the majority of this virally suppressed cohort, reflecting ongoing neuropathogenic processes that are only partially worsened by historical HAND and HIV duration. Longer-term studies will be important for determining the prognosis of these slowly evolving neurochemical abnormalities.

White matter measures are near normal in controlled HIV infection except in those with cognitive impairment and longer HIV duration.

The objective of the current study was to quantify the degree of white matter (WM) abnormalities in chronic and virally suppressed HIV-infected (HIV+) persons while carefully taking into account demographic and disease factors. Diffusion tensor imaging (DTI) was conducted in 40 HIV- and 82 HIV+ men with comparable demographics and life style factors. The HIV+ sample was clinically stable with successful viral control. Diffusion was measured across 32 non-colinear directions with a b-value of 1000 s/mm2; fractional anisotropy (FA) and mean diffusivity (MD) maps were quantified with Itrack IDL. Using the ENIGMA DTI protocol, FA and MD values were extracted for each participant and in 11 skeleton regions of interest (SROI) from standard labels in the JHU ICBM-81 atlas covering major striato-frontal and parietal tracks. We found no major differences in FA and MD values across the 11 SROI between study groups. Within the HIV+ sample, we found that a higher CNS penetrating antiretroviral treatment, higher current CD4+ T cell count, and immune recovery from the nadir CD4+ T cell count were associated with increased FA and decreased MD (p < 0.05-0.006), while HIV duration, symptomatic, and asymptomatic cognitive impairment were associated with decreased FA and increased MD (p < 0.01-0.004). Stability of HIV treatment and antiretroviral CNS penetration efficiency in addition to current and historical immune recovery were related to higher FA and lower MD (p = 0.04-p < 0.01). In conclusion, WM DTI measures are near normal except for patients with neurocognitive impairment and longer HIV disease duration.

Maraviroc-intensified combined antiretroviral therapy improves cognition in virally suppressed HIV-associated neurocognitive disorder.

OBJECTIVE: To investigate whether intensification of combined antiretroviral therapy (cART) with the CC chemokine receptor type 5 (CCR5) entry inhibitor maraviroc leads to improvement in global neurocognitive functioning in virally suppressed men with HIV-associated neurocognitive disorder (HAND). DESIGN: Prospective, double observer-blinded, open-label pilot randomized-controlled trial. Participants were randomized to remain on their existing cART regimen (control arm; n = 8) or receive maraviroc-intensification (maraviroc arm; n = 9). METHODS: Participants completed a five-domain neuropsychological battery at baseline, 6- and 12-month visits. Raw scores were transformed into age-corrected z-scores and averaged into a global z-score. Single voxel (H)-magnetic resonance spectroscopy (MRS) major cerebral metabolite concentrations were collected at baseline and 12 months in the basal ganglia and frontal white matter and quantified using jMRUI. Neuroinflammatory biomarkers cerebrospinal fluid neopterin and ß2-microglobulin were also measured. RESULTS: Fourteen of the 17 participants completed the study: nine maraviroc arm and five control. We found medium to large effect sizes in favour of improved global neurocognitive performance in the maraviroc arm over time {arm*time interaction: P < 0.05; 6 month: [ß=-0.10, standard error (SE)= 0.04, 90% confidence interval (90%CI)= -0.18,.03; P < 0.03] yielding a large effect-size d = 0.77 (90%CI = -0.19,1.71); 12 month: [ß=-0.01; SE = 0.05; 90%CI = -0.09, 0.06; P < 0.77] yielding a moderate effect-size d = 0.55 (90%CI = -0.47,1.55)}. No treatment-related changes were detected for H-MRS metabolites or cerebrospinal fluid biomarkers. CONCLUSION: This pilot study provides feasibility, tolerability, proof-of-concept and preliminary evidence for clinically relevant neurocognitive improvement in cART enhancement with maraviroc in virally suppressed HAND patients. Lack of concomitant brain metabolite and biomarker change may be related to complex dynamics of brain repair.

HIV, vascular and aging injuries in the brain of clinically stable HIV-infected adults: a (1)H MRS study.

BACKGROUND: Cardiovascular disease (CVD) and premature aging have been hypothesized as new risk factors for HIV associated neurocognitive disorders (HAND) in adults with virally-suppressed HIV infection. Moreover, their significance and relation to more classical HAND biomarkers remain unclear. METHODS: 92 HIV- infected (HIV+) adults stable on combined antiretroviral therapy (cART) and 30 age-comparable HIV-negative (HIV-) subjects underwent (1)H Magnetic Resonance Spectroscopy (MRS) of the frontal white matter (targeting HIV, normal aging or CVD-related neurochemical injury), caudate nucleus (targeting HIV neurochemical injury), and posterior cingulate cortex (targeting normal/pathological aging, CVD-related neurochemical changes). All also underwent standard neuropsychological (NP) testing. CVD risk scores were calculated. HIV disease biomarkers were collected and cerebrospinal fluid (CSF) neuroinflammation biomarkers were obtained in 38 HIV+ individuals. RESULTS: Relative to HIV- individuals, HIV+ individuals presented mild MRS alterations: in the frontal white matter: lower N-Acetyl-Aspartate (NAA) (p<.04) and higher myo-inositol (mIo) (p<.04); in the caudate: lower NAA (p = .01); and in the posterior cingulate cortex: higher mIo (p<.008- also significant when Holm-Sidak corrected) and higher Choline/NAA (p<.04). Regression models showed that an HIV*age interaction was associated with lower frontal white matter NAA. CVD risk factors were associated with lower posterior cingulate cortex and caudate NAA in both groups. Past acute CVD events in the HIV+ group were associated with increased mIo in the posterior cingulate cortex. HIV duration was associated with lower caudate NAA; greater CNS cART penetration was associated with lower mIo in the posterior cingulate cortex and the degree of immune recovery on cART was associated with higher NAA in the frontal white matter. CSF neopterin was associated with higher mIo in the posterior cingulate cortex and frontal white matter. CONCLUSIONS: In chronically HIV+ adults with long-term viral suppression, current CVD risk, past CVD and age are independent factors for neuronal injury and inflammation. This suggests a tripartite model of HIV, CVD and age likely driven by chronic inflammation.

A radiologic study of the tympanic bone: anatomy and surgery.

OBJECTIVE: The aim of this study was to obtain data on the anatomic structure of the tympanic bone using parasagittal reformatted images created from high-resolution axial computed tomographic scans. In particular, the thickness of the bone in the region of the temporomandibular joint and the floor of the external auditory canal was assessed. The findings are discussed with particular emphasis on the relevance to surgery in this area. BACKGROUND: Surgical management of the tympanic bone forms the basis of canalplasty, which is an essential step in the management of disorders of the external auditory canal. Adequate canalplasty is also crucial in the provision of access for tympanoplasty and to ensure optimal cavity geometry in canal wall down mastoidectomy. Tympanic bone removal is a major step in approaches to the lateral skull base and infratemporal fossa. The tympanic bone is also important because it has critical neurovascular relations in this region of the skull base. METHODS: Computed tomography of the tympanic bone (parasagittal reformatted images) in 54 consecutive adults. RESULTS: The mean thickness of the anterosuperior, anteroinferior, and inferior aspects of the tympanic bone are 2.6, 2.8, and 8 mm, respectively. CONCLUSION: Canalplasty is safely performed in the regions outlined. The technique of canalplasty described in this article is essential for good exposure in external ear, middle ear, mastoid, and skull base surgery.