Echocardiographic findings in acromegaly: prevalence of concentric left ventricular remodeling in a large single-center cohort.

PURPOSE: Acromegaly is a rare disease and is associated with increased cardiovascular (CV) morbidity and mortality, especially in patients with uncontrolled disease. We aimed to analyze the prevalence and severity of cardiomyopathy and valvular heart disease in a large cohort of patients with a confirmed acromegaly diagnosis, at baseline and after treatment. METHODS: We retrospectively reviewed an institutional approved database; 190 patients with confirmed acromegaly and follow-up data available (years 2006-2018). Patients with at least one baseline echocardiogram, were included. Demographic, disease control and echocardiogram variables were collected for analysis. RESULTS: Of the 190 patients 110 (58%) had a baseline echocardiogram and 43 (39.1%) had at least one follow-up echocardiogram after surgical, medical or multimodal treatment. Baseline left ventricular hypertrophy (LVH) prevalence was 17.8% (64.7% concentric; 35.3% eccentric), diastolic and systolic dysfunction, and overt cardiomyopathy with heart failure were 15.8, 7.9, and 3.0%, respectively. Concentric remodeling of the left ventricle (LV) was noted in 31.4% of patients without LVH. Valve defects were found in 87.3% of patients (14.6% with significant valvular heart disease). CONCLUSION: Early diagnosis of acromegaly and disease control should be attempted to prevent LVH/LV dysfunction and development of valvular heart disease. Concentric LV remodeling develops prior to obvious LV hypertrophy in almost a third of patients with acromegaly, which is a novel finding. Similar to other epidemiological studies, we found a high prevalence of LVH/LV dysfunction. Although possible, reversal of systolic and diastolic dysfunction is sporadic after treatment of acromegaly.

Distinguishing Extravascular from Intravascular Ferumoxytol Pools within the Brain: Proof of Concept in Patients with Treated Glioblastoma.

BACKGROUND AND PURPOSE: Glioblastoma-associated macrophages are a major constituent of the immune response to therapy and are known to engulf the iron-based MR imaging contrast agent, ferumoxytol. Current ferumoxytol MR imaging techniques for localizing macrophages are confounded by contaminating intravascular signal. The aim of this study was to assess the utility of a newly developed MR imaging technique, segregation and extravascular localization of ferumoxytol imaging, for differentiating extravascular-from-intravascular ferumoxytol contrast signal at a delayed 24-hour imaging time point. MATERIALS AND METHODS: Twenty-three patients with suspected post-chemoradiotherapy glioblastoma progression underwent ferumoxytol-enhanced SWI. Segregation and extravascular localization of ferumoxytol imaging maps were generated as the voxelwise difference of the delayed (24 hours) from the early (immediately after administration) time point SWI maps. Continuous segregation and extravascular localization of ferumoxytol imaging map values were separated into positive and negative components. Image-guided biologic correlation was performed. RESULTS: Negative segregation and extravascular localization of ferumoxytol imaging values correlated with early and delayed time point SWI values, demonstrating that intravascular signal detected in the early time point persists into the delayed time point. Positive segregation and extravascular localization of ferumoxytol imaging values correlated only with delayed time point SWI values, suggesting successful detection of the newly developed extravascular signal. CONCLUSIONS: Segregation and extravascular localization of ferumoxytol MR imaging improves on current techniques by eliminating intrinsic tissue and intravascular ferumoxytol signal and may inform glioblastoma outcomes by serving as a more specific metric of macrophage content compared with uncorrected T1 and SWI techniques.

Brainstem control of cerebral blood flow and application to acute vasospasm following experimental subarachnoid hemorrhage.

Symptomatic ischemia following aneurysmal subarachnoid hemorrhage (SAH) is common but poorly understood and inadequately treated. Severe constriction of the major arteries at the base of the brain, termed vasospasm, traditionally has been thought to be a proximal event underlying these ischemias, although microvascular changes also have been described. The vast majority of studies aimed at understanding the pathogenesis of ischemic deficits, and vasospasm have focused on the interaction of the "spasmogen" of the extravasated blood with the smooth muscle and endothelium of the arteries. This has led to a comparative neglect of the contribution of the CNS to the maintenance of cerebral perfusion. In the present study, we focused on the role of the rostral ventromedial medulla (RVM) in modulating cerebral perfusion at rest and following an experimental SAH in the rat. Changes in cerebral blood flow (CBF) were measured using laser-Doppler flowmetry and three-dimensional optical microangiography. Focal application of a GABA(A) receptor agonist and antagonist was used to respectively inactivate and activate the RVM. We show here that the RVM modulates cerebral blood flow under resting conditions, and further, contributes to restoration of cerebral perfusion following a high-grade SAH. Failure of this brainstem compensatory mechanism could be significant for acute perfusion deficits seen in patients following subarachnoid hemorrhage.

Purinergic receptor immunoreactivity in the rostral ventromedial medulla.

The rostral ventromedial medulla (RVM) has long been recognized to play a pivotal role in nociceptive modulation. Pro-nociception within the RVM is associated with a distinct functional class of neurons, ON-cells that begin to discharge immediately before nocifensive reflexes. Anti-nociceptive function within the RVM, including the analgesic response to opiates, is associated with another distinct class, OFF-cells, which pause immediately prior to nocifensive reflexes. A third class of RVM neurons, NEUTRAL-cells, does not alter firing in association with nocifensive reflexes. ON-, OFF- and NEUTRAL-cells show differential responsiveness to various behaviorally relevant neuromodulators, including purinergic ligands. Iontophoresis of semi-selective P2X ligands, which are associated with nociceptive transmission in the spinal cord and dorsal root ganglia, preferentially activate ON-cells. By contrast, P2Y ligands activate OFF-cells and P1 ligands suppress the firing of NEUTRAL cells. The current study investigates the distribution of P2X, P2Y and P1 receptor immunoreactivity in RVM neurons of Sprague-Dawley rats. Co-localization with tryptophan hydroxylase (TPH), a well-established marker for serotonergic neurons was also studied. Immunoreactivity for the four purinergic receptor subtypes examined was abundant in all anatomical subdivisions of the RVM. By contrast, TPH-immunoreactivity was restricted to a relatively small subset of RVM neurons concentrated in the nucleus raphe magnus and pallidus, as expected. There was a significant degree of co-localization of each purinergic receptor subtype with TPH-immunoreactivity. This co-localization was most pronounced for P2Y1 receptor immunoreactivity, although this was the least abundant among the different purinergic receptor subtypes examined. Immunoreactivity for multiple purinergic receptor subtypes was often co-localized in single neurons. These results confirm the physiological finding that purinergic receptors are widely expressed in the RVM. Purinergic neurotransmission in this region may play an important role in nociception and/or nociceptive modulation, as at other levels of the neuraxis.

Purinergic actions on neurons that modulate nociception in the rostral ventromedial medulla.

The rostral ventromedial medulla (RVM) serves as a critical link in bulbo-spinal nociceptive modulation. Within the RVM, 'off-cells' pause and 'on-cells' discharge immediately prior to a nocifensive reflex. These neurons are also activated and inactivated, respectively, by local or systemic application of opioids. Off-cell activation leads to behavioral anti-nociception and on-cell activation to hyperalgesia. Thus, on- and off-cell populations allow bi-directional modulation of nociception by the RVM. A third neuronal population, neutral cells, shows no reflex-related change in discharge. The role of neutral cells in nociception, if any, is unknown. We investigated the responses of on-, off- and neutral cells to the iontophoretic application of purinergic ligands in lightly anesthetized rats. On-cell firing increased rapidly in response to application of ATP and to the P2X-receptor agonist, alpha,beta-methylene ATP. Off-cell firing increased gradually in response to ATP and to the P2Y-receptor agonist, 2-methylthio-ATP. All of these responses were attenuated or reversed by the non-specific P2-receptor antagonists, suramin and pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). Activation of off-cells was preferentially antagonized by the relatively selective P2Y antagonist, MRS2179. By contrast with activation of on- and off-cells by ATP, neutral cell firing was depressed by ATP, adenosine and the P1-receptor agonist, 5'-(N-ethylcarboxamido) adenosine (NECA). Neutral cell responses to these agonists were at least partially reversed by the adenosine-receptor antagonist, 8-phenyltheophylline (8PT). These data imply that on-cells preferentially express P2X-receptors, off-cells P2Y-receptors and neutral cells P1-receptors. Immunohistochemical localization of purinergic receptors confirms the presence of some subtypes of P2X, P2Y and A1 receptors on neuronal cell bodies and fibers within the RVM. The differential responses of on-, off- and neutral-cells to purinergic ligands highlight the value of pharmacological signatures in further delineation of the anatomy, connectivity and function of this therapeutically important system.

Frequency organization and cellular lamination in the medial geniculate body of the rabbit.

Cellular laminae within the tonotopically organized ventral division of the medial geniculate body (MGV) of the cat have been proposed as the anatomical substrate for physiologically defined isofrequency contours. In most species, the laminae are not visible with routine Nissl stains, but are defined by the dendritic fields of principal cells and the terminal arbors of afferents arising from the inferior colliculus. In the present study, we have used the rabbit to directly examine the relationship between the laminar and tonotopic organization of the MGV. Best frequency maps of the MGV in anesthetized adult New Zealand white rabbits were generated from cluster responses recorded at 30-100 microm intervals to randomly presented tone bursts. Parallel vertical penetrations, roughly perpendicular to the laminae, revealed a low-to-high frequency gradient within the MGV. Non-laminated regions of the ventral division, generally found at the rostral or caudal poles, did not demonstrate a systematic frequency gradient. In contrast to a predicted smooth gradient, best frequencies shifted in discrete steps across the axis of the laminae. A similar step-wise frequency gradient has been shown in the central nucleus of the inferior colliculus of the cat. It is proposed that the central laminated core of the MGV represents an efficient architecture for creating narrow frequency filters involved in fine spectral analysis.

Thalamocortical afferents of Lorente de Nó: medial geniculate axons that project to primary auditory cortex have collateral branches to layer I.

The injection of anterograde tracers into the ventral division of the medial geniculate body (MGV) of both rats and rabbits labels terminal axons in layer I of auditory cortex as well as the more conventional terminal arbors in layers III/IV. Whether these layer I projections represent a separate lemniscal pathway to the molecular layer or arise as collaterals of axons terminating in III/IV has not been addressed. Focal injections of the anterograde tracers biocytin or biotinylated dextran amine were made into the MGV of young rabbits. Serial section reconstruction of single MGV axons in auditory cortex revealed that layer I axons were collaterals of thalamocortical afferents that formed multiple divergent patches within III/IV. MGV collaterals to layer I often coursed tangentially for several millimeters before terminating. In some cases, the layer I collaterals descended to arborize within a thalamocortical patch in layers III/IV. These results suggest considerable radial and tangential divergence in the auditory thalamocortical pathway and argue for an expanded role for layer I in the processing of specific sensory stimuli.