Persistent Pulmonary Hypertension in Corrected Valvular Heart Disease: Hemodynamic Insights and Long-Term Survival.

Background The determinants and consequences of pulmonary hypertension after successfully corrected valvular heart disease remain poorly understood. We aim to clarify the hemodynamic bases and risk factors for mortality in patients with this condition. Methods and Results We analyzed long-term follow-up data of 222 patients with pulmonary hypertension and valvular heart disease successfully corrected at least 1 year before enrollment who had undergone comprehensive hemodynamic and imaging characterization as per the SIOVAC (Sildenafil for Improving Outcomes After Valvular Correction) clinical trial. Median (interquartile range) mean pulmonary pressure was 37 mm Hg (32-44 mm Hg) and pulmonary artery wedge pressure was 23 mm Hg (18-26 mm Hg). Most patients were classified either as having combined precapillary and postcapillary or isolated postcapillary pulmonary hypertension. After a median follow-up of 4.5 years, 91 deaths accounted for 4.21 higher-than-expected mortality in the age-matched population. Risk factors for mortality were male sex, older age, diabetes mellitus, World Health Organization functional class III and higher pulmonary vascular resistance-either measured by catheterization or approximated from ultrasound data. Higher pulmonary vascular resistance was related to diabetes mellitus and smaller residual aortic and mitral valve areas. In turn, the latter correlated with prosthetic nominal size. Six-month changes in the composite clinical score and in the 6-minute walk test distance were related to survival. Conclusions Persistent valvular heart disease-pulmonary hypertension is an ominous disease that is almost universally associated with elevated pulmonary artery wedge pressure. Pulmonary vascular resistance is a major determinant of mortality in this condition and is related to diabetes mellitus and the residual effective area of the corrected valve. These findings have important implications for individualizing valve correction procedures. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00862043.This study was funded by the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain, the European Union–European Regional Development Fund (EC07/90772 and PI19/00649), and the Consorcio de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV).S

Anterograde examination of the projections of the hippocampal formation and basal amygdala to the ventral tegmental area in the macaque monkey

The subiculum (Sub) of the hippocampal formation (HF) and the basal amygdala (Amy) control memory and other critical cognitive processes in part through the regulation of dopamine release from mesodiencephalic projecting neurons of the ventral tegmental area (VTA) (Phillips et al. 2003 Nsci Biobehav Rev 27:543-54; Belujon Grace 2011 ANYAS 1216:114-21). Models of the dopaminergic system proposed that HF regulates the activity of VTA through strong indirect pathways involving the striatum and lateral septum, without direct connections between HF and VTA (e.g., Lisman et al. 2005 Neuron 46:703-13). A prior tracing study in macaque monkeys showed that the central nucleus of Amy (CeA) projects to VTA (Amaral et al. 1981 J Nsci 1:1242-59); but evidence for a direct projection from other Amy nuclei, in particular the basal nucleus, is still missing. Here, we examined whether HF and amygdala nuclei other than CeA contribute direct monosynaptic projections to VTA. We analyzed the distribution of anterograde labeling produced in VTA with injections of biotin dextran amine and Phaseolus vulgaris leucoagglutinin in distinct architectonic regions in HF and Amy. Within HF, injections in the subiculum (Sub) produced dense anterograde labeling dispersed throughout VTA. Injections in the Ammon horns (CA1-3), dentate gyrus (DG) produced no labeling in VTA; and injections in entorhinal cortex (EC) produced labeling only in cases in which the injection contaminated the basal amygdala. Accordingly, baring CeA, injections in the amygdala produced labeling in VTA only for these injections that involved the magnocellular (Bmc), intermediate (Bi) or parvocellular (Bpc) parts of the basal nucleus, or the primate-specific paralaminar nucleus (PL). A comparison of the spatial distribution of anterogradely labeled fibers in VTA revealed a considerable overlap with only a subtle trend for two distinct labelling patterns; that is, either restricted to the rostral level of VTA, or dispersed throughout the rostrocaudal extent of VTA. While tenuous, the direct projections of Sub and basal Amy to VTA in the macaque monkey could produce direct regulation of dopaminergic release in parallel and/or independently of the classical indirect pathways involving ventral striatum and lateral septum

Hippocampal formation and amygdalar projections to the locus coeruleus in the macaque monkey

The locus coeruleus (LC) neuromodulates the limbic system through direct projections to the hippocampal formation (HF) and amygdala (Amy) (Morgane et al. 2005 Prog Neurobiol 75:143-60). HF and Amy could in turn regulate noradrenergic activity necessary for memory processes (McIntyre et al. 2012 Neurosci Biobehav Rev 36:1750-62). Here, we examined whether such regulation could be substantiated by direct monosynaptic projections from HF and Amy to LC. We analyzed the distribution of anterograde labeling produced in LC in macaque monkeys with injections of biotin-dextran amine or Phaseolus vulgaris leucoagglutinin in the entorhinal cortex (EC), Ammon horn (CA1-3), dentate gyrus (DG), and subiculum (Sub), as well as in different nuclei of the amygdala, baring the central nucleus which was previously shown to project to LC (Price Amaral 1981 J Nsci 1:1242-59). Within HF, injections in Sub resulted in the highest number of labeled terminals in LC, particularly throughout the entire rostrocaudal extent of the lateral portion of the nucleus. Injections placed in EC produced labeling only in cases where Amy was also involved. However, different labeling patterns were obtained in LC after injections in the same amygdala nuclei with contamination of different EC fields. Injections in CA1-3 or DG did not label LC. Within the amygdala, only injections made in the basal magnocellular nucleus (Bmc) and in the paralaminar nucleus (PL) produced labeling in the lateral portion of LC, similar to the labeling produced with injections in Sub. Prior studies showed that both Sub and basal Amy receive projections from LC; the present study suggests that these projections are bidirectional in primates. Notably, whereas prior rodent studies proposed that basolateral amygdala regulates LC indirectly through CeA (Bouret et al. 2003 J Neurosci 23:3491-7), the present tracing data indicates that the primate Bmc can directly regulate LC. Although it is unclear whether the converging hippocampo- and amygdalo-coerulean projections identified here are functionally related, prior evidence from animal and human studies suggests that both could have a role in memory. The subicular projection to LC offers an ideal substrate for the hippocampal regulation of forebrain noradrenergic activity necessary for memory retrieval (Eldridge et al. 2005 J Nsci 25:3280-6; Sara 2010 Front Behav Nsci 4: 1-5). Accordingly, the direct projections from Bmc to LC could contribute in restoring central arousal states that promote emotional memory consolidation (Sterpenich et al. 2006 J Neursci 26:7416-23). Supported by the Max Planck Society and the Center for Integrative Neuroscience

Hippocampal Formation Projection To Ventral Tegmental Area: An Anatomical Study In The Non-Human Primate

The Hippocampal Formation (HF) has a critical role in episodic memory. One of the major components in episodic memory is the encoding of novel stimuli, which is associated to dopaminergic system. Lisman and Grace (2005) proposed that novelty signals in the hippocampus modulate the activity of dopaminergic neurons in the ventral tegmental area (VTA) and that, via a feedback loop, the increase of dopamine in hippocampal neurons promotes the encoding for the novel event. Retrograde tracer studies have demonstrated that the VTA projects directly to the HF in primates (Amaral and Cowan, 1980; Insausti et al., 1987) as well as in rodents. However, whether these projections are reciprocal or not is unknown. Despite this lack of evidence of a direct projection, functional studies indicate that the dopaminergic neurons of the VTA are strongly influenced by the hippocampus indirectly through either lateral septum (Luo et al. 2011) or nucleus accumbens-ventral pallidum pathways (Lisman and Grace 2005). In order to determine the existence of direct inputs from the HF to the VTA and which are the specific fields within the HF responsible of the projection, the retrograde tracers were placed in the mesencephalic ventral and dorsal tegmentum of the Macaca fascicularis monkey, including the VTA. The retrograde cell labeling was analyzed with an epifluorescence microscope coupled to a computerized charting system. Our preliminary results showed scarce labeled cells in the HF, specifically in dorsal subiculum, and deep layers of the caudomedial portion of the entorhinal cortex (subfield EO and medialmost EI). These results clarify the functional HF-VTA loop playing a role in learning and memory, and different neuropsychiatric diseases (schizophrenia, Alzheimer´s and Parkinson's disease

Brainstem afferents to the hippocampal formation: Comparative immunohistochemical study in the Macaca fascicularis monkey

The synaptic plasticity of the Hippocampal Formation (HF, which includes the dentate gyrus -DG-, CA3, CA2, CA1, subiculum, pre-parasubiculum and the entorhinal cortex -EC) is strongly influenced by neurotransmiters (presumably Dopaminergic -DA, Ventral Tegmental Area-VTA; Noradrenergic -NA, Locus Coeruleus-LC and Serotoninergic -5-HT, Raphe Nuclei- RN, respectively), (Otmakhova and Lisman, 1996; Katsuki et al., 1997), although the anatomical basis of the chemical modulation of memory in the HF is far from being understood. The neuroanatomical connections between the brainstem and in the HF in the nonhuman primate are still unclear. Previous tracer studies showed retrogradely labeled neurons in the brainstem areas including the VTA, LC and RN, after deposits in the hippocampus (Amaral and Cowan, 1980), as well as in the EC (Insausti et al., 1987). In order to characterize the neurochemical nature of those projections, as well as their topographic and laminar differences, we studied comparatively the distribution on those substances in the HF using immunohistochemical techniques. Immunohistochemistry for each DA (Tyrosine Hydroxylase, TH), NA (Dopamine Beta Hydroxylase -DBH-, and 5-HT) as well as double-immunohistochemical techniques using Alexa 488 (5-HT detection) and Alexa 568 (TH or DBH labeling) disclosed that: • The polymorphic layer of the DG had fibers with the three neurotransmitters, whereas the molecular layer showed only TH and 5-HT immunolabeling, without double-stained processes. • The pyramidal layer of CA3 showed denser 5-HT fiber labeling than TH; CA1 showed only scattered TH and 5-HT fibers, without double labeling profiles. • The subiculum and presubiculum showed fibers immunoreactive for TH, SER and BHD in the molecular layer. No double-labeled TH-5HT or DBH-5HT fibers were seen. • The superficial layers of the rostral EC (I and II) displayed TH- or 5-HT-labelled processes, while the most lateral subdivisions of EC (ELR/ELc) had TH- or DBH-positive fibers; they did not show co-localization. The preferential location of these positive fibers in ELR/ELc is significant, as this portion of the EC receives abundant unimodal and polymodal sensory input and innervates the body and tail of the hippocampus, and therefore it might be an important step for the monoaminergic modulation memory consolidation. Our preliminary anatomical results suggest that the HF function may be modulated independently by monoaminergic neurotransmitters

Frontal cortex afferents to the ventral tegmental area in the Macaca fascicularis monkey

The prefrontal cortico-midbrain pathway is thought to play an important role in the regulation of the firing pattern in the ventral tegmental area (VTA) neurons. The understanding of the mechanisms that underlie the regulation of the midbrain dopamine neurons is critical to elucidate the reward system as well as certain pathological conditions such as drug addiction or schizophrenia. Descending prefrontal cortex (PFC) projections to the VTA have been primarily documented in the rodent brain (Maurice et al., 1999; Sesack and Carr, 2002). Furthermore, several anatomical studies based on the use of anterograde tracers in the nonhuman primate, have shown labeled fibers in the VTA that originated in the medial frontal cortex and anterior cingulate cortex (areas 25, 32 and 24), orbitofrontal cortex (areas 11 and 14) and dorsolateral prefrontal cortex (area 9 and 46) (Chiba et al., 2001; Frankle et al., 2006). In order to complete the study of the direct inputs from the PFC to the VTA, the retrograde tracer 3 Fast Blue (FB) was placed in the mesencephalic ventral and dorsal tegmentum in Macaca fascicularis monkey, including the ventral tegmental area. We analyzed three cases injected with FB through a Hamilton syringe in the ventral mesencephalon. A magnetic resonance (MR) examination to localize the stereotaxic coordinates of the injection site was performed in all the animals used in this study. After 2 weeks survival, animals were deeply anesthetized and perfused through the heart with 4 paraformaldehyde. Several additional cases with 3H-aminoacid injections reported previously (Insausti and Amaral, 2008) were also available for analysis under dark field illumination. Our preliminary results showed labeled neurons in the deep layers of principally, the medial frontal and orbitofrontal cortices, including areas 24, 32 and 25, and the orbitofrontal cortex (areas 11, 13, 12 and 14). Comparatively, the dorsolateral prefrontal (area 10, 9, 46 and 6) cortex displayed far fewer labeled neurons. Most of the labeled neurons were situated at the level of the medial part of caudal area 9 and rostral area 6. The anterograde tracer experiments (5 cases with 3H-aminoacid deposits placed in the orbitofrontal cortex, and 3 cases in the medial frontal cortex) confirmed the existence of these projections, thus ruling out the contamination by fibers of passage at the retrograde tracer injection sites. Our data suggest that the influence of medial frontal and orbitofrontal cortices on the dopaminergic ascending projections is much higher than from the dorsolateral prefrontal cortex

Clinical indications for image-guided interventional procedures in the musculoskeletal system: a Delphi-based consensus paper from the European Society of Musculoskeletal Radiology (ESSR)—Part II, elbow and wrist

Background: Although image-guided interventional procedures of the elbow and wrist are routinely performed, there is poor evidence in the literature concerning such treatments. Our aim was to perform a Delphi-based consensus on published evidence on image-guided interventional procedures around the elbow and wrist and provide clinical indications on this topic. Methods: A board of 45 experts in image-guided interventional musculoskeletal procedures from the European Society of Musculoskeletal Radiology were involved in this Delphi-based consensus study. All panelists reviewed and scored published papers on image-guided interventional procedures around the elbow and wrist updated to September 2018 according to the Oxford Centre for Evidence-based Medicine levels of evidence. Consensus on statements drafted by the panelists about clinical indications was considered as “strong” when more than 95% of panelists agreed and as “broad” if more than 80% agreed. Results: Eighteen statements were drafted, 12 about tendon procedures and 6 about intra-articular procedures. Only statement #15 reached the highest level of evidence (ultrasound-guided steroid wrist injections result in greater pain reduction and greater likelihood of attaining clinically important improvement). Seventeen statements received strong consensus (94%), while one received broad consensus (6%). Conclusions: There is still poor evidence in published papers on image-guided interventional procedures around the elbow and wrist. A strong consensus has been achieved in 17/18 (94%) statements provided by the panel on clinical indications. Large prospective randomized trials are needed to better define the role of these procedures in clinical practice. Key Points: • The panel provided 18 evidence-based statements on clinical indications of image-guided interventional procedures around the elbow and wrist. • Only statement #15 reached the highest level of evidence: ultrasound-guided steroid wrist injections result in greater pain reduction and greater likelihood of attaining clinically important improvement. • Seventeen statements received strong consensus (94%), while broad consensus was obtained by 1 statement (6%)

Clinical indications for image-guided interventional procedures in the musculoskeletal system: a Delphi-based consensus paper from the European Society of Musculoskeletal Radiology (ESSR)—part VII, nerves of the lower limb

Objectives: To perform a Delphi-based consensus on published evidence on image-guided interventional procedures for peripheral nerves of the lower limb (excluding Morton’s neuroma) and provide clinical indications. Methods: We report the results of a Delphi-based consensus of 53 experts from the European Society of Musculoskeletal Radiology who reviewed the published literature for evidence on image-guided interventional procedures offered around peripheral nerves in the lower limb (excluding Morton’s neuroma) to derive their clinical indications. Experts drafted a list of statements and graded them according to the Oxford Centre for evidence-based medicine levels of evidence. Consensus was considered strong when > 95% of experts agreed with the statement or broad when > 80% but < 95% agreed. The results of the Delphi-based consensus were used to write the paper. Results: Nine statements on image-guided interventional procedures for peripheral nerves of the lower limb have been drafted. All of them received strong consensus. Image-guided pudendal nerve block is safe, effective, and well tolerated with few complications. US-guided perisciatic injection of anesthetic provides good symptom relief in patients with piriformis syndrome; however, the addition of corticosteroids to local anesthetics still has an unclear role. US-guided lateral femoral cutaneous nerve block can be used to provide effective post-operative regional analgesia. Conclusion: Despite the promising results reported by published papers on image-guided interventional procedures for peripheral nerves of the lower limb, there is still a lack of evidence on the efficacy of most procedures. Key Points: • Image-guided pudendal nerve block is safe, effective, and well tolerated with few complications. • US-guided perisciatic injection of anesthetic provides good symptom relief in patients with piriformis syndrome; however, the addition of corticosteroids to local anesthetics still has an unclear role. • US-guided lateral femoral cutaneous nerve block can be used to provide effective post-operative regional analgesia. The volume of local anesthetic affects the size of the blocked sensory area