Cardiovascular diseases are traditionally related to well known risk factors like dyslipidemia, smoking, diabetes and hypertension. More recently, stress, anxiety and depression have been proposed as risk factors for cardiovascular diseases including heart failure, ischemic disease, hypertension and arrhythmias. Interestingly, this association has been established largely on the basis of epidemiological data, due to insufficient knowledge on the underlying pathophysiologic mechanisms. This review will revisit evidence on the interaction between the cardiovascular and nervous systems, highlighting the perspective on how the central nervous system is involved in the pathogenesis of cardiovascular diseases. Such knowledge is likely to be of relevance for the development of better strategies to treat patients in a holistic perspective.

The central autonomic response to autonomic challenges is altered in patients with Takotsubo cardiomyopathy, thus suggesting a dysregulation of the central autonomic nervous system network. Subsequent studies are needed to unveil whether these alterations are causal or predisposing factors to Takotsubo cardiomyopathy.

Cardiac function is under the control of the autonomic nervous system, composed by the parasympathetic and sympathetic divisions, which are finely tuned at different hierarchical levels. While a complex regulation occurs in the central nervous system involving the insular cortex, the amygdala and the hypothalamus, a local cardiac regulation also takes place within the heart, driven by an intracardiac nervous system. This complex system consists of a network of ganglionic plexuses and interconnecting ganglions and axons. Each ganglionic plexus contains numerous intracardiac ganglia that operate as local integration centres, modulating the intricate autonomic interactions between the extrinsic and intracardiac nervous systems. Herein, we summarize the current understanding on the intracardiac nervous system, and acknowledge its role in the pathophysiology of cardiovascular diseases.

BackgroundChronic stress is associated with increased risk of glucose intolerance and cardiovascular diseases, albeit through undefined mechanisms. With the aim of gaining insights into the latter, this study examined the metabolic profile of young adult male rats that were exposed to chronic unpredictable stress.MethodsYoung adult male rats were submitted to 4 weeks of chronic unpredictable stress and allowed to recover for 5 weeks. An extensive analysis including of morphologic, biochemical and molecular parameters was carried out both after chronic unpredictable stress and after recovery from stress.ResultsAfter 28 days of chronic unpredictable stress (CUS) the animals submitted to this protocol displayed less weight gain than control animals. After 5 weeks of recovery the weight gain rebounded to similar values of controls. In addition, following CUS, fasting insulin levels were increased and were accompanied by signs of impaired glucose tolerance and elevated serum corticosteroid levels. This biochemical profile persisted into the post-stress recovery period, despite the restoration of baseline corticosteroid levels. The mRNA expression levels of peroxisome proliferator-activated receptor (PPAR)-γ and lipocalin-2 in white adipose tissue were, respectively, down- and up-regulated.ConclusionsReduction of PPAR-γ expression and generation of a pro-inflammatory environment by increased lipocalin-2 expression in white adipose tissue may contribute to stress-induced glucose intolerance.

Takotsubo syndrome (TTS) is an acute, reversible cardiomyopathy. The central autonomic nervous system (ANS) is believed to play a role in this disease. The aim of the present study was to investigate the patterns of brain functional connectivity in a sample of patients who had experienced a previous episode of TTS. Brain functional connectivity, both at rest and in response to the stressful stimulus of topical cold stimulation, was explored using functional magnetic resonance imaging (fMRI), network-based statistics (NBS) and graph theory analysis (GTA) in a population consisting of eight patients with a previous episode of TTS and eight sex- and age-matched controls. At rest, a network characterized by increased connectivity in the TTS group compared to controls and comprising elements of the central ANS was identified. GTA revealed increased local efficiency, clustering and strength in regions of the bilateral hippocampus in subjects with a previous episode of TTS. When stressed by local exposure to cold, the TTS group differed significantly from both a pre-stress baseline interval and from the control group, showing increased connectivity in a network that included the left amygdala and the right insula. Based on the results, patients with TTS display a reorganization of cortical and subcortical networks, including areas associated with the emotional response and autonomic regulation. The findings tend to support the hypothesis that a deregulation of autonomic control at the central level plays a significant role in this syndrome.

The applicability of CMCht/PAMAM dendrimer nanoparticles for CNS applications was investigated. AFM and TEM observations revealed that the nanoparticles possessed a nanosphere-like shape with a size from 22.0 to 30.7 nm. The nanoparticles could be bound to fluorescent-probe FITC for tracing purposes. Post-natal hippocampal neurons and cortical glial cells were both able to internalize the FITC-labeled CMCht/PAMAM dendrimer nanoparticles with high efficiency. The percentage of positive cells internalizing the nanoparticles varied, reaching a peak after 48 h of incubation. Further experiments for periods up to 7 d revealed that the periodical addition of FITC-labelled CMCht/PAMAM dendrimer nanoparticles was needed to maintain the overall percentage of cells internalizing them. Finally, it was also observed that cell viability was not significantly affected by the incubation of dendrimer nanoparticles.

Detection of right heart thrombi (RHT) in the context of pulmonary thromboembolism (PE) is uncommon (4–18%) and increases the risk of mortality beyond the presence of PE alone. Type A thrombi are serpiginous and highly mobile and are thought to be originated from large veins and captured in-transit within the right heart. Optimal management of RHT is still uncertain. A 79-year-old woman, with a history of recent total hysterectomy with adnexectomy and a Wells procedure, presented to the emergency department following an episode of syncope. Computed tomography revealed bilateral PE and the presence of a right atrial thrombus. Transthoracic echocardiography demonstrated a free-floating type A thrombus in the right atrium, protruding into the right ventricle, and signs of pulmonary hypertension and right ventricle dysfunction. Considering the recent surgery and clinical stability, treatment with heparin alone was decided. Subsequent clinical improvement was observed and echocardiographic follow-up revealed complete thrombus dissolution and complete recovery of right ventricle function. Most authors recommend treatment of PE with RHT with thrombolysis or embolectomy followed by anticoagulation, although evidence is scarce. Individual risk of hemorrhage and operatory-related mortality should be taken into account when defining the treatment strategy especially when benefit is not firmly established.

Carboxymethylchitosan/poly(amidoamine) (CMCht/PAMAM) dendrimer nanoparticles, comprised of a PAMAM dendrimer core grafted with chains of CMCht, have recently been proposed for intracellular drug delivery. In previous reports, these nanoparticles had improved cytotoxicity compared with traditional dendrimers. In this study, the short-term in vivo biodistribution of fluorescein isothiocyanate (FITC)-labeled CMCht/PAMAM dendrimer nanoparticles after intravenous (IV) injections in Wistar Han rats was determined. The brain, liver, kidney, and lung were collected at 24, 48, and 72 h after injection and stained with phalloidin-tetramethylrhodamine isothiocyanate (TRITC, red) and 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI, blue)[AQ: 1]to trace the nanoparticles within these tissues. The liver, kidney, and lung were also stained for hematoxylin and eosin to assess any morphological alterations of these organs. CMCht/PAMAM dendrimer nanoparticles were observed within the vascular space and parenchyma of liver, kidney, and lung and in the choroid plexus, after each injection period. No particles were observed in the brain parenchyma, nor any apparent deleterious histological changes were observed within these organs. The CMCht/PAMAM dendrimer nanoparticles were stable in circulation for a period of up to 72 h and targeted the main organs of the systems by internalizing by the cells present in their parenchyma.[AQ: 2]These results provide positive indicators to their potential use in the future as intracellular drug delivery systems.