Alzheimer disease (AD) is marked by profound neurodegeneration, neuroinflammation, and cognitive decline. Pathologically, AD is characterized by the accumulation of extracellular amyloid and... Show moreAlzheimer disease (AD) is marked by profound neurodegeneration, neuroinflammation, and cognitive decline. Pathologically, AD is characterized by the accumulation of extracellular amyloid and intraneuronal tangles, consisting of hyperphosphorylated tau. To date, factors leading to disease onset and progression are still an important topic of investigation. Various epidemiological studies revealed cardiovascular disease as an important contributor to the development and progression of AD, leading to the so-called vascular hypothesis. Vascular risk factors, such as hypertension, diabetes, and hyperhomocysteinemia, are associated with a significantly increased chance of developing AD, suggesting an additive or even synergistic effect. These vascular risk factors are often linked to a reduction in cerebral blood flow and the resulting chronic cerebral hypoperfusion is suggested to play a key role in the onset of AD. However, the causal effects of such vascular risk factors for AD onset remain largely unknown. Evidence from animal studies support that chronic cerebral hypoperfusion induction causes a strong aggravation of AD-related pathology, but a comprehensive overview of how the various cardiovascular disease risk factors contribute to disease is lacking. Therefore, we here critically review current literature, to unravel the existing evidence derived from in vivo mouse studies and define the role of cardiovascular disease and chronic cerebral hypoperfusion in AD development. We conclude that, although many aspects of the vascular hypothesis are well supported by observational studies, in-depth mechanistic studies and well-designed randomized controlled trials are highly needed to establish temporal and causal relationships. Described new insights can have major prospective potential for therapeutic interventions. Show less
Vlastra, W.; Nieuwkerk, A.C. van; Bronzwaer, A.S.G.T.; Versteeg, A.; Bron, E.E.; Niessen, W.J.; ... ; Delewi, R. 2020
BACKGROUND Transcatheter aortic valve implantation (TAVI) is a minimally invasive, life-saving treatment for patients with severe aortic valve stenosis that improves quality of life. We examined... Show moreBACKGROUND Transcatheter aortic valve implantation (TAVI) is a minimally invasive, life-saving treatment for patients with severe aortic valve stenosis that improves quality of life. We examined cardiac output and cerebral blood flow in patients undergoing TAVI to test the hypothesis that improved cardiac output after TAVI is associated with an increase in cerebral blood flow. DESIGN Prospective cohort study. SETTING European high-volume tertiary multidisciplinary cardiac care. PARTICIPANTS Thirty-one patients (78.3 +/- 4.6 years; 61% female) with severe symptomatic aortic valve stenosis. MEASUREMENTS Noninvasive prospective assessment of cardiac output (L/min) by inert gas rebreathing and cerebral blood flow of the total gray matter (mL/100 g per min) using arterial spin labeling magnetic resonance imaging in resting state less than 24 hours before TAVI and at 3-month follow-up. Cerebral blood flow change was defined as the difference relative to baseline. RESULTS On average, cardiac output in patients with severe aortic valve stenosis increased from 4.0 +/- 1.1 to 5.4 +/- 2.4 L/min after TAVI (P= .003). The increase in cerebral blood flow after TAVI strongly varied between patients (7% +/- 24%;P= .41) and related to the increase in cardiac output, with an 8.2% (standard error = 2.3%;P= .003) increase in cerebral blood flow per every additional liter of cardiac output following the TAVI procedure. CONCLUSION Following TAVI, there was an association of increase in cardiac output with increase in cerebral blood flow. These findings encourage future larger studies to determine the influence of TAVI on cerebral blood flow and cognitive function. Show less
Seijkens, T.T.P.; Poels, K.; Meiler, S.; Tiel, C.M. van; Kusters, P.J.H.; Reiche, M.; ... ; Lutgens, E. 2018
The E3-ligase CBL-B (Casitas B-cell lymphoma-B) is an important negative regulator of T cell activation that is also expressed in macrophages. T cells and macrophages mediate atherosclerosis, but... Show moreThe E3-ligase CBL-B (Casitas B-cell lymphoma-B) is an important negative regulator of T cell activation that is also expressed in macrophages. T cells and macrophages mediate atherosclerosis, but their regulation in this disease remains largely unknown; thus, we studied the function of CBL-B in atherogenesis.The expression of CBL-B in human atherosclerotic plaques was lower in advanced lesions compared with initial lesions and correlated inversely with necrotic core area. Twenty weeks old Cblb−/−Apoe−/− mice showed a significant increase in plaque area in the aortic arch, where initial plaques were present. In the aortic root, a site containing advanced plaques, lesion area rose by 40%, accompanied by a dramatic change in plaque phenotype. Plaques contained fewer macrophages due to increased apoptosis, larger necrotic cores, and more CD8+ T cells. Cblb−/−Apoe−/− macrophages exhibited enhanced migration and increased cytokine production and lipid uptake. Casitas B-cell lymphoma-B deficiency increased CD8+ T cell numbers, which were protected against apoptosis and regulatory T cell-mediated suppression. IFNγ and granzyme B production was enhanced in Cblb−/−Apoe−/− CD8+ T cells, which provoked macrophage killing. Depletion of CD8+ T cells in Cblb−/−Apoe−/− bone marrow chimeras rescued the phenotype, indicating that CBL-B controls atherosclerosis mainly through its function in CD8+ T cells. Casitas B-cell lymphoma-B expression in human plaques decreases during the progression of atherosclerosis. As an important regulator of immune responses in experimental atherosclerosis, CBL-B hampers macrophage recruitment and activation during initial atherosclerosis and limits CD8+ T cell activation and CD8+ T cell-mediated macrophage death in advanced atherosclerosis, thereby preventing the progression towards high-risk plaques. Show less
In healthy subjects, variation in cardiovascular responses to sympathetic stimulation evoked by submaximal lower body negative pressure (LBNP) is considerable. This study addressed the question... Show moreIn healthy subjects, variation in cardiovascular responses to sympathetic stimulation evoked by submaximal lower body negative pressure (LBNP) is considerable. This study addressed the question whether inter-subject variation in cardiovascular responses coincides with consistent and reproducible responses in an individual subject. In 10 healthy subjects (5 female, median age 22 years), continuous hemodynamic parameters (finger plethysmography: Nexfin, Edwards Lifesciences), and time-domain baroreflex sensitivity (BRS) were quantified during three consecutive 5-min runs of LBNP at 50 mmHg. The protocol was repeated after 1 week to establish intra-subject reproducibility. In response to LBNP, 5 subjects (3 females) showed a prominent increase in heart rate (HR: 54 14%, p = 0.001) with no change in total peripheral resistance (TPR p = 0.25) whereas the other 5 subjects (2 females) demonstrated a significant rise in TPR (7 3%, p = 0.017) with a moderate increase in HR (21 +/- 9%, p = 0.004). These different reflex responses coincided with differences in resting BRS (22 8 vs. 11 3 ms/mmHg, p = 0.049) and resting HR (57 +/- 8 vs. 71 +/- 12 bpm, p = 0.047) and were highly reproducible over time. In conclusion, we found distinct cardiovascular response patterns to sympathetic stimulation by LBNP in young healthy individuals. These patterns of preferential autonomic blood pressure control appeared related to resting cardiac BRS and HR and were consistent over time. Show less
Bronzwaer, A.S.G.T.; Verbree, J.; Buchem, M.A. van; Daemen, M.J.A.P.; Osch, M.J.P. van; Lieshout, J.J. van 2016
Objective: To investigate the potential of gadofosveset-enhanced MR imaging for the characterization of human carotid atherosclerotic plaques. Materials and Methods: Sixteen (9 symptomatic, 7... Show moreObjective: To investigate the potential of gadofosveset-enhanced MR imaging for the characterization of human carotid atherosclerotic plaques. Materials and Methods: Sixteen (9 symptomatic, 7 asymptomatic) patients with 70% to 99% carotid stenosis (according to NASCET criteria) were included (13 men, 3 women, mean age 67.6 years). All patients underwent baseline precontrast MR imaging of the carotid plaque. Immediately after completion of the baseline examination, 0.03 mmol/kg gadofosveset was administered. At 24 hours postinjection, the acquisition was repeated. Twelve patients were scheduled for carotid endarterectomy. Carotid endarterectomy specimens were HE-, CD31-, CD68-, and albumin-stained to correlate signal enhancement with plaque composition, intraplaque microvessel density, and macrophage and albumin content. A random intercept model was used to compare signal enhancement between symptomatic and asymptomatic patients, adjusting for size of various plaque components. This study was approved by the institutional medical ethics committee. All participants gave written informed consent. Results: Signal enhancement (SE) of the plaque was significantly higher in symptomatic patients compared with asymptomatic patients (median log SE 0.182 vs. -0.109, respectively, P < 0.001). A positive association (as expressed by a regression coefficient beta = 0.0035) was found between signal enhancement on the log scale and intraplaque albumin content (P = 0.038). There was no association between signal enhancement and various other plaque components. Conclusion: In this study, the potential of gadofosveset-enhanced human carotid plaque MR imaging for identification of high-risk plaques was demonstrated. Signal enhancement of the plaque after administration of gadofosveset was associated with differences in intraplaque albumin content. Although promising, we emphasize that these results are based on a small patient population. Larger prospective studies are warranted. Show less
