Background: Hypertension induction (HTI) is often used for treating delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH); however, high-quality studies on its... Show moreBackground: Hypertension induction (HTI) is often used for treating delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH); however, high-quality studies on its efficacy are lacking. We studied immediate and 3-/6-month clinical efficacy of HTI in aSAH patients with clinical DCI.Methods: A retrospective, multicenter, comparative, observational cohort study in aSAH patients with clinical deterioration due to DCI, admitted to three tertiary referral hospitals in the Netherlands from 2015 to 2019. Two hospitals used a strategy of HTI (HTI group) and one hospital had no such strategy (control group). We calculated adjusted relative risks (aRR) using Poisson regression analyses for the two primary (clinical improvement of DCI symptoms at days 1 and 5 after DCI onset) and secondary outcomes (DCI-related cerebral infarction, in-hospital mortality, and poor clinical outcome [modified Rankin Scale 4-6] assessed at 3 or 6 months), using the intention-to-treat principle. We also performed as-treated and per-protocol analyses.Results: The aRR for clinical improvement on day 1 after DCI in the HTI group was 1.63 (95% CI 1.17-2.27) and at day 5 after DCI 1.04 (95% CI 0.84-1.29). Secondary outcomes were comparable between the groups. The as-treated and per-protocol analyses yielded similar results.Conclusions: No clinical benefit of HTI is observed 5 days after DCI due to spontaneous reversal of DCI symptoms in patients treated without HTI. The 3-/6-month clinical outcome was similar for both groups. Therefore, these data suggest that one may consider to not apply HTI in aSAH patients with clinical DCI. Show less
Dolmans, R.G.F.; Robertson, F.C.; Eijkholt, M.; Vliet, P. van; Broekman, M.L.D. 2023
Traumatic brain injury (TBI) is a significant cause of mortality and morbidity worldwide and many patients with TBI require intensive care unit (ICU) management. When facing a life-threatening... Show moreTraumatic brain injury (TBI) is a significant cause of mortality and morbidity worldwide and many patients with TBI require intensive care unit (ICU) management. When facing a life-threatening illness, such as TBI, a palliative care approach that focuses on noncurative aspects of care should always be considered in the ICU. Research shows that neurosurgical patients in the ICU receive palliative care less frequently than the medical patients in the ICU, which is a missed opportunity for these patients. However, providing appropriate palliative care to neurotrauma patients in an ICU can be difficult, particularly for young adult patients. The patients' prognoses are often unclear, the likelihood of advance directives is small, and the bereaved families must act as decision-makers. This article highlights the different aspects of the palliative care approach as well as barriers and challenges that accompany the TBI patient population, with a particular focus on young adult patients with TBI and the role of their family members. The article concludes with recommendations for physicians for effective and adequate communication to successfully implement the palliative care approach into standard ICU care and to improve quality of care for patients with TBI and their families. Show less
Background: Traumatic brain injury (TBI) is a major cause of death and disability across all ages. After the primary impact, the pathophysiologic process of secondary brain injury consists of a... Show moreBackground: Traumatic brain injury (TBI) is a major cause of death and disability across all ages. After the primary impact, the pathophysiologic process of secondary brain injury consists of a neuroinflammation response that critically leads to irreversible brain damage in the first days after the trauma. A key catalyst in this inflammatory process is the complement system. Inhibiting the complement system could therefore be a therapeutic target in TBI.Objective: To study the safety and efficacy of C1-inhibitor (C1-INH) compared to placebo in patients with TBI. By temporarily blocking the complement system, we hypothesize a decrease in the posttraumatic neuroinflammatory response resulting in a less unfavorable clinical outcome for TBI patients.Methods: CIAO@TBI is a multicenter, randomized, blinded, phase II placebo-controlled trial. Adult TBI patients with GCS < 13 requiring intracranial pressure (ICP) monitoring will be randomized, using block randomization, within 12 h after trauma to one dose 6000 IU C1-INH or placebo. A total of 106 patients will be included, and follow-up will occur up to 12 months. The primary endpoints are (1) Therapy Intensity Level (TIL) Scale, (2) Glasgow Outcome Scale-Extended (GOSE) at 6 months, and (3) complication rate during hospitalization. Outcomes will be determined by a trial nurse blinded for the treatment allocation. Analyses will be conducted in an intention-to-treat analysis.Discussion: We expect that C1-INH administration will be safe and potentially effective to improve clinical outcomes by reducing neuroinflammation in TBI patients. Show less
Grim, C.C.A.; Termorshuizen, F.; Bosman, R.J.; Cremer, O.L.; Meinders, A.J.; Nijsten, M.W.N.; ... ; Jonge, E. de 2021
OBJECTIVES: In critically ill patients, dysnatremia is common, and in these patients, in-hospital mortality is higher. It remains unknown whether changes of serum sodium after ICU admission affect... Show moreOBJECTIVES: In critically ill patients, dysnatremia is common, and in these patients, in-hospital mortality is higher. It remains unknown whether changes of serum sodium after ICU admission affect mortality, especially whether normalization of mild hyponatremia improves survival. DESIGN: Retrospective cohort study. SETTING: Ten Dutch ICUs between January 2011 and April 2017. Patients: Adult patients were included if at least one serum sodium measurement within 24 hours of ICU admission and at least one serum sodium measurement 24-48 hours after ICU admission were available. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A logistic regression model adjusted for age, sex, and Acute Physiology and Chronic Health Evaluation-IV-predicted mortality was used to assess the difference between mean of sodium measurements 24-48 hours after ICU admission and first serum sodium measurement at ICU admission (Delta 48 hr-[Na]) and in-hospital mortality. In total, 36,660 patients were included for analysis. An increase in serum sodium was independently associated with a higher risk of in-hospital mortality in patients admitted with normonatremia (Delta 48 hr-[Na] 5-10 mmol/L odds ratio: 1.61 [1.44-1.79], Delta 48 hr-[Na] > 10 mmol/L odds ratio: 4.10 [3.20-5.24]) and hypernatremia (Delta 48 hr-[Na] 5-10 mmol/L odds ratio: 1.47 [1.02-2.14], Delta 48 hr-[Na] > 10 mmol/L odds ratio: 8.46 [3.31-21.64]). In patients admitted with mild hyponatremia and Delta 48 hr-[Na] greater than 5 mmol/L, no significant difference in hospital mortality was found (odds ratio, 1.11 [0.99-1.25]). CONCLUSIONS: An increase in serum sodium in the first 48 hours of ICU admission was associated with higher in-hospital mortality in patients admitted with normonatremia and in patients admitted with hypernatremia. Show less
Vliet, P. van; Hilt, A.D.; Thijs, R.D.; Dijk, J.G. van 2016
BACKGROUND AND PURPOSE Epidemiological studies have shown mixed findings on the association between hypertension and stroke in the oldest old. Heterogeneity of the populations under study may... Show moreBACKGROUND AND PURPOSE Epidemiological studies have shown mixed findings on the association between hypertension and stroke in the oldest old. Heterogeneity of the populations under study may underlie variation in outcomes. We examined whether the level of physical and cognitive function moderates the association between blood pressure and stroke. METHODS We included 513 subjects aged 85 years old from the population-based Leiden 85-plus Study. Systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure were measured at baseline. Activities of daily living and Mini-Mental State Examination were assessed to estimate level of physical and cognitive function, respectively. Five-year risk of stroke was estimated with Cox regression analysis. RESULTS In the entire cohort, there were no associations between various measures of blood pressure and risk of stroke except for the inverse relation between pulse pressure and stroke risk (hazard ratio [HR], 0.80 [95% confidence interval [CI], 0.66-0.98]). Among subjects with impaired physical functioning, higher systolic blood pressure (HR, 0.74 [95% CI, 0.59-0.92]), mean arterial pressure (HR: 0.68 [95% CI, 0.47-0.97]), and pulse pressure (HR, 0.71 [95% CI, 0.55-0.93]) were associated with reduced risk of stroke. Likewise, among subjects with impaired cognitive functioning, higher systolic blood pressure was associated with reduced risk of stroke (HR, 0.80 [95% CI, 0.65-0.98]). In subjects with unimpaired cognitive functioning, higher diastolic blood pressure (HR: 1.98 [95% CI, 1.21-3.22]) and mean arterial pressure (HR, 1.70 [95% CI, 1.08-2.68]) were associated with higher risk of stroke. CONCLUSIONS Our findings suggest that impaired physical and cognitive function moderates the association between blood pressure and stroke. Show less
Sabayan, B.; Vliet, P. van; Ruijter, W. de; Gussekloo, J.; Craen, A.J.M. de; Westendorp, R.G.J. 2013
BACKGROUND AND PURPOSE: Alteration in cerebrovascular hemodynamics has reported in both ageing and dementia. However, it is still unclear whether this alteration follows similar pattern in ageing... Show moreBACKGROUND AND PURPOSE: Alteration in cerebrovascular hemodynamics has reported in both ageing and dementia. However, it is still unclear whether this alteration follows similar pattern in ageing and in different dementia pathologies. The aim of this meta-analysis was to investigate changes in cerebral blood flow velocity and pulsatility index in two most common forms of dementia; Alzheimer's disease and vascular dementia, using transcranial Doppler studies. METHODS: A literature search was conducted in Pubmed, EMBASE and Web of Science. After initial screening of 304 articles and removing duplicates, a total of 53 articles, published between 1980 and 2010, were reviewed. Finally 12 articles were included in the meta-analysis. For each study, effect sizes (ES) indicating the standardized mean differences of the hemodynamic measures between two groups were calculated. Using random effect models, pooled estimates of ES were measured. RESULTS: Patients with Alzheimer's disease (ES=-1.09, 95% CI -1.77 to -0.44, p=0.004) and vascular dementia (ES=-1.62, 95% CI -2.26 to -0.98, p<0.001) had significantly lower cerebral blood flow velocity compared with healthy aged-matched controls. In addition, pulsatility index was significantly higher in both Alzheimer's disease (ES=0.5, 95% CI 0.28-0.72, p<0.001) and vascular dementia patients (ES=2.34, 95% CI 1.39-3.29, p<0.001). Patients with Alzheimer's disease had lower pulsatility index (ES=-1.22, 95% CI -1.98 to -0.46, p=0.002) compared to subjects with vascular type of dementia. CONCLUSIONS: Patients with Alzheimer's disease and vascular dementia have a pronounced disturbance in their cerebrovascular hemodynamics. The severity of disturbances in cerebral hemodynamics is significantly lower in Alzheimer's disease compared to vascular dementia. Show less
The main objective of this thesis was to clarify the observed reversal of effect of classical risk factors for dementia and mortality with increasing age and to gain better insight in the... Show moreThe main objective of this thesis was to clarify the observed reversal of effect of classical risk factors for dementia and mortality with increasing age and to gain better insight in the biological mechanism behind the relation between both phenotypic and genetic variation in apolipoprotein E (apoE) and cognitive function. Although high cholesterol levels in midlife associate with worse cognitive function and dementia in late-life, this association attenuates and even reverses with increasing age. In memory outpatient clinic patients high blood pressure associated with better cognitive function, only in patients with structural brain damage. In the Leiden 85-Plus Study, a decline in global cognitive function preceded declines in total cholesterol levels, HDL cholesterol levels, and blood pressure, and not vice versa. Moreover, mortality was associated with larger declines in body mass index, total cholesterol levels, HDL cholesterol levels, and blood pressure. High plasma apoE levels associated with worse cognitive function, whereas offspring from Alzheimer__s disease patients had lower plasma apoE levels when measured in midlife compared to offspring from cognitively intact controls. Finally, high serum calcium levels were strongly associated with worse cognitive function in APOE _3_4 carriers, to a lesser extent in _3_3 carriers, but not in _2_3 carriers. Show less
Vliet, P. van; Westendorp, R.G.J.; Heemst, D. van; Craen, A.J.M. de; Oleksik, A.M. 2010
Introduction Although obesity, hypercholesterolaemia and hypertension in midlife are risk factors for dementia in late life, dementia is associated with lower body mass index, cholesterol levels... Show moreIntroduction Although obesity, hypercholesterolaemia and hypertension in midlife are risk factors for dementia in late life, dementia is associated with lower body mass index, cholesterol levels and blood pressures. It is unclear whether declines in these vascular risk factors are preceded by declines in cognitive function or vice versa. Methods Within the Leiden 85-plus Study, a prospective population-based study of 599 subjects aged 85 years, the authors annually measured body mass index, total cholesterol, high-density lipoprotein (HDL) cholesterol, glucose levels and blood pressure, and assessed global cognitive function using the Mini Mental State Examination (MMSE) during a 5-year follow-up. Results For the whole population who survived up to the age of 90 years, strong annual declines in MMSE score, body mass index, total cholesterol levels, glucose levels, and blood pressure, and an annual increase in HDL cholesterol levels were observed during the follow-up period (all p <= 0.010). Annual changes in MMSE score from age 85 to 87 years were associated positively with annual changes from age 87 to 90 years in total and HDL cholesterol levels (p=0.002 and p=0.013), systolic and diastolic blood pressure (p=0.008 and p=0.048), but not BMI. Parameter value changes from age 85 to 87 years were not associated with changes in MMSE score from age 87 to 90 years. Discussion In old age, cognitive decline precedes declines in total cholesterol levels, HDL cholesterol levels and blood pressure, and not vice versa. Possibly, brain lesions in metabolic and blood pressure regulation centres cause dysregulation of lipid metabolism and blood pressure. Show less
Vliet, P. van; Boer, T.P. de; Heyden, M.A.G. van der; Tamer, M.K. el; Sluijter, J.P.G.; Doevendans, P.A.; Goumans, M.J. 2010
In the past years, cardiovascular progenitor cells have been isolated from the human heart and characterized. These cells can differentiate into cardiomyocytes, smooth muscle cells and endothelial... Show moreIn the past years, cardiovascular progenitor cells have been isolated from the human heart and characterized. These cells can differentiate into cardiomyocytes, smooth muscle cells and endothelial cells and are therefore of great value for investigation of the mechanisms that drive progenitor cell function and plasticity, drug testing and, potentially, therapeutical purposes. In this respect, most studies have focused on enhancing differentiation with chemicals or growth factors, or co-culture with other cell types. Although they have revealed important mechanisms, protocols need to be established that exclude the need for such factors when one considers using progenitor cells to repair the human heart. In this study we tested whether we could induce cardiomyogenic differentiation of human cardiomyocyte progenitor cells (CMPCs) by altering their membrane potential. We induced hyperpolarization in CMPCs by either co-culturing them with a K(ir)2.1-overexpressing cell line or by overnight culture in medium containing low potassium concentrations. Hyperpolarization led to increased intracellular calcium concentrations, activation of calcineurin signaling, increased cardiac-specific gene and protein expression levels and, ultimately, to the formation of spontaneously beating cardiomyocytes. Thus, hyperpolarization is sufficient to induce differentiation of CMPCs, thereby revealing a novel mechanism for cardiomyogenic differentiation of heart-derived progenitor cells. Show less
Vliet, P. van; Oleksik, A.M.; Heemst, D. van; Craen, A.J.M. de; Westendorp, R.G.J. 2010
Background. In contrast to middle age, higher body mass index (BMI), cholesterol levels, and blood pressures associate no longer with increased mortality in old age. With increasing age, these risk... Show moreBackground. In contrast to middle age, higher body mass index (BMI), cholesterol levels, and blood pressures associate no longer with increased mortality in old age. With increasing age, these risk factors are prone to change over time. It is unclear whether dynamics of these traditional metabolic risk factors in late life associate with mortality and whether they occur in concert with each other. Methods. Within the Leiden 85-plus Study, a prospective population-based study of 599 participants aged 85 years, participants were annually assessed during a 5-year follow-up period and observed for mortality for 10 years. Results. BMI, total cholesterol levels, glucose levels, and blood pressures declined and HDL cholesterol levels increased between ages 85 and 90 years (all p < .005). Participants who died at age 90 years had stronger annual declines in BMI, total cholesterol levels, and diastolic blood pressure and weaker increases in HDL cholesterol levels than participants who survived until the end of follow-up (all p <= .001). In a principal component analysis, annual changes in total, LDL, and HDL cholesterol levels; blood pressures; and glucose, albumin, hemoglobin, leukocyte, and C-reactive protein levels grouped together in one component (all correlation r with component >.40), which associated with all-cause and cancer mortality. Conclusions. In old age, larger declines in BMI, total cholesterol levels, and blood pressures and weaker increases in HDL cholesterol levels associate with mortality. We identified distinct clustering in the dynamics of these traditional metabolic risk factors and indicators of health and disease in a profile that is suggestive of underlying wasting disease. Show less
Sluijter, J.P.G.; Mil, A. van; Vliet, P. van; Metz, C.H.G.; Liu, J.; Doevendans, P.A.; Goumans, M.J. 2010
Objective-To improve regeneration of the injured myocardium, it is necessary to enhance the intrinsic capacity of the heart to regenerate itself and/or replace the damaged tissue by cell... Show moreObjective-To improve regeneration of the injured myocardium, it is necessary to enhance the intrinsic capacity of the heart to regenerate itself and/or replace the damaged tissue by cell transplantation. Cardiomyocyte progenitor cells (CMPCs) are a promising cell population, easily expanded and efficiently differentiated into beating cardiomyocytes. Recently, several studies have demonstrated that microRNAs (miRNAs) are important for stem cell maintenance and differentiation via translational repression. We hypothesize that miRNAs are also involved in proliferation/differentiation of the human CMPCs in vitro. Methods and Results-Human fetal CMPCs were isolated, cultured, and efficiently differentiated into beating cardiomyocytes. miRNA expression profiling demonstrated that muscle-specific miR-1 and miR-499 were highly upregulated in differentiated cells. Transient transfection of miR-1 and -499 in CMPC reduced proliferation rate by 25% and 15%, respectively, and enhanced differentiation into cardiomyocytes in human CMPCs and embryonic stem cells, likely via the repression of histone deacetylase 4 or Sox6. Histone deacetylase 4 and Sox6 protein levels were reduced, and small interference RNA (siRNA)-mediated knockdown of Sox6 strongly induced myogenic differentiation. Conclusion-miRNAs regulate the proliferation of human CMPC and their differentiation into cardiomyocytes. By modulating miR-1 and -499 expression levels, human CMPC function can be altered and differentiation directed, thereby enhancing cardiomyogenic differentiation. (Arterioscler Thromb Vasc Biol. 2010; 30: 859-868.) Show less
Vliet, P. van; Smits, A.M.; Boer, T.P. de; Korfage, T.H.; Metz, C.H.G.; Roccio, M.; ... ; Goumans, M.J. 2010
In the past years, cardiovascular progenitor cells have been isolated from the human heart and characterized. Up to date, no studies have been reported in which the developmental potential of... Show moreIn the past years, cardiovascular progenitor cells have been isolated from the human heart and characterized. Up to date, no studies have been reported in which the developmental potential of foetal and adult cardiovascular progenitors was tested simultaneously. However, intrinsic differences will likely affect interpretations regarding progenitor cell potential and application for regenerative medicine. Here we report a direct comparison between human foetal and adult heart-derived cardiomyocyte progenitor cells (CMPCs). We show that foetal and adult CMPCs have distinct preferences to differentiate into mesodermal lineages. Under pro-angiogenic conditions, foetal CMPCs form more endothelial but less smooth muscle cells than adult CMPCs. Foetal CMPCs can also develop towards adipocytes, whereas neither foetal nor adult CMPCs show significant osteogenic differentiation. Interestingly, although both cell types differentiate into heart muscle cells, adult CMPCs give rise to electrophysiologically more mature cardiomyocytes than foetal CMPCs. Taken together, foetal CMPCs are suitable for molecular cell biology and developmental studies. The potential of adult CMPCs to form mature cardiomyocytes and smooth muscle cells may be essential for cardiac repair after transplantation into the injured heart. Show less
We recently demonstrated that neointima formation of adult heterozygous apolipoprotein E (apoE(+/-)) offspring from hypercholesterolemic apoE(-/-) mothers was significantly increased as compared... Show moreWe recently demonstrated that neointima formation of adult heterozygous apolipoprotein E (apoE(+/-)) offspring from hypercholesterolemic apoE(-/-) mothers was significantly increased as compared with genetically identical apoE(+/-) offspring from normocholesterolemic wild-type mothers. Since atherosclerosis is the consequence of a complex microenvironment and local cellular interactions, the effects of in utero programming and type of postnatal diet on epigenetic histone modifications in the vasculature were studied in both groups of offspring. An immunohistochemical approach was used to detect cell-specific histone methylation modifications and expression of accompanying lysine methyltransferases in the carotid arteries. Differences in histone triple-methylation modifications in vascular endothelial and smooth muscle cells revealed that the offspring from apoE(-/-) mothers had significantly different responses to a high cholesterol diet when compared with offspring from wild-type mothers. Our results suggest that both in utero programming and postnatal hypercholesterolemia affect epigenetic patterning in the vasculature, thereby providing novel insights regarding initiation and progression of vascular disease in adults. Show less
