Frailty score for elderly patients is associated with short-term clinical outcomes in patients with ST-segment elevated myocardial infarction treated with primary percutaneous coronary intervention.

OBJECTIVE: Consistent with the aging population in the Western world, there is a growing number of elderly patients with ST-segment elevation myocardial infarction (STEMI). Primary percutaneous coronary intervention (PCI) is the recommended reperfusion strategy in elderly patients; risk models to determine which of these patients are prone to have poor clinical outcomes are, however, essential. The purpose of this study was to assess the association between frailty and short-term mortality and PCI-related serious adverse events (SAE) in elderly patients. METHODS: All STEMI patients (aged ≥70 years) treated with primary PCI in 2013-2015 at the Leiden University Medical Centre were assessed. The Safety Management Programme (VMS) score was used to identify frail elderly patients. The primary endpoint was 30-day all-cause mortality; the secondary endpoint included 30-day clinical death, target vessel failure, major bleeding, contrast induced kidney insufficiency and stroke. RESULTS: A total of 206 patients were included (79 ± 6.4 years, 119 [58%] male). The VMS score was ≥1 in 28% of all cases. Primary and secondary endpoint rates were 5 and 23% respectively. VMS score ≥1 was an independent predictor for both 30-day mortality (odds ratio [OR] 9.6 [95% confidence interval, CI 1.6-56.9] p-value = 0.013) and 30-day SAE (OR 2.9 [95% CI 1.1-7.9] p-value = 0.038). CONCLUSIONS: VMS score for frailty is independently associated with short-term mortality and PCI-related SAE in elderly patients with STEMI treated with primary PCI. These results suggest that frailty in elderly patients is an important feature to measure and to be taken into account when developing risk models.

Impaired cognition is associated with adverse outcome in older patients in the Emergency Department; the Acutely Presenting Older Patients (APOP) study.

Objective: to investigate whether cognitive impairment, measured early after Emergency Department (ED) arrival and irrespective of its cause, is independently associated with functional decline or mortality after 3 and 12 months in older ED patients. Design and setting: a prospective multi-centre cohort study in all Acutely Presenting Older Patients visiting the Emergency Department (APOP study) of three hospitals in the Netherlands. Participants: 2,130 patients, ≥70 years. Measurements: data on demographics, disease severity and geriatric characteristics were collected during the first hour of the ED visit. Cognition was measured using the 6-Item-Cognitive-Impairment-Test ('6CIT'). Cognitive impairment was defined as 6CIT ≥11, self-reported dementia or the inability to perform the cognition test. The composite adverse outcome after 3 and 12 months was defined as a 1-point decrease in Katz Activities of Daily Living (ADL), new institutionalisation or mortality. Multivariable regression analysis was used to assess whether cognitive impairment independently associates with adverse outcome. Results: of 2,130 included patients, 588 (27.6%) had cognitive impairment at baseline and 654 patients (30.7%) suffered from adverse outcome after 3 months. Cognitive impairment associated with increased risk for adverse outcome (adjusted odds ratio (OR) 1.72, 95%CI 1.37-2.17). After 12 months, 787 patients (36.9%) suffered from adverse outcome. Again, cognitive impairment independently associated with increased risk for adverse outcome (adjusted OR 1.89, 95%CI 1.46-2.46). ORs were similar for patients who were discharged home versus hospitalised patients. Conclusion: cognitive impairment measured during the early stages of ED visit, irrespective of the cause, is independently associated with adverse outcome after 3 and 12 months in older patients.

Are elevated circulating intercellular adhesion molecule 1 levels more strongly predictive of diabetes than vascular risk? Outcome of a prospective study in the elderly.

AIMS/HYPOTHESIS: The aim of this prospective study was to determine whether circulating intercellular adhesion molecule (ICAM) 1, as a potential surrogate of 'endothelial activation', is more strongly associated with risk of vascular events than with incident diabetes. METHODS: We related baseline ICAM-1 levels to vascular events (866 CHD and stroke events in 5,685 participants) and incident diabetes (292 in 4,945 without baseline diabetes) in the elderly over 3.2 years of follow-up. RESULTS: ICAM-1 levels correlated positively with triacylglycerol but negatively with LDL- and HDL-cholesterol. ICAM-1 levels were higher in those who developed diabetes (388.6 +/- 1.42 vs 369.4 +/- 1.39 ng/ml [mean+/-SD], p = 0.011) and remained independently associated with new-onset diabetes (HR 1.84, 95% CI 1.26-2.69, p = 0.0015 per unit increase in log[ICAM-1] after adjusting for classical risk factors and C-reactive protein). By contrast, ICAM-1 levels were not significantly (p = 0.40) elevated in those who had an incident vascular event compared with those who remained event-free, and corresponding adjusted risk associations were null (HR 0.98, 95% CI 0.80-1.22, p = 0.89) in analyses adjusted for other risk factors. CONCLUSIONS/INTERPRETATION: We show that elevated ICAM-1 levels are associated with risk of incident diabetes in the elderly at risk, despite no association with incident cardiovascular disease risk. We suggest that perturbations in circulating ICAM-1 levels are aligned more towards diabetes risk.

Low blood pressure in the very old, a consequence of imminent heart failure: the Leiden 85-plus Study.

Low blood pressure in the very old has been associated with organ dysfunction and excess mortality but the underlying mechanism has yet to be elucidated. We hypothesized that cardiac dysfunction contributes to low blood pressure in the very old. We invited a convenience sample consisting of 82 participants all aged 90 years from a population-based cohort study in the very old. Blood pressure was measured twice, and all but one underwent echocardiography to assess cardiac dimensions and functional cardiac parameters. Some 47 participants were free from haemodynamically significant valvular disease and were included in the present analyses. There were low values for mean cardiac output (2.04 l(-1) min(-1) m(-2), s.e. 0.40) and mean stroke volume (31.4 ml m(-2), s.e. 7.7). For every 10-mm Hg decrease in systolic blood pressure, cardiac output was 0.09 l(-1) min(-1) m(-2) lower (s.e. 0.04, P=0.019), and stroke volume was 1.58 ml m(-2) lower (s.e. 0.68, P=0.024). Mean left ventricular ejection fraction was normal and 2.39% (s.e. 1.16, P=0.046) higher for each 10-mm Hg decrease in systolic blood pressure. Mean left ventricular dimensions were normal but the E/A ratio was reduced (0.68, s.d. 0.21), indicating diastolic dysfunction. In conclusion, among the oldest old, low systolic blood pressure correlates with low cardiac output. Systolic ventricular function is not impaired.

Genetic variation in the interleukin-1 beta-converting enzyme associates with cognitive function. The PROSPER study.

Inflammation is thought to play an important role in the development of cognitive decline and dementia in old age. The interleukin-1 signalling pathway may play a prominent role in this process. The gene encoding for interleukin-1 beta-converting enzyme (ICE) is likely to influence IL-1 beta levels. Inhibition of ICE decreases the age-related increase in IL-1 beta levels and may therefore improve memory function. We assessed whether genetic variation in the ICE gene associates with cognitive function in an elderly population. All 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) were genotyped for the 10643GC, 9323GA, 8996AG and 5352GA polymorphisms in the ICE gene. Cross-sectional associations between the polymorphisms and cognitive function were assessed with linear regression. Longitudinal associations between polymorphisms, haplotypes and cognitive function were assessed with linear mixed models. All associations were adjusted for sex, age, education, country, treatment with pravastatin and version of test where appropriate. Subjects carrying the variants 10643C and 5352A allele had significantly lower IL-1 beta production levels (P < 0.01). Furthermore, we demonstrated that homozygous carriers of the 10643C and the 5352A allele performed better on all executive function tests at baseline and during follow-up compared to homozygous carriers of the wild-type allele (all P < 0.02). The haplotype with two variants present (10643C and 5352A) was associated with better executive function (all P < 0.02) compared to the reference haplotype without variants. For memory function the same trend was observed, although not significant. Genetic variation in the ICE gene is associated with better performance on cognitive function and lower IL-1 beta production levels. This suggests that low levels of IL-1 beta are protective for memory and learning deficits. Inhibition of ICE may therefore be an important therapeutic target for maintaining cognitive function in old age.

Lymphotoxin-alpha C804A polymorphism is a risk factor for stroke. The PROSPER study.

Inflammation plays a prominent role in the development of atherosclerosis, which is the most important risk factor for vascular events. Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine and is found to be expressed in atherosclerotic lesions. We investigated the association between the C804A polymorphism within the LTA gene and coronary and cerebrovascular events in 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). The primary endpoint was the combined endpoint of death from coronary heart disease, non-fatal myocardial infarction, and clinical stroke. Secondary endpoints were the coronary and cerebrovascular components separately. All associations were assessed with a Cox-proportional hazards model adjusted for sex, age, pravastatin use, and country. Our overall analysis showed a significant association between the C804A polymorphism and the primary endpoint (p = 0.03). After stratification for gender, this association was found only in males. Furthermore, we found that the association between the C804A polymorphism and the primary endpoint was mainly attributable to clinical strokes (p = 0.02). The C804A polymorphism in the LTA gene associates with clinical stroke, especially in men. But further research is warranted to confirm our results.

Single Physical Performance Measures Cannot Identify Geriatric Outpatients with Sarcopenia.

BACKGROUND: Sarcopenia is highly prevalent in the older population and is associated with several adverse health outcomes. Equipment to measure muscle mass and muscle strength to diagnose sarcopenia is often unavailable in clinical practice due to the related expenses while an easy physical performance measure to identify individuals who could potentially have sarcopenia is lacking. OBJECTIVES: This study aimed to assess the association between physical performance measures and definitions of sarcopenia in a clinically relevant population of geriatric outpatients. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional study was conducted, consisting of 140 community-dwelling older adults that were referred to a geriatric outpatient clinic. No exclusion criteria were applied. MEASUREMENTS: Physical performance measures included balance tests (side-by-side, semi-tandem and tandem test with eyes open and -closed), four-meter walk test, timed up and go test, chair stand test, handgrip strength and two subjective questions on mobility. Direct segmental multi-frequency bioelectrical impedance analysis was used to measure muscle mass. Five commonly used definitions of sarcopenia were applied. Diagnostic accuracy was determined by sensitivity, specificity and area under the curve. RESULTS: Physical performance measures, i.e. side-by-side test, tandem test, chair stand test and handgrip strength, were associated with at least one definition of sarcopenia. Diagnostic accuracy of these physical performance measures was poor. CONCLUSIONS: Single physical performance measures could not identify older individuals with sarcopenia, according to five different definitions of sarcopenia.

Optimization of the APOP screener to predict functional decline or mortality in older emergency department patients: Cross-validation in four prospective cohorts.

INTRODUCTION: Many screening instruments to predict adverse health outcomes in older patients visiting the emergency department (ED) have been developed, but successful implementation has been hampered because they are insufficiently validated or not tailored for the intended use of everyday clinical practice. The present study aims to refine and validate an existing screening instrument (the APOP screener) to predict 90-day functional decline or mortality in older ED patients. METHODS: Consecutive older patients (≥70 years) visiting the EDs of four hospitals were included and prospectively followed. First, an expert panel used predefined criteria to decide which independent predictors (including demographics, illness severity and geriatric parameters) were suitable for refinement of the model predicting functional decline or mortality after 90 days. Second, the model was cross-validated in all four hospitals and predictive performance was assessed. Additionally, a pilot study among triage nurses experiences and clinical usability of the APOP screener was conducted. RESULTS: In total 2629 older patients were included, with a median age of 79 years (IQR 74-84). After 90 days 805 patients (30.6%) experienced functional decline or mortality. The refined prediction model included age, gender, way of arrival, need of regular help, need help in bathing/showering, hospitalization the prior six months and impaired cognition. Calibration was good and cross-validation was successful with a pooled area under the curve of 0.71 (0.69-0.73). In the top 20% patients predicted to be at highest risk in total 58% (95%CI 54%-62%) experienced functional decline or mortality. Triage nurses found the screener well suited for clinical use, with room for improvement. CONCLUSION: In conclusion, optimization of the APOP screener resulted in a short and more simplified screener, which adequately identifies older ED patients at highest risk for functional decline or mortality. The findings of the pilot study were promising for clinical use.

Genetic variation in the interleukin-10 gene promoter and risk of coronary and cerebrovascular events: the PROSPER study.

Proinflammatory cytokines, like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), are implicated in the development of atherosclerosis. The role of anti-inflammatory cytokines, like IL-10, is largely unknown. We investigated the association of four single nucleotide polymorphisms (SNPs) in the promoter region of the IL-10 gene (4259AG, -1082GA, -592CA, and -2849GA), with coronary and cerebrovascular disease in participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. All associations were assessed with Cox proportional hazards models adjusted for sex, age, pravastatin use, and country. Haplotype analysis of the four SNPs showed a significant association between haplotype 4 (containing the -592A variant allele) and risk of coronary events (P = 0.019). Moreover, analysis of separate SNPs found a significant association between -2849AA carriers with incident stroke (HR (95%CI) 1.50 (1.04-2.17), P value = 0.02). Our study suggests that not only proinflammatory processes contribute to atherosclerosis, but that also anti-inflammatory cytokines may play an important role.

Optimising the ISAR-HP to screen efficiently for functional decline in older patients.

INTRODUCTION: The Identification of Seniors At Risk-Hospitalised Patients (ISAR-HP) has recently been included in guidelines as a frailty indicator to identify patients for comprehensive geriatric assessment. Previous studies showed that the conventional cut-off score incorrectly classifies a high percentage of patients as high risk. We aimed to optimise the predictive value of ISAR-HP by using different cut-offs in older acutely hospitalised patients. METHODS: A prospective follow-up study was performed in two Dutch hospitals. Acutely hospitalised patients aged ≥ 70 years were included. Demographics, illness severity parameters, geriatric measurements and the ISAR-HP scores were obtained at baseline. The primary outcome was a combined end point of functional decline or mortality during 90-day follow-up. RESULTS: In total 765 acutely hospitalised older patients were included, with a median age of 79 years, of whom 276 (36.1%) experienced functional decline or mortality. The conventional ISAR-HP cut-off of ≥ 2 assigned 432/765 patients (56.5%) as high risk, with a positive predictive value (PPV) of 0.49 (95%CI 0.45-0.54) and a negative predictive value of 0.81 (95%CI 0.76-0.85). Thus, 51% of those whom the ISAR-HP denoted as high risk did not experience the outcome of interest. Raising the cut-off to ≥ 4 assigned 205/765 patients (26.8%) as high risk, with a marginally increased PPV to 0.55 (95%CI 0.48-0.62). CONCLUSION: The ISAR-HP with the conventional cut-off of ≥ 2 incorrectly identifies a large group of patients at high risk for functional decline or mortality and raising the cut-off to 4 only marginally improved performance. Caution is warranted to ensure efficient screening and follow-up interventions.

Not all age-related white matter hyperintensities are the same: a magnetization transfer imaging study.

PURPOSE: Our aim was to assess whether presumed histologic heterogeneity of age-related white matter hyperintensities (WMH) is reflected in quantitative magnetization transfer imaging measures. MATERIALS AND METHODS: From a group of patients participating in a double-blind placebo-controlled multicenter study on the effect of pravastatin (PROSPER), we selected 56 subjects with WMH. WMH were classified as periventricular WMH (PVWMH) and deep WMH (DWMH). PVWMH were subclassified as irregular or smooth, depending on the aspect of their border. Signal intensity of WMH on T1-weighted images was scored as iso- or hypointense. The mean magnetization transfer ratio (MTR) value of different types of WMH was assessed and compared. As a control group, we selected 19 subjects with no or limited WMH. RESULTS: Mean (SE) MTR of PVWMH (frontal, 31.2% [0.2%]; occipital, 32.2% [0.2%]) was lower than that of DWMH (33.7% [0.5%]). The mean MTR of frontal PVWMH (31.2% [0.2%]) was lower than that of occipital PVWMH (32.2% [0.2%]). Compared with occipital PVWMH, frontal PVWMH more often had a smooth lining (72% frontal versus 8% occipital) and an area with low signal intensity on T1-weighted images (76% frontal versus 35% occipital). MTR did not differ between smooth (31.1% [0.3%]) and irregular (31.6% [0.5%]) PVWMH. CONCLUSION: Age-related WMH are heterogeneous, despite their similar appearance on T2-weighted images. By taking into account heterogeneity of age-related WMH, both in terms of etiology and in terms of severity of tissue destruction, one may obtain better understanding on the causes and consequences of these lesions.

Measuring longitudinal white matter changes: comparison of a visual rating scale with a volumetric measurement.

BACKGROUND AND PURPOSE: Detection of longitudinal changes in white matter hyperintensities (WMH) by using visual rating scales is problematic. We compared a widely used visual rating scale with a volumetric method to study longitudinal white matter changes. METHODS: WMH were assessed with the visual Scheltens scale and a volumetric method in 100 elderly subjects aged 70-81 years for whom repetitive MR images were available with an interval of 33 (SD, 1.4) months. Reliability was determined by intraclass correlation coefficients. To examine the sensitivity of both the visual and volumetric method, we calculated Spearman rank correlations of WMH ratings and volume measurements with age. RESULTS: Reliability of the visual rating scale was good, whereas reliability of the volumetric measurement was excellent. For baseline measurements of WMH, we found weaker associations between WMH and age when assessed with the visual scale (r = 0.20, P = .045) than with the volumetric method (r = 0.31, P = .002). Longitudinal evaluation of WMH assessments showed regression in 26% of the subjects when analyzed with the visual rating scale against 12% of the subjects when using volumetric measurements. Compared with the visual rating, the correlation between progression in WMH and age was twice as high when using the volumetric measurement (r = 0.19, P = .062 and r = 0.39, P < .001, respectively). CONCLUSION: Volumetric measurements of WMH offer a more reliable, sensitive, and objective alternative to visual rating scales in studying longitudinal white matter changes.

Predicting adverse health outcomes in older emergency department patients: the APOP study.

BACKGROUND: Older patients experience high rates of adverse outcomes after an emergency department (ED) visit. Early identification of those at high risk could guide preventive interventions and tailored treatment decisions, but available models perform poorly in discriminating those at highest risk. The present study aims to develop and validate a prediction model for functional decline and mortality in older patients presenting to the ED. METHODS: A prospective follow-up study in patients aged ≥ 70, attending the EDs of the LUMC, the Netherlands (derivation) and Alrijne Hospital, the Netherlands (validation) was conducted. A baseline assessment was performed and the main outcome, a composite of functional decline and mortality, was obtained after 90 days of follow-up. RESULTS: In total 751 patients were enrolled in the Leiden University Medical Center of whom 230 patients (30.6%) experienced the composite outcome and 71 patients (9.5%) died. The final model for the composite outcome resulted in an area under the curve (AUC) of 0.73 (95% CI 0.67-0.77) and was experienced in 69% of the patients at highest risk. For mortality the AUC was 0.79 (95% CI 0.73-0.85) and 36% of the patients at highest risk died. External validation in 881 patients of Alrijne Hospital showed an AUC of 0.71 (95% CI 0.67-0.75) for the composite outcome and 0.67 (95% CI 0.60-0.73) for mortality. CONCLUSION: We successfully developed and validated prediction models for 90-day composite outcome and 90-day mortality in older emergency patients. The benefits for patient management by implementing these models with preventive interventions have to be investigated.

Impaired endothelium-dependent vasodilation in type 2 diabetes mellitus and the lack of effect of simvastatin.

OBJECTIVE: Although type 2 diabetes is recognized as an independent risk factor for cardiovascular disease and cardiovascular disease is associated with endothelial dysfunction, the influence of type 2 diabetes per se on the endothelial function is controversial. HMG-CoA-reductase inhibitors have been shown to have short-term beneficial effects on endothelial dysfunction among patients with dyslipidemia or cardiovascular disease. The effect of HMG-CoA reductase inhibitors on the endothelial function in diabetes is largely unknown. METHODS: Seventeen patients with type 2 diabetes, free of cardiovascular disease and no other cardiovascular risk factors, except for dyslipidemia, were studied together with ten healthy volunteers. The effect of 5-hydroxytryptamine, as an endothelium-dependent vasodilator, and sodium nitroprusside, as an endothelium-independent vasodilator, on the forearm blood flow was measured using venous occlusion plethysmography. RESULTS: 5-Hydroxytryptamine and sodium nitroprusside, infused in the brachial artery, caused a dose-dependent vasodilation. The vasodilator response to 5-hydroxytryptamine was significantly lower among the diabetic patients, 42 and 56%, than among the controls, 73 and 103%, at a dose of 0.3 and 0.9 ng/kg/min, respectively (P<0.05 and P<0.001). Vasodilator responses to sodium nitroprusside were comparable among the diabetic patients and controls. A 6-week treatment with simvastatin 40 mg once daily did not change the vasodilator responses to 5-hydroxytryptamine or sodium nitroprusside among the patients with diabetes. CONCLUSIONS: The results of this study indicate that the endothelial function is impaired in type 2 diabetes and is not restored after a 6-week treatment period with simvastatin 40 mg.

Insulin resistance but not hypertriglyceridemia per se is associated with endothelial dysfunction in chronic hypertriglyceridemia.

OBJECTIVES: To infer the relative impact of elevated triglyceride levels and insulin resistance on endothelial dysfunction in patients with chronic hypertriglyceridemia (HTG). METHODS: Endothelial function was studied in 11 HTG patients and 16 normolipidemic controls. Cumulative-dose infusions of 5-hydroxytryptamine (5HT) and sodium nitroprusside were infused locally into the brachial artery to study endothelium-dependent and endothelium-independent vasodilation, respectively. Data of the HTG patients were dichotomized around the median of insulin resistance, calculated as HOMA-index, forming HTG groups with mild (HTG-MIR) and severe insulin resistance (HTG-SIR). RESULTS: HTG patients had higher triglyceride levels and smaller LDL particle size than controls (both P< or =0.001), whereas these parameters did not differ between both HTG groups. Insulin resistance was higher in both HTG groups than in controls (11.1 (7.0-14.5) and 4.9 (4.0-6.7) vs. 2.4 (4.9-5.2), respectively, both P<0.001). Similarly, free fatty acid levels, another indicator of insulin resistance, were highest in the HTG-SIR group, followed by those in the HTG-MIR and control group (0.7 (0.6-0.8), 0.5 (0.4-0.6) and 0.4 (0.3-0.4) mmol/l, respectively, all P<0.05). Endothelial-dependent vasodilation was similar in HTG-MIR and controls. In contrast, the response to 5HT was attenuated in the HTG-SIR group compared to controls (low and high dose by, respectively, -60 and -44%, both P<0.01), and tended to be lower than in the HTG-MIR group (-43%, P=0.068 and -41%, P=0.100, respectively). Endothelium-independent vasodilation did not differ between the three groups. CONCLUSION: These findings indicate that chronic hypertriglyceridemia per se is not associated with endothelial dysfunction. In contrast, the presence of insulin resistance, characterized by hyperinsulinemia and FFA elevation, contributes to the induction of endothelial dysfunction in chronic HTG.

Evidence-based medicine in older patients: how can we do better?

Evidence-based medicine (EBM) aims to integrate three elements in patient care: the patient situation, scientific evidence, and the doctors' expertise. This review aims 1) to assess how these elements are systematically different in older patients and 2) to propose strategies how to improve EBM in older patients. The ageing process systematically affects all three elements that constitute EBM. First, ageing changes the physiology of the older body, makes the patient more vulnerable with more multimorbidity and polypharmacy and affects somatic, psychological and social function. The heterogeneity of older patients may lead to overtreatment of vulnerable and undertreatment of fit older patients. Second, representative older patients are underrepresented in clinical studies and endpoints studied may not reflect the specific needs of older patients. Third, adequate clinical tools and schooling are lacking to aid physicians in clinical decision-making. Strategies to improve elements of EBM include: first systematically acknowledging that physical, mental and social function may reveal patients vulnerability and specific treatment goals. Second, clinical studies specifically targeting more representative older patients and studying endpoints relevant to older patients are warranted. Finally, teaching of physicians may increase their experience and expertise in treating older patients. In conclusion, in older patients the same elements constitute EBM, but the elements need tailoring to the older patient. In the clinic, a thorough assessment of individual patient preferences and physical, mental and social functioning in combination with increased level of experience of the doctor can increase the quality of EBM in older patients.

Regional vascular effects of serotonin and ketanserin in young, healthy subjects.

The local hemodynamic effects of serotonin (5-hydroxytryptamine; 5-HT) and the selective 5-HT2 antagonist ketanserin were investigated in the forearm of 20 healthy volunteers. Single doses of 5-HT (0.1-80 ng/kg/min) and ketanserin (5-125 ng/kg/min) were administered intra-arterially. The relative alpha 1-adrenergic receptor and 5-HT2 blocking potencies of ketanserin were investigated using intra-arterial infusions of cumulative doses of methoxamine (0.1, 0.3, and 0.5 microgram/kg/min), tyramine (0.25, 0.50, and 1.25 microgram/kg/min), and 5-HT (10, 30, and 80 ng/kg/min) together with a low dose (5 ng/kg/min) and a high dose (50 ng/kg/min) of ketanserin. Forearm blood flow was measured by venous occlusion plethysmography. Heart rate and intra-arterial blood pressure were recorded semicontinuously. Intra-arterial infusion of 5-HT induced an initial transient vasodilatation, followed by a steady vasodilatation for the low doses of 5-HT (0.1-10 ng/kg/min; p less than 0.05). A steady vasoconstriction was only obtained at the highest dose of 5-HT. Ketanserin induced a dose-dependent increase in forearm blood flow from 15 ng/kg/min (p less than 0.05) onward. The vasodilatation induced by 5-HT (1 ng/kg/min) was significantly enhanced by ketanserin (125 ng/kg/min; p less than 0.05), whereas the vasoconstriction elicited by 5-HT (80 ng/kg/min) was reversed by ketanserin (50 ng/kg/min; p less than 0.05), thus confirming that 5-HT2 receptors were stimulated by 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

The acute and chronic antihypertensive effects of ketanserin cannot be explained by blockade of vascular serotonin, type 2, receptors or alpha 1-adrenergic receptors.

The mechanism underlying the antihypertensive effect of acute and chronic administration of ketanserin was investigated in eight hypertensive patients. Intrabrachial artery infusions of serotonin and the selective alpha 1-adrenergic receptor agonist methoxamine were given before and 1 hour after a single oral dose of 20 mg ketanserin and after 4 weeks of treatment with 20 to 40 mg twice daily. Blood pressure was reduced by ketanserin both after the initial dose (p less than 0.01) and after 4 weeks of treatment (p less than 0.01). During placebo, serotonin, 1 ng/kg/min, increased forearm blood flow by 51% +/- 9% (p less than 0.01), whereas the highest dose induced a decrease in flow (-33% +/- 6%; p less than 0.01). Methoxamine elicited a vasoconstriction (p less than 0.001). These effects of serotonin and methoxamine were not influenced by either the initial dose of ketanserin or after 4 weeks of treatment. It is concluded that serotonin cannot be considered a general endogenous pressor agent in these patients. The antihypertensive effects of ketanserin cannot be attributed to either vascular alpha 1-receptor or serotonin, type 2, receptor blockade.

Atherosclerosis and cognitive impairment are linked in the elderly. The Leiden 85-plus Study.

Post-mortem analyses suggest that atherosclerosis more often contributes to late-onset dementia than hitherto expected. We set out to further unravel the relation between atherosclerosis and cognitive impairment. We therefore tested the hypothesis that the number of cardiovascular pathologies is positively associated with cognitive impairment in elderly subjects, and that the smaller number of cardiovascular pathologies in women explains the better cognitive function of elderly women. Within the Leiden 85-plus Study, we assessed the atherosclerotic burden by counting the number of cardiovascular pathologies in the medical histories of a population-based sample of 599 subjects aged 85 years (response 87%). Significantly more men than women had a history of cardiovascular pathologies (67% compared to 59%, P<0.001). In addition, cognitive function was assessed. All subjects completed the Mini-Mental State Examination (MMSE). Cognitive speed and memory were determined with specific neuro-psychological tests in those with a MMSE-score above 18 points. There was a highly significant dose-response relationship between the number of cardiovascular pathologies and cognitive impairment for both men and women. The median MMSE-score was 26 points in subjects without cardiovascular disease and decreased to 25 points for subjects who had two or more cardiovascular pathologies (P for trend =0.003). Similar associations were found for cognitive speed but not for memory. Our data confirm that in old age atherosclerosis significantly contributes to cognitive impairment. Since treatments for atherosclerosis appear to be particularly effective in elderly people, we consider our finding of utmost clinical importance in possibly preventing cognitive impairment and late-onset dementia.

Bezafibrate reduces heart rate and blood pressure in patients with hypertriglyceridemia.

OBJECTIVE: In hypertriglyceridemic patients, hypertension occurs frequently and may be associated with hyperinsulinemia and elevated plasma levels of free fatty acids (FFA). Besides the lipid-lowering effects, fibrates have been shown to reduce blood pressure in hypertensive patients. The present study was undertaken to investigate the effects of bezafibrate on hemodynamics in relation to insulin, FFA, sympathetic activity, renal sodium absorption, cyclic-GMP (cGMP) and endothelin-1 in hypertriglyceridemic patients. SUBJECTS AND METHODS: Hypertriglyceridemic patients (17) were randomized to receive in a double-blind placebo-controlled study bezafibrate or placebo for 6 weeks. At the end of both treatment periods, blood pressure and heart rate were measured automatically. Plasma insulin, FFA, aldosterone, catecholamines, cGMP, endothelin-1 levels and 24 h urine catecholamines and sodium excretion were assessed. RESULTS: Bezafibrate therapy decreased serum triglycerides (-65%, P < 0.001) and hemodynamic parameters: heart rate decreased from 69 to 66/min (P = 0.009), systolic blood pressure from 137 to 132 mmHg (P = 0.01), diastolic blood pressure from 81 to 79 mmHg (P = 0.07) and mean blood pressure from 102 to 99 mmHg (P = 0.06). Bezafibrate therapy reduced FFA and insulin (-55 and -57% respectively, both P < 0.001), while sympathetic activity and renal sodium absorption were not affected. cGMP increased (+17%, P = 0.008), whereas endothelin-1 levels tended to decrease upon bezafibrate therapy (-10%, P = 0.077) CONCLUSION: Bezafibrate reduces heart rate, blood pressure, insulin and FFA in hypertriglyceridemic patients. The hemodynamic effects cannot be attributed to changes in sympathetic activity or renal sodium absorption. Instead, based on the increase in plasma cGMP levels, the bezafibrate-induced hemodynamic effects are most likely to be caused by bezafibrate-induced improvement of endothelial function.