Gemtuzumab ozogamicin plus midostaurin in combination with standard '7 + 3' induction therapy in newly diagnosed AML: Results from the SAL-MODULE phase I study.

We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.

Adrenomedullary function, obesity and permissive influences of catecholamines on body mass in patients with chromaffin cell tumours.

BACKGROUND: Obesity-associated activation of sympathetic nervous outflow is well documented, whereas involvement of dysregulated adrenomedullary hormonal function in obesity is less clear. This study assessed relationships of sympathoadrenal function with indices of obesity and influences of circulating catecholamines on body mass. METHODS: Anthropometric and clinical data along with plasma and 24-h urine samples were collected from 590 volunteers and 1368 patients tested for phaeochromocytoma and paraganglioma (PPGL), among whom tumours were diagnosed in 210 individuals. RESULTS: Among patients tested for PPGL, those with tumours less often had a body mass index (BMI) above 30 kg/m2 (12 vs. 31%) and more often a BMI under 25 kg/m2 (56 vs. 32%) than those without tumours (P < 0.0001). Urinary outputs of catecholamines in patients with PPGL were negatively related to BMI (r = -0.175, P = 0.0133). Post-operative weight gain (P < 0.0001) after resection of PPGL was positively related to presurgical tumoural catecholamine output (r = 0.257, P = 0.0101). Higher BMI in men and women and percent body fat in women of the volunteer group were associated with lower plasma concentrations and urinary outputs of adrenaline and metanephrine, the former indicating obesity-related reduced adrenaline secretion and the latter obesity-related reduced adrenomedullary adrenaline stores. Daytime activity was associated with substantial increases in urinary adrenaline and noradrenaline excretion, with blunted responses in obese subjects. CONCLUSIONS: The findings in patients with PPGL support an influence of high circulating catecholamines on body weight. Additional associations of adrenomedullary dysfunction with obesity raise the possibility of a permissive influence of the adrenal medulla on the regulation of body weight.

Sudomotor Testing of Diabetes Polyneuropathy.

Objective: The performance of the Sudoscan technology for diagnosing diabetic polyneuropathy (DPN) was evaluated against the quantitative sudomotor axon reflex test (QSART). Furthermore, the association of Sudoscan with two clinical neuropathy scoring systems was evaluated. Methods: Forty-seven patients with type 2 diabetes (20 without DPN, 27 with DPN) and 16 matched controls were examined for neuropathic symptoms and for the extent of sensory deficits. Sweat latency and volume by QSART and the skin electrochemical conductance (ESC) by Sudoscan were measured. Results: The feet and hand ESC was significantly lower in patients with DPN as compared to controls. Patients with DPN had also lower hand ESC than patients without DPN. Sensitivity and specificity of feet and hand ESC for detecting DPN were 70/85% and 53/50% respectively. QSART could not differentiate between the three groups. ESC was inversely related to neuropathic symptoms and sensory impairment. ESC was significantly correlated with sensory impairment and pain. Conclusions: Sudoscan shows a good performance in detecting subjects with DPN and it correlates well with clinical signs and symptoms of neuropathy. Significance: This study provides evidence that Sudoscan has high potential to be used as screening tool for DPN and possibly also for small fiber neuropathy in diabetic patients. HIGHLIGHTS - The sudomotor function test Sudoscan shows a good performance to detect diabetes peripheral neuropathy.- Sudoscan measures significantly correlate with clinical signs and symptoms of neuropathy.- The Sudoscan technology may help to secure clinical diagnosis of small fiber neuropathy.

Modulation of Cardiac Autonomic Function by Fingolimod Initiation and Predictors for Fingolimod Induced Bradycardia in Patients with Multiple Sclerosis.

Objective: It is well-known that initiation of fingolimod induces a transient decrease of heart rate. However, the underlying cardiac autonomic regulation is poorly understood. We aimed to investigate the changes of autonomic activity caused by the first dose of fingolimod using a long-term multiple trigonometric spectral analysis for the first time. In addition, we sought to use the continuous Holter ECG recording to find predictors for fingolimod induced bradycardia. Methods: Seventy-eight patients with relapsing-remitting multiple sclerosis (RRMS) were included. As a part of the START study (NCT01585298), continuous electrocardiogram was recorded before fingolimod initiation, and until no <6 h post medication. Time domain and frequency domain heart rate variability (HRV) parameters were computed hourly to assess cardiac autonomic regulation. A long-term multiple trigonometric regressive spectral (MTRS) analysis was applied on successive 1-h-length electrocardiogram recordings. Decision tree analysis was used to find predictors for bradycardia following fingolimod initiation. Results: Most of the HRV parameters representing parasympathetic activities began to increase since the second hour after fingolimod administration. These changes of autonomic regulations were in accordance with the decline of heart rate. Baseline heart rate was highly correlated with nadir heart rate, and was the only significant predicting factor for fingolimod induced bradycardia among various demographic, clinical and cardiovascular variables in the decision tree analysis. Conclusions: The first dose application of fingolimod enhances the cardiac parasympathetic activity during the first 6 h post medication, which might be the underlying autonomic mechanism of reduced heart rate. Baseline heart rate is a powerful predictor for bradycardia caused by fingolimod.

Subthalamic nucleus stimulation and levodopa modulate cardiovascular autonomic function in Parkinson's disease.

We aimed to explore the effects of bilateral subthalamic nucleus stimulation and levodopa on cardiovascular autonomic function in Parkinson's disease. Twenty-six Parkinson's disease patients with bilateral subthalamic nucleus stimulation in a stable state were tested under stimulation off and dopaminergic medication off (OFF-OFF), stimulation on and dopaminergic medication off (ON-OFF), and stimulation on and medication (levodopa) on (ON-ON) conditions by recording continuously blood pressure, ECG, and respiration at rest, during metronomic deep breathing, and head-up tilt test. Thirteen patients were diagnosed as orthostatic hypotension by head-up tilt test. Baroreflex sensitivity and spectral analyses were performed by trigonometric regressive spectral analysis. Subthalamic nucleus stimulation and levodopa had multiple influences. (1) Systolic blood pressure during tilt-up was reduced by subthalamic nucleus stimulation, and then further by levodopa. (2) Subthalamic nucleus stimulation and levodopa had different effects on sympathetic and parasympathetic regulations in Parkinson's disease. (3) Levodopa decreased baroreflex sensitivity and RR interval only in the orthostatic hypotension group, and had opposite effects on the non-orthostatic hypotension group. These findings indicate that subthalamic nucleus stimulation and levodopa have different effects on cardiovascular autonomic function in Parkinson's disease, which are modulated by the presence of orthostatic hypotension as well.

Troponin T release is associated with silent myocardial ischaemia in black men: The SABPA Study.

Background High sensitivity cardiac troponin T (hs-cTnT) is a validated marker of myocardial damage and may reflect the degree of silent myocardial ischaemia (SMI) and ventricular strain. Our aim was to compare hs-cTnT levels in black and white South Africans taking SMI into consideration. We further explored the capability of hs-cTnT to predict the presence of compensatory systolic hypertension in this South African cohort. Methods A bi-ethnic sex cohort ( n = 404) with similar socioeconomic status (198 black participants and 206 white participants, aged 20-65 years) participated in this target population study where 24 h ambulatory blood pressure, electrocardiogram and overnight fasting cardiometabolic variables were measured. Results Hypertension, higher glycated haemoglobin levels and more frequent and longer SMI events were observed more often in the black participants. Multivariate linear regression analysis showed positive associations between SMI events [Adj. R2 = 0.19; ß 0.35 (0.08-0.62); p < 0.01], SMI event maximum duration [Adj. R2 = 0.17, ß 0.43 (0.16-0.70), p < 0.01], SMI total duration [Adj. R2 = 0.12; ß 0.37 (0.10; 0.65), p = 0.05] and hs-cTnT in black males only.] A lower hs-cTnT cut-point ≥4.2 pg/ml for 24 h systolic hypertension was predicted in the black participants compared with ≥5.6 pg/ml in the white participants (area under the curve 0.66-67 (95% CI: 0.57-0.75), p < 0.001) with a respective sensitivity/specificity of 64/68% and 61/71%. Conclusions hs-cTnT may be a potential marker of SMI in the prediction of systolic blood pressure increases, as well as clusters of risk factors for cardiovascular disease. Ethnic- and possibly sex-specific references values for hs-cTnT should be considered for risk stratification.

Comparison of baroreflex sensitivity estimated from ECG R-R and inter-systolic intervals obtained by finger plethysmography and radial tonometry.

Spontaneous BRS estimates may considerable vary according to the technique of blood pressure and heart rate assessment. To optimise and standardise BRS estimation for clinical use we evaluated possible differences between spontaneous BRS indices estimated from either finger plethysmography or radial tonometry. Forty-five healthy volunteers underwent simultaneous recordings of electrocardiogram, finger plethysmography and radial tonometry in supine position and during 60° head-up tilt. BRS was computed by spectral analysis from either R-R time series and/or arterial pressure pulse. Radial tonometry generated higher mean BRS estimates than finger plethysmography. The difference decreased upon postural change from supine to upright. In the upright position, BRS estimates based on R-R interval proved to be generally lower compared to BRS indices estimated from arterial pressure pulse. The ratio of low-to-high-frequency power of inter-systolic interval and systolic blood pressure from tonometry was lower than that from plethysmography in supine and approximated in upright position. Spectral parameters of inter-systolic interval and R-R interval did not differ in supine but diverged in upright position. Changes of spectral parameters were most pronounced in R-R interval. Arterial pressure pulse is adequate for estimation of BRS under resting conditions but it may distort BRS estimates under physical load. We, therefore, recommend using an ECG signal for BRS estimation especially in non-stationary conditions.

Chronic depression symptoms and salivary NOx are associated with retinal vascular dysregulation: The SABPA study.

BACKGROUND: Depression has been associated with impaired nitric oxide (NO)-mediated vasodilation and vascular dysregulation (VD). Whether depression and NO levels will disturb retinal haemodynamics is not clear. OBJECTIVES AND METHODS: Associations between the retinal vasculature, diastolic ocular perfusion pressure (DOPP) as measure of hypoperfusion, NO metabolites (NOx) and depression symptoms were assessed. Chronic VD risk markers [depression symptoms (Patient Health Questionnaire/PHQ-9 ≥ 10) and 24 h pulse pressure] were determined in a bi-ethnic cohort (n = 313; 48.6 ± 9 years; 53.9% men). At 3 year follow-up, retinal vessel calibre and retinopathy signs were quantified from digital images. Salivary NOx was obtained pre- and post-flicker light-induced provocation (FLIP). DOPP was defined as diastolic blood pressure minus intraocular pressure. RESULTS: Chronic VD risk was evident in Blacks opposed to acute risk in Whites (P < 0.05). At follow-up, retinopathy (Blacks 60.4%/Whites 39.6%), lower pre-FLIP (µM) and higher post-FLIP NOx (changes from baseline, %), arteriolar narrowing and wider venular calibre values were evident in Blacks compared to Whites, independent of confounders. A wider venular calibre, an index of stroke risk, was associated with chronic depression symptoms [cut point 248 MU: Area under the curve 0.61 (95% CI: 0.51, 0.72); 71% sensitivity; 55% specificity] as well as with hypoperfusion in the Blacks. In this group, arteriolar narrowing was associated with hypoperfusion; and attenuated arteriolar dilation with increased post-FLIP NOx responses. CONCLUSIONS: Chronic depression symptoms may alter NO regulation and facilitate VD. NO-mediated vasoconstriction presumably impeded perfusion, retinal haemodynamics and -remodelling; potentiating stroke risk in Blacks.

Three-year changes of prothrombotic factors in a cohort of South Africans with a high clinical suspicion of obstructive sleep apnea.

A hypercoagulable state might be one important mechanism linking obstructive sleep apnea (OSA) with incident myocardial infarction and stroke. However, previous studies on prothrombotic factors in OSA are not uniform and cross-sectional. We longitudinally studied prothrombotic factors in relation to OSA risk, adjusting for baseline levels of prothrombotic factors, demographics, metabolic parameters, aspirin use, and life style factors. The Berlin Questionnaire and/or neck circumference were used to define high OSA risk in 329 South African teachers (48.0% male, 44.6% black) at baseline and at three-year follow-up. Von Willebrand factor (VWF), fibrinogen, D-dimer, plasminogen activator inhibitor-1, clot lysis time (CLT), and soluble urokinase-type plasminogen activator receptor (suPAR) were measured in plasma. At baseline 35.7% of participants had a high risk of OSA. At follow-up, persistently high OSA risk, persistently low OSA risk, OSA risk remission, and new-onset OSA risk were present in 26.1%, 53.2%, 9.4%, and 11.3% of participants, respectively. New-onset OSA risk was associated with a significant and longitudinal increase in VWF, fibrinogen, CLT, and suPAR relative to persistently low OSA risk; in VWF, fibrinogen, and suPAR relative to remitted OSA risk; and in VWF relative to persistently high OSA risk. Persistently high OSA risk was associated with an increase in CLT and suPAR relative to persistently low OSA risk and in D-dimer relative to remitted OSA risk. Remitted OSA risk was associated with D-dimer decrease relative to persistently low OSA risk. In OSA, hypercoagulability is a dynamic process with a most prominent three-year increase in individuals with new-onset OSA risk.

Local endothelial dysfunction does not affect global endothelial function.

BACKGROUND: The purpose of this study was to evaluate two alternative non-invasive techniques for assessment of endothelial function in adults with special focus on their ability to monitor acute changes. PATIENTS AND METHODS: Twenty-five clinically healthy men (mean age 24 ± 2 years) underwent endothelial function measurements twice in fasting state and twice after experimental induction of transient endothelial dysfunction by oral application of 0.1g/kg L-methionine and by ingestion of 500 ml whipped cream (30 % fat), respectively. Microvascular vasodilator responses to flickering-light by retinal vessel analysis and vascular responses to inhaled salbutamol by pulse wave analysis were assessed at each occasion. Ultrasound based flow-mediated dilation (FMD) was used as reference method. RESULTS: Transient endothelial dysfunction in response to acute hyperlipidaemia and hyperhomocysteinaemia was verified by blunted brachial responses to hyperaemia. Retinal vessel analysis demonstrated significantly impaired flicker-responses of retinal vessels to both challenges depending on the vessel type. Pulse wave analysis did not show any significant changes in salbutamol responses. Reproducibility of retinal vessel analysis was comparable to FMD and slightly better than pulse wave analysis. CONCLUSIONS: Acute changes in endothelial function can be monitored by retinal vessel analysis with comparable reproducibility as FMD. Salbutamol based pulse wave analysis is currently unsuited to detect endothelial dysfunction in serial measurements.

Different responses of the retinal and cutaneous microcirculation to transient dysmetabolic conditions.

OBJECTIVE: This study evaluated the responses of the retinal and cutaneous microcirculation to acute hyperlipidemia and hyperhomocysteinemia. METHODS: Twenty-five clinically healthy men (mean age 24 ± 2 years) were studied four times in a randomized order, with intervals of at least one week between the two dietary interventions always preceded by a day for baseline assessment. The two interventions consisted of either 0.1 g/kg l-methionine to induce hyperhomocysteinemia or of 500 ml whipping cream (30% fat) to induce hyperlipidemia. Microvascular vasodilator responses to flickering-light and to cutaneous acetylcholine iontophoresis were assessed by retinal vessel analysis and laser Doppler flowmetry respectively. RESULTS: The fat load produced significant increases in triglycerides and total cholesterol which was accompanied by a reduction of the retinal arterial flicker response. Methionine administration induced a threefold increase in homocysteine levels and a concomitant decrease in retinal venous flicker response. Acute hyperlipidemia and hyperhomocysteinemia had no effect on cutaneous microvascular vasodilator responses to acetylcholine. The inter- and intra-subject reproducibility was higher for retinal vessel analysis as compared to laser Doppler flowmetry. CONCLUSION: The retinal microcirculation is more sensitive to metabolic changes than the cutaneous microcirculation and can be reliably assessed by retinal vessel analysis. Reproducibility of retinal vessel analysis may be enhanced by multi-vessel assessment.

Acute hyperlipidemia but not hyperhomocysteinemia impairs reflex regulation of the cardiovascular system.

BACKGROUND: Elevated circulating lipids and homocysteine may affect autonomic cardiovascular function by decreasing baroreflex sensitivity (BRS) and cardiovagal outflow and by increasing sympathetic drive. METHODS: To test this hypothesis 25 clinically healthy men (mean age 24 ± 2 years) received 500 ml whipping cream (30% fat) and 0.1 g/kg l-methionine, respectively, at intervals of one week apart to induce hyperlipidemia and hyperhomocysteinemia, respectively. Cardiovascular parameters and endothelial function were assessed before and 2 h after the fat load and before and 4 h after the methionine load, respectively. Cardiovascular responses to sublingual application of a nitrovasodilator and a beta-agonist were also determined. RESULTS: Hyperlipidemia elicited a significant decline in BRS and an increase in heart rate and sympathetic drive. Reductions in BRS were associated with changes in total cholesterol but not with triglycerides or endothelial function. Autonomic and hemodynamic variables remained unaltered during transient hyperhomocysteinemia although there was a trend to lower BRS. Autonomic and hemodynamic responses to pharmacological vasodilation and beta-adrenoceptor stimulation were preserved under both conditions. CONCLUSIONS: These data provide experimental support for the concept that acute hyperlipidemia but not hyperhomocysteinemia impairs reflex regulation of the circulatory system.

Insulin is a key determinant of elevated retinal arteriolar flicker response in insulin-resistant individuals.

AIMS/HYPOTHESIS: Insulin may link metabolic disorders to retinal microvascular pathology. The aim of the present study was to investigate the impact of early insulin resistance on retinal microcirculation. METHODS: Retinal diameter responses to flicker-light stimulation were investigated in 81 clinically healthy participants (32 ± 6 years [mean ± SD], 59% women) who were recruited according to their BMI. All participants underwent an OGTT and euglycaemic-hyperinsulinaemic clamp (40 mU/m(2) · min(-1) insulin dose). After stratification by low and high insulin sensitivity based on a clamp-derived glucose disposal rate of ≤ or >4.9 mg/kg body mass, respectively, baseline retinal diameters and their relative changes to flicker stimulation were compared while controlling for mean arterial pressure, BMI and sex. RESULTS: The arterial vasodilator response at the end of flicker stimulation (p = 0.044) and the area under the arterial reaction curve during flicker stimulation (p = 0.015) were significantly higher in individuals with low vs high insulin sensitivity. Vasodilatory responses of retinal veins to flicker stimulation and baseline retinal diameters did not differ between insulin-sensitive and insulin-resistant participants (p > 0.05). In a stepwise linear regression analysis, fasting insulin remained the only predictor of the arterial vasodilator response to flicker-light (p < 0.01). Waist circumference also contributed, although to a lesser extent, to the arterial vasodilator response (p = 0.023). CONCLUSIONS/INTERPRETATION: Insulin sensitivity is an important determinant of retinal microvascular function. We propose that the elevated arterial flicker response in insulin-resistant states is a result of higher circulating insulin levels.

Progression of cardiovascular risk factors in black Africans: 3 year follow up of the SABPA cohort study.

Recent work identified a high prevalence of modifiable risk factors for cardiovascular disease (CVD) among urban black South Africans. The aim was to track the progression of CVD risk factors in a multi-ethnic sample of South Africans. Participants were 173 black (aged 47.5 ± 7.8 yrs) and 186 white teachers (aged 49.6 ± 9.9 yrs) that were examined at baseline and 3 years follow-up. Blacks demonstrated a substantially higher prevalence of composite CVD burden (defined as history of physician diagnosed heart disease, use of anti-hypertensives, anti-diabetic, or statin medications at either time point) compared to whites (49.1 vs. 32.0%, p = 0.012) respectively. After controlling for baseline, the black participants demonstrated greater increases in 24 h systolic and diastolic blood pressure, total cholesterol, fasting glucose, fibrinogen, D-dimer, and waist circumference in comparison with whites. In summary, an adverse progression of CVD risk factors was observed in the whole sample, although to a larger degree in black participants. Aggressive treatment strategies for controlling risk factors in black Africans are needed to reduce the increasing burden of CVD in South Africa.

Seasonal variation in plasma free normetanephrine concentrations: implications for biochemical diagnosis of pheochromocytoma.

BACKGROUND: Higher plasma concentrations of catecholamines in winter than in summer have been established, but whether this impacts the plasma concentrations of metanephrines used for the diagnosis of pheochromocytoma is unknown. OBJECTIVE: In this study, we examined seasonal variations in the plasma concentrations of metanephrines, the impact of this on diagnostic test performance and the influences of forearm warming ('arterialization' of venous blood) on blood flow and measured concentrations. METHODS: The measurements of the plasma concentrations of metanephrines were recorded from 4052 patients tested for pheochromocytoma at two clinical centers. Among these patients, 107 had tumors. An additional 26 volunteers were enrolled for the measurements of plasma metanephrines and forearm blood flow before and after forearm warming. RESULTS: There was no seasonal variation in the plasma concentrations of metanephrines among patients with pheochromocytoma, whereas among those without tumors, the plasma concentrations of normetanephrine were higher (P<0.0001) in winter than in summer. Lowest concentrations of normetanephrine were measured in July, with those recorded from December to April being more than 21% higher (P<0.0001). These differences resulted in a twofold higher (P=0.0012) prevalence of false-positive elevations of normetanephrine concentrations in winter than in summer, associated with a drop in overall diagnostic specificity from 96% in summer to 92% in winter (P=0.0010). Forearm warming increased blood flow and lowered (P=0.0020) plasma normetanephrine concentrations. CONCLUSIONS: The plasma concentrations of normetanephrine are subject to seasonal variation with a resulting higher prevalence of false-positive results in winter than in summer. Lowered plasma concentrations of normetanephrine with forearm warming suggest an effect of temperature. These results have implications for considerations of temperature to minimize false-positive results.

Effects of acute and chronic stress on the L-arginine nitric oxide pathway in black and white South Africans: the sympathetic activity and ambulatory blood pressure in Africans study.

OBJECTIVE: This study investigated the impact of stress on effectors of the L-arginine/nitric oxide (NO) system including the endogenous inhibitor asymmetric dimethylarginine (ADMA). METHODS: Black (n = 168) and white (n = 206) South African teachers were exposed to a mental and a physical stressor for 1 minute, respectively. Serum samples for determination of l-arginine, NO metabolites, ADMA, and symmetric dimethylarginine (SDMA) were obtained at rest and during stress exposure. Perception of task stressfulness was assessed on a 7-point Likert scale, and psychological distress was estimated by the General Health Questionnaire. RESULTS: Black South Africans exhibited higher resting levels of NO metabolites (adjusted mean [standard error of the mean] = 11.3 [1.3] versus 3.9 [1.1] µmol/l, p < .001) but lower circulating ADMA (0.62 [0.02] versus 0.70 [0.02] µmol/l, p = .004) and SDMA (0.41 [0.01] versus 0.53 [0.01] µmol/l, p < .001) than did white South Africans. Ethnicity-by-psychological distress interaction was observed for resting levels of ADMA (p = .002), SDMA (p = .038), and L-arginine (p = .048). Ethnic differences in responses to experimental stress were evident for NO metabolites (blacks versus whites: 5.94 [1.55] versus -0.74 [1.25] µmol/l, p = .004) and SDMA (blacks versus whites: -0.02 [0.01] versus 0.02 [0.01] µmol/l, p = .004). Ethnicity-by-psychological distress interaction for stress responses was found for l-arginine/ADMA ratio (p = .027). CONCLUSIONS: The l-arginine/NO system is affected by psychosocial distress with higher susceptibility in black South Africans. This interaction may contribute to the higher cardiovascular disease risk in black South Africans.

Trigonometric regressive spectral analysis: an innovative tool for evaluating the autonomic nervous system.

Biological rhythms, describing the temporal variation of biological processes, are a characteristic feature of complex systems. The analysis of biological rhythms can provide important insights into the pathophysiology of different diseases, especially, in cardiovascular medicine. In the field of the autonomic nervous system, heart rate variability (HRV) and baroreflex sensitivity (BRS) describe important fluctuations of blood pressure and heart rate which are often analyzed by Fourier transformation. However, these parameters are stochastic with overlaying rhythmical structures. R-R intervals as independent variables of time are not equidistant. That is why the trigonometric regressive spectral (TRS) analysis--reviewed in this paper--was introduced, considering both the statistical and rhythmical features of such time series. The data segments required for TRS analysis can be as short as 20 s allowing for dynamic evaluation of heart rate and blood pressure interaction over longer periods. Beyond HRV, TRS also estimates BRS based on linear regression analyses of coherent heart rate and blood pressure oscillations. An additional advantage is that all oscillations are analyzed by the same (maximal) number of R-R intervals thereby providing a high number of individual BRS values. This ensures a high confidence level of BRS determination which, along with short recording periods, may be of profound clinical relevance. The dynamic assessment of heart rate and blood pressure spectra by TRS allows a more precise evaluation of cardiovascular modulation under different settings as has already been demonstrated in different clinical studies.

Anti-Vascular endothelial growth factor therapy impairs endothelial function of retinal microcirculation in colon cancer patients - an observational study.

BACKGROUND: To assess acute effects of bevacizumab (anti-VEGF therapy) on cerebral microvessels and systemic cardiovascular regulation. DESIGN AND SUBJECTS: 20 consecutive patients with colorectal cancer (median age: 60.4 years, range 45.5-73.9 years) received bevacizumab intravenously (5 mg/kg) uncoupled of chemotherapy. Prior to and within the first 24 hours after bevacizumab infusion, patients were investigated for retinal endothelial function. A series of a triple 24-hour ambulatory blood pressure measurement was conducted. Retinal endothelial function was determined as flicker light-induced vasodilation. The integrity of baroreflex arc and autonomic cardiovascular control was examined by stimulatory manoeuvres. RESULTS: Bevacizumab therapy significantly reduced the vasodilatory capacity of retinal arterioles in response to flicker light. A slight decrease in diastolic pressure and heart rate was observed after bevacizumab infusion but this was unrelated to changes in retinal function. The pressure response upon nitroglycerin was largely preserved after bevacizumab infusion. The proportion of patients with abnormal nocturnal blood pressure regulation increased under anti-angiogenic therapy. Autonomic blood pressure control was not affected by bevacizumab treatment. CONCLUSIONS: Bevacizumab acutely impairs microvascular function independent of blood pressure changes. Imaging of the retinal microcirculation seems a valuable tool for monitoring pharmacodynamic effects of bevacizumab. TRIAL REGISTRATION: NCT ID: NCT00740168.

Lipoprotein apheresis of hypercholesterolemic patients mediates vasoprotective gene expression in human endothelial cells.

OBJECTIVE: Hypercholesterolemia is an important risk factor of cardiovascular diseases. Lipoprotein apheresis is an efficient strategy to reduce the serum low-density lipoprotein (LDL)-cholesterol and lipoprotein(a) levels and cardiovascular complications in patients with severe hypercholesterolemia. The underlying molecular mechanisms are not well-understood. In this study, we analyzed the impact of lipoprotein apheresis on gene expression in human endothelial cells. METHODS: Human endothelial cells were stimulated with serum of hypercholesterolemic patients before and after lipoprotein apheresis. The expression of endothelial lipoprotein receptors, nitric oxide (NO) synthase and adhesion molecules was quantified by real-time PCR and Western blot. RESULTS: Lipoprotein apheresis reduced the expression of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells. Low-density lipoprotein (LDL) receptor expression remained unchanged. The mRNA expression of the endothelial nitric oxide synthase (eNOS) was increased with serum of hypercholesterolemic patients after lipoprotein apheresis. In contrast, endothelial expression of vascular cell adhesion molecule 1 (VCAM-1) was reduced in response to serum after lipoprotein apheresis. CONCLUSION: Lipoprotein apheresis reduced the expression of the proatherosclerotic oxLDL receptor LOX-1 and adhesion molecule VCAM-1 and increased the expression of vasoprotective and NO generating eNOS in human endothelial cells in response to serum of hypercholesterolemic patients. These novel molecular mechanisms may account for the antiatherosclerotic and vasoprotective potential of lipoprotein apheresis in patients with hypercholesterolemia.

Nocturnal blood pressure, 3-methoxy-4-hydroxyphenylglycol and carotid intima-media thickness: The SABPA study.

BACKGROUND: Research demonstrated a significant relationship between elevated nocturnal blood pressure and sympathetic hyperactivity. The study aimed to investigate possible associations between norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), nocturnal BP and carotid intima-media thickness (CIMT) in urban African and Caucasian men. METHODS: The study included 82 African and 100 Caucasian male teachers, aged 33-56 years, recruited in the North-West Province, South Africa. Ambulatory BP and fasting saliva and blood samples were collected. B-mode ultrasound images were obtained to determine CIMT. RESULTS: Despite higher usage of anti-hypertensive medication usage (p=0.039), a large number of the African men were nocturnal hypertensives (75, 61%). The nocturnal systolic blood pressure (SBP) (p<0.001), diastolic blood pressure (DBP) (p<0.001) and heart rate (p<0.001) of the African men were higher. After stratifying groups into only nocturnal hypertensives the trend was the same (SBP p<0.001; DBP p<0.001; heart rate p=0.058). In the African and Caucasian men, CIMT was linearly predicted by SBP (ß=0.33, p<0.001) and DBP (ß=0.24, p=0.016) respectively, but not MHPG. CONCLUSION: No associations were firstly demonstrated between MHPG as sympathetic activity marker and CIMT or secondly, between MHPG and nocturnal blood pressure. Novel findings of elevated nocturnal BP evidently seem to promote structural vascular disease in urban African and Caucasian men.