These data show pharmacological undertreatment and a low adherence to nutritional guidelines. Uncontrolled BP is common in T2DM, and our data show a window of opportunity for improving BP control, especially in nutritional management. To improve treatment quality, we advocate to incorporate the integrated monitoring of nutritional management in quality improvement cycles in routine care.Cardiovascular risk management is an integral part of treatment in Type 2 Diabetes Mellitus (T2DM), and requires pharmacological as well as nutritional management. We hypothesize that a systematic assessment of both pharmacological and nutritional management can identify targets for the improvement of treatment quality. Therefore, we analysed blood pressure (BP) management in the DIAbetes and LifEstyle Cohort Twente (DIALECT). DIALECT is an observational cohort from routine diabetes care, performed at the ZGT Hospital . BP was measured for 15 min with one minute intervals. Sodium and potassium intake was derived from 24-hour urinary excretion. We determined the adherence to pharmacological and non-pharmacological guidelines in patients with BP on target (BP-OT) and BP not on target (BP-NOT). In total, 450 patients were included from August 2009 until January 2016. The mean age was 63 ± 9 years, and the majority was male (58%). In total, 53% had BP-OT. In those with BP-NOT, pharmacological management was suboptimal (zero to two antihypertensive drugs) in 62% of patients, and nutritional guideline adherence was suboptimal in 100% of patients (only 8% had a sodium intake on target, 66% had a potassium intake on target, 3% had a sodium-to-potassium ratio on target, and body mass index was <30 kg/m Type 2 Diabetes Mellitus (T2DM), with an estimated number of 422 million patients worldwide, is one of the major conditions associated with cardiovascular events and cardiovascular death . TherefoPharmacological and nutritional management are often studied as separate entities, despite the fact that both are crucial elements of treatment. We hypothesize that a systematic assessment of both pharmacological and nutritional management can identify targets for the improvement of treatment quality. The DIAbetes and LifEstyle Cohort Twente (DIALECT) cohort study was specifically designed for this purpose. DIALECT is an observational study in T2DM patients in a well-defined region in The Netherlands, and uses validated and detailed real-world data on nutritional habits, pharmacological treatment, and current clinical condition. To obtain non-biased data on individual nutrient intake, 24-hour urine collections were used and stored in a biobank to allow for future analyses .We aim to address how well the targets for blood pressure management are reached, and how this is related to (1) pharmacological management; and (2) nutritional management , and is registered in the Netherlands Trial Register .2), and body surface area was estimated by applying the universally adopted formula of DuBois . Dichotomous variables are presented in number and percentage. First, we divided the population according to the presence of albuminuria and/or a reduced eGFR (<60 mL/min), as in these groups the target BP is different . Second, we divided the population into two groups, according to the reached blood pressure. These groups are denoted as “Blood pressure on target” (BP-OT) and “Blood pressure not on target” (BP-NOT), respectively. The differences between the groups were analysed using the student Between September 2009 and January 2016, 1082 eligible patients were identified and invited to participate in the study, of whom 470 were enrolled in the study and performed the baseline visit. The most common causes for not participating in the study were: No interest in research, and inability due to co-morbidity . Twenty 2, reflecting a predominantly obese T2DM population, and BMI did not differ among the groups (The baseline data are presented in e groups .n = 136) had albuminuria, either with a preserved  or reduced renal function . Fifty-two patients (12%) had a reduced renal function without albuminuria (eGFR <60/Alb−). The mean systolic blood pressure was 139 ± 16 mmHg, and the mean diastolic BP was 76 ± 9 mmHg. Most of the patients (81%) used one or more antihypertensive drugs. The target BP was reached in 53% of all patients, while 47% had BP not on target. In patients with albuminuria, 33% and 24% reached the target blood pressure in eGFR ≥60 and in eGFR <60, respectively (p < 0.001). In contrast, the antihypertensive drug use in the eGFR ≥60/Alb+ group is not higher than in the other groups (2 (1–3) drugs). Patients without chronic kidney disease (CKD) . In the overall population, only 53 patients (12%) adhered to the dietary guidelines for dietary salt intake, ≤6 g/day, and in the eGFR ≥60/Alb+ group this percentage was even lower, i.e., 6%. In total, 8% of patients had a salt intake of ≤5 g/day as recommended by the WHO. The mean potassium intake was 3.9 ± 1.3 g/day, and 66% of patients had an intake, as recommended, above 3.5 g/day . The meaP = 0.018), and had a higher HbA1C . While the presence of albuminuria was a strong predictor of uncontrolled BP , poor BP control was not associated with an eGFR <60 mL/min (24% vs. 22%).Patients with BP-OT used loop diuretics more often than those with BP-NOT . There wp = 0.22). In patients with BP-NOT, 8% had a dietary salt intake below the recommended 6 g/day, which was lower than those with BP-OT . Adherence to the potassium guideline (66% of patients) did not differ among the groups. Only 3% of patients had a sodium-to-potassium ratio ≤1.0 in both BP groups. There were only three patients (1%) who adhered to both the recommended intakes of salt and potassium. BMI was ≤30 kg/m2 in 35% of patients, and this proportion did not differ among the BP groups. The smoking and alcohol guidelines were adhered to by 83% and 86% of all patients, and these proportions were not different among the BP groups. We found no differences in the other nutritional factors between the BP-OT and BP-NOT groups .In this paper, we present the blood pressure management of Type 2 diabetes patients (T2DM), using combined data on pharmacological and nutritional management in a real-life secondary health care setting. As anticipated, the prevalence of hypertension was high, and 81% of patients were on antihypertensives. However, BP control was poor, as the target BP was not reached in 47% of patients. An integrated assessment of pharmacological and nutritional management demonstrated a large window of opportunity for improving BP control in T2DM, both by intensifying antihypertensive drug treatment, and increasing nutritional guideline adherence.The proportion of patients with their blood pressure on target (BP-OT) in our cohort is in line with findings in other T2DM cohorts , as wellAn important issue when evaluating the pharmacological management of blood pressure is treatment non-adherence, which reportedly ranges from 31 to 40% in patients with poorly controlled blood pressure ,36. ThusWhat can be done to improve BP control in T2DM? Our data, and data from other trials, clearly show that true therapy-resistant hypertension, defined as hypertension persisting despite three antihypertensive drugs at maximum tolerable dosage of which one is a diuretic, is not the issue in most patients with BP-NOT. The majority of BP-NOT patients (62%) do not use more than two antihypertensive drugs, illustrating the opportunity for intensifying pharmacological treatment. One promising option in this regard is the removal of excess extracellular fluid with diuretics, especially in those patients with a high salt intake.Our data show that, especially for nutritional management, there is a large window of opportunity for improvement, as in the total population only one patient adhered to all of the nutritional guidelines simultaneously. This is highly relevant, since lifestyle interventions have the potential to not only reduce BP, but to also reduce the overall cardiovascular risk ,38,39,40There is evidence that a combined dietary approach aimed at reducing salt while increasing potassium intake has the potential to improve cardiovascular risk management ,47. Howe2. While a relationship between obesity and blood pressure has previously been demonstrated [2, and therefore did not have a large enough dispersion to differentiate between the BP groups. Intentional weight loss has been associated with beneficial effects, both on BP and on other cardiovascular risk factors such as LDL cholesterol and glycemic control [To improve blood pressure control, dietary intervention could also be aimed at reducing body weight. The mean BMI in our cohort was above 30 kg/mnstrated ,48, we d control . TherefoFinally, an association between the intake of magnesium and phosphate and blood pressure has been reported previously ,18,50,51It should be noted that the adherence to nutritional guidelines was equally poor in the BP-OT and BP-NOT groups. While in the BP-NOT group there is more urgency to adhere to these guidelines, namely to correct BP, the adherence to the guidelines in the BP-OT group should not be overlooked. In regard to salt intake, previously it has been shown that a higher salt intake while under RAASi is associated with worse cardiovascular outcomes, even independent of BP . FurtherThe DIALECT study has several strengths, including the use of real-world data from a cohort representative of secondary health care in T2DM, at least in the context of the Dutch referral health care setting. Second, we study the integrated role of non-biased data on both pharmacological and non-pharmacological parameters on BP, which is an important approach, as in cardiovascular risk management pharmacological and non-pharmacological interventions go hand in hand. Third, through the use of 24-hour urine collections, we provide objective measurements of dietary intake and several relevant nutrients.There are also some limitations. An observational study cannot prove causal relationships. Also, there is some risk of response bias, although patient characteristics were similar between those who did and did not participate.What are the implications of our study? Adequate management equals the sum of measures taken in combination with compliance. Our data on poor nutritional management do not distinguish between a lack of adequate nutritional counselling and a lack of compliance. However, it is well established that sustained lifestyle change is difficult to achieve, demonstrating that currently no modus of adequate counselling and therefore adequate management exists. The question, therefore, is how to establish this. Previous well-designed studies, using interventions of intensive nurse practitioner support and self-management, both did not lead to neither long-standing changes in nutritional habits, nor a reduction of cardiovascular outcomes ,58. As aUncontrolled BP is common in T2DM, especially in those with microalbuminuria. An integrated assessment of pharmacological and nutritional management demonstrated a window of opportunity for improving BP treatment, especially in nutritional management. We advocate that incorporating the integrated monitoring of pharmacological and nutritional management in quality control cycles has the potential to improve treatment quality in T2DM.


Background: We previously demonstrated the effectiveness of renal denervation (RDN) to lower blood pressure (BP) at least partially via the reduction of sympathetic stimulation to the kidney. A number of adipocyte-derived factors are implicated in BP control in obesity.Aim: The aim of this study was to examine whether RDN may have salutary effects on the adipokine profile in patients with resistant hypertension (RH).Methods: Fifty seven patients with RH undergoing RDN program have been included in this study . Throughout the study, the patients were on an average of 4.5 ± 2.7 antihypertensive drugs. Automated seated office BP measurements and plasma concentrations of leptin, insulin, non-esterified fatty acids (NEFA), adiponectin and resistin were assessed at baseline and the 3 months after RDN.Results: There was a significant reduction in mean office systolic  and diastolic  BP 3 months after RDN. Body weight, plasma leptin and resistin levels and heart rate remained unchanged. Fasting insulin concentration significantly increased 3 months after the procedure . There was a significant drop in circulating NEFA at follow up . Adiponectin concentration was significantly higher after RDN .Conclusions: This is the first study to demonstrate that RDN is associated with potentially beneficial effects on aspects of the adipokine profile. Increased adiponectin and reduced NEFA production may contribute to BP reduction via an effect on metabolic pathways.Clinical Trial Registration Number: NCT00483808, NCT00888433. Resistant hypertension (RH) is a condition characterized by elevated blood pressure (BP) that persists despite the use of a diuretic and at least two other antihypertensive medications. Patients with RH are at an increased risk of a future cardiovascular events compared to those whose BP is controlled  on the reduction of BP, which is, at least partially, achieved via the reduction of sympathetic stimulation to the kidney, has been examined in the last couple of years, not much is known in relation to the effect of RDN on adipokines. The aim of the current study was to determine the effect of renal ablation on adipokine profile in obese patients with RH. In particular whether the potential effect of RDN on the adipokine profile is associated with the fall in BP in patients with RH.Fifty seven consecutive patients with RH participating in our RDN program formed the cohort for this study. The cohort comprised patients participating in the Symplicity I and II trials and their selection criteria was described in the previously published papers , leptin and insulin by radio-immuno assays  and non-esterified fatty acids (NEFA) using an enzymatic colorimetric method  according to the manufacturers' instructions. Sample absorbencies for adiponectin, resistin and NEFA were recorded using a Benchmark Plus Microplate spectrophotometer . A gamma counter  was used to measure gamma radiation for insulin and leptin assays.t-test was applied to data to compare the effect of RDN. Univariate correlation between the baseline BP and reduction in BP and physiological and experimental variables were evaluated using Pearson's correlation coefficient. Data are expressed as mean ± SEM. Statistical significance was set at p < 0.05.Statistical analyses were performed using SigmaStat for Windows Version 3.5 . Paired 2. There were no differences in baseline BMI, BP or HR between genders. As expected, females had higher leptin  and adiponectin  levels.Details of the study participants are presented in Table n = 37) were on statin medication. No differences were observed in baseline systolic or diastolic BP and HR between those participants that were on statin medication vs. those that were not. However, the absolute reduction and percentage change in systolic BP at 3 months follow up was significantly greater in statin users (data not shown).Sixty five percent of patients (p < 0.001). Similarly, there was a significant drop in DBP  . There was no significant correlation between adiponectin and BMI after the procedure . There was a significant increase in plasma adiponectin levels in patients after the procedure  . There was no association between baseline adiponectin levels and the change in SBP at follow-up. Further analysis of the data revealed three patients that had high adiponectin levels (2 patients with high levels before and after denervation and one patient that had high adiponectin at follow-up). However, removing these data points from analysis did not change the significance of the finding . No significant association were found between baseline adiponectin and BP reduction after renal ablation.As expected adiponectin had a strong inverse relationship with BMI at baseline . Baseline resistin concentration did not have any association with baseline SBP nor with change in SBP after RDN.There was no change in plasma resistin levels in patients after RDN (7.06 ± 0.46 vs. 7.17 ± 0.36 ng/ml) (p = 0.080) . As expected, BMI was significantly associated with plasma leptin concentration (p < 0.001) both at baseline and follow up visits.Leptin concentration was not significantly affected by RDN    being a risk factor for hypertension. Baden and colleagues have demonstrated a significant negative correlation between adiponectin levels and BP in a group of healthy people over a wide adiponectin range  group.While patients were instructed to keep their medications unchanged for the duration of the study, medication adherence was not confirmed.It is possible that there was a Hawthorn-type effect and patients modified their behavior for the duration of the study. However, previous studies showed denervation resulted in cardiac remodeling  Pharmaceuticals, BI, Novartis Pharmaceuticals, and Medtronic and has received honoraria and travel support from Abbott, BI, Servier, Novartis, and Medtronic.


We hypothesized that elevated standard bicarbonate, a proxy for increased carbonic anhydrase activity, is associated with apnea severity and higher blood pressure in patients with obstructive sleep apnea.Obstructive sleep apnea is characterized by intermittent hypoxia and hypercapnia. COn = 830) studied by ambulatory polygraphy. Office systolic/diastolic blood pressure, lung function, and arterial blood gases were assessed during daytime.A retrospective analysis of a sleep apnea cohort (p < 0.001). Standard bicarbonate was independently associated with apnea hypopnea index after adjustment for sex, age, body mass index, smoking, alcohol, hypertension, pO2 and pCO2 . Log-transformed standard bicarbonate was associated with a diagnosis of hypertension or diastolic blood pressure but not systolic blood pressure adjusting for cofounders .Arterial standard bicarbonate was increased with apnea severity  contains supplementary material, which is available to authorized users. The severity of these changes is determined not only by altered ventilation during the apneic cycle, but also by the extent of tissue oxidative metabolism and tissue deposition of CO2 in the body [2 production, transport and elimination are influenced by the activity of the enzyme carbonic anhydrase (CA). CA catalyzes the inter-conversion of CO2 and water into carbonic acid, protons and bicarbonate (StHCO3-) [3- concentration (a surrogate for CA activity) was elevated in relation to the degree of disordered breathing in OSA patients.Obstructive sleep apnea (OSA) is associated with intermittent oscillations of oxygen and carbon dioxide  consisted patients successively referred to the Marburg Sleep Disorders Center between 1989–1992 due to clinical symptoms of sleep related breathing disorder [3-, were collected. A home sleep study and lung function test using full body plethysmography  were undertaken. All patients gave their written consent for participation in the study according to the contemporary regulations for medical research at the Marburg University, Marburg, Germany in 1989–1992.The study cohort (disorder . Patientn = 210), blood gas data (n = 163), lung function test data (n = 20) and sleep data (n = 3). Patients with obesity hypoventilation syndrome , chronic obstructive pulmonary disease, defined as the ratio of forced expiratory volume in 1 s to forced vital capacity of less than 0.70, were excluded (n = 163). In addition, 12 respiratory failure patients with arterial blood gas pO2 ≤ 8.0 kPa and/or pCO2 ≥ 6.5 kPa were excluded. Finally, non-OSA patients with apnea hypopnea index (AHI) <5 n/h were excluded from the analysis (n = 217) and a total of 830 patients were included in the data analysis  and diastolic (DBP) blood pressures were obtained with the patient in a sitting position after a minimum of 10 minutes rest, between 9.00 and 11.00 a.m., using the World Health Organization standard protocol . Heart rHypertension was defined as patients with a previous positive history of diagnosed hypertension and/or on ongoing hypertensive medication. Normotension was defined as patients with no previous hypertensive medical history and no ongoing anti-hypertensive treatment.All patients underwent unattended home monitoring of nocturnal breathing on two consecutive nights using the MESAM 4 polygraphy device . The polygraphy system was applied in the afternoon for a recording span between 6.00 p.m. and 8.00 a.m. Time to bed, lights out, final awakening, longer periods of sleep interruption and estimated sleep time were assessed using a patient diary. The first night was an adaptation night and the AHI value used for calculation in this study was obtained from the second night. Only when the recording was technically insufficient (<10% of recordings) or the subjective sleep time was <5 hours (<1% of recordings), then AHI was obtained from the first night.The MESAM 4 device records oxygen saturation using finger pulse oximetry, snoring using an electret-miniature microphone placed over the larynx, beat to beat heart rate analysis using ECG, and body position using a circular sensor taped just below the sternum. It is a validated sleep diagnostic instrument for clinical and epidemiological studies , 14. In 3- and AHI, SBP and DBP. Fisher exact test was used to compare catergory variables. Depending on data distribution, differences across apnea severity groups and StHCO3- quartiles were assessed by one-way analysis of variance (ANOVA) or Kruskal-Wallis test. Multivariate generalized linear models were used to address the independent association between StHCO3-, apnea severity and hypertension. StHCO3- was log-transformed in order to enable parametric statistics. Data are presented as mean ± SD. A p-value <0.05 was considered statistically significant.Statistical analysis was conducted using IBM SPSS 20 . Kolmogorov-Simirnov test was used to determine the distribution of the data. Spearman correlation was used to study the association between arterial StHCO2, AHI 32 ± 24 n/h). Hypertension was prevalent in 53.3% of the patients and increased with OSA severity class. Patient characteristics in different OSA severity classes are shown in Table 2 decreased with approximately 0.5 kPa from mild to severe OSA patients (p < 0.001). Mean pCO2 increased slightly in patients with severe OSA (p = 0.046). The pH and lung function values did not change along with severity class of OSA.In total 830 patients were included in the study  to 39 ± 26 n/h (StHCO3- quartile 4) in the whole population  compared with normotensive (n = 388) patients . The percentage of patients with a clinical hypertension diagnosis is 46.8, 49.8, 54.3 and 62.7% respectively across StHCO3- quartiles (Q1 to Q4) . In generalized linear models with SBP and DBP, respectively, as dependent variables, a positive independent association was found between LogStHCO3- and DBP  but not with SBP  after adjustment for sex, age, BMI, smoking, alcohol usage, pO2, pCO2 and apnea severity  and pre-clinical OHS [3- and OSA is less well studied. In this study we excluded patients with chronic obstructive pulmonary disease and OHS based on information of a gold- standard evaluation of respiratory function and a blood gas analysis. Our data unequivocally demonstrated a dose dependent association between OSA and daytime arterial StHCO3- concentration in this group of patients without a chronic respiratory disorder. Although the magnitude of the StHCO3- elevation across the spectrum of OSA severity may be considered as rather limited, the association was statistically significant and remained after extensive control of important confounders. To our knowledge this is the first study to demonstrate this association in a well characterized clinical OSA cohort. The exact mechanism behind this finding in OSA remains unknown. Severe OSA may lead to mild nocturnal hypercapnia. The long term effect of OSA on PCO2 (i.e. StHCO3-) is determined by the net change of CO2 over each cycle of apnea/hyperventilation and asymmetry in how the rise and fall of CO2 affects the kidney. It is likely that changes of CA activity can modulate the transition of obstructive apnea/ventilation cycle and influence the increase in StHCO3- [3- and/or that a chronic increase of StHCO3- production [Elevated StHCOical OHS , 17. The StHCO3- –20. We toduction  is induc3- concentration is known to be influenced by CA enzyme activity. One major function of this enzyme includes the catalysis of the interconversion of bicarbonate and protons into CO2 and water for subsequent removal of CO2 via the respiratory apparatus [2 may induce CA enzyme activity and increase arterial StHCO3- concentration. Alternatively, anaerobic metabolism and respiratory acidosis following intermittent hypoxia may induce an increased activity of enzymes and transporters involved in cellular pH regulation and erythrocyte acid-base handling [3- concentration in patients with sleep disordered breathing [StHCOhandling . In thisreathing , 22, 23 3- and hypertension status or diastolic blood pressure. It may be argued that this association could be explained by the well-established link between OSA and hypertension [3- was linked to hypertension independently of the AHI. Only few studies have addressed the possible association between StHCO3- and hypertension. In a population based study of middle-aged non-obese females, lower plasma StHCO3- was associated with an elevated incidence of hypertension [- is mainly confined to subjects with severe OSA. As previously stated several different mechanisms, including increased renal re-absorption of StHCO3-, extended CO2 loading and/or increased CA activity, could all have increased of StHCO3- in OSA [- in our study might have resulted from the effect of hypertension on renal StHCO3- reabsorption. However, this is less likely the explanation considering that StHCO3- was elevated only in the severe OSA group with hypertension. We therefore propose that increased CA activity in OSA may provide a novel intermediary mechanism for hypertension development in OSA.A particularly interesting finding in the current study was the strong association between StHCOrtension . Howeverrtension . A smallrtension  whereas rtension , 27. How- in OSA , 28. In - in OSA . The CA - in OSA  or via a- in OSA . It cann3- like arterial blood gas samples and pulmonary function tests. Second, blood pressure and hypertension status were carefully assessed during daytime as part of the study protocol. Sleep disordered breathing was assessed with a contemporary polygraphy recording device on two consecutive nights in order to exclude inaccuracy of the AHI value due to a first night effect [3- and blood pressure although the influence of thiazides on StHCO3- is likely to be very limited [Our study has both strengths and limitations. First, this large predominently male clinical OSA cohort applied a rigorous and unique control of important confounders of StHCOt effect . Weaknes limited . Informa3- concentration was independently associated with AHI, a hypertension diagnosis and office diastolic blood pressure in OSA patients. The potential causal relationship (s) behind these associations remain unclear. Higher StHCO3- was linked to more intense OSA indicating that high or upregulated CA activity is associated with OSA. In addition, StHCO3- was associated with hypertension independent of sleep apnea suggesting a novel CA–related mechanism for blood pressure regulation in hypertensive OSA patients.It is concluded that StHCO


Orthostatic intolerance, one of the principle causes of syncope, can occur secondary to concomitant venous pooling and enhanced capillary filtration. We aimed to evaluate a prototype portable calf active compression brace (ACB) designed to improve orthostatic haemodynamic control. Fourteen healthy volunteers participated in a randomized, placebo controlled, cross-over, double-blind study. Testing consisted of head-upright tilting and walking on a treadmill conducted on two consecutive days with a pair of ACBs wrapped around both calves. The ACB was actuated on one test day, but not on the other (placebo). Wearability, comfort, and ambulatory use of the ACB were assessed using questionnaires. The average calf pressure exerted by the ACB was 46.3±2.2 mmHg and the actuation pressure was 20.7±1.7 mmHg. When considering the differences between ACB actuation and placebo during tilt after supine rest there were trends for a larger stroke volume  and lower heart rate  with ACB actuation, with no effect on systolic arterial pressure . The decrease in stroke volume after ten minutes of tilting was positively correlated with the height:calf circumference . The increase in heart rate after ten minutes of tilting was negatively correlated with the height:calf circumference  and was positively correlated with the average calf circumference . Participants reported good ACB wearability and comfort during ambulatory use. These data verify that the ACB increased stroke volume during tilting in healthy controls. Active calf compression garments may be a viable option for the management of orthostatic intolerance. We performed a randomised, placebo controlled trial to evaluate the efficacy of an innovative active compression brace (ACB) to improve orthostatic haemodynamic control in fourteen healthy volunteers. The wearability, comfort, and ambulatory use of the device were also evaluated. Device actuation enhanced stroke volume and reduced orthostatic tachycardia. Participants reported good ACB wearability and comfort ratings during ambulatory use. Active calf compression garments may be a viable option for the management of orthostatic intolerance.Compression therapy · Active compression brace · Shape memory alloys · Orthostatic intolerance · Syncope.Syncope, or fainting, refers to a transient loss of consciousness and postural tone that typically occurs when upright and is associated with reduced cerebral blood flow ,2. The pStatic external compression stockings are commonly recommended for the management of syncope. They are prescribed for those suffering from orthostatic intolerance, where the external counter-pressure of the lower limbs or abdomen can reduce venous pooling and capillary filtration, thus increase venous return ,12. GarmWe recently developed an active compression brace (ACB) for the calf that utilizes artificial muscle technology. This ACB has been prototyped using smart alloy technology and its performance has previously been investigated in vitro . SpecifiIn this study, we aimed to evaluate the efficacy of the ACB for the improvement of stroke volume (SV) and cardiovascular hemodynamics during orthostatic stress using a randomised placebo-controlled double-blind crossover design. We compared responses with the device activated and with it wrapped but actuation pressure not applied (placebo). We measured the compression on the calves exerted by the ACB and obtained cardiovascular and lower limb circumference changes through beat-to-beat blood pressure monitoring, electrocardiography (ECG), and leg strain gauge plethysmography. We hypothesized that during orthostasis the actuated ACB would reduce the leg volume change, and increase venous return, with an associated increase in SV and decrease in heart rate (HR). We also evaluated the effect of walking on the compression pressures applied, as well as on calf volume changes and cardiovascular responses. Finally, we evaluated the ACB viability, comfort and wearability during ambulation based on participant surveys.After the details and procedures of the study had been fully explained to them, all participants gave written informed consent to participate. This study received ethical approval from the Simon Fraser University Office of Research Ethics for all measurements (study #2014s0590). All investigations were performed in association with the Declaration of Helsinki of the World Medical Association.Fourteen adults  were recruited for this study. Participants completed a brief medical history; all volunteers were healthy and free of cardiovascular and neurological disease. None of the participants were taking any medication. Each participant completed testing on two consecutive days with a pair of ACBs wrapped around both legs. The ACB was not actuated on one testing, and it was actuated on the other testing. The ACBs were placed around the widest part of the calf. The wrapping pressure was adjusted to 15 mmHg in the supine resting position. For the test where we had the ACB actuated, an electrical current of 180 mA per SMA wires was applied to each of the ACBs. Testing was conducted in a randomised double-blind fashion, at the same time of day. Female participants were tested in the same phase of their menstrual cycle by testing on consecutive days. Participants were asked to refrain from strenuous exercise for twelve hours prior to each test, eat a light breakfast, and avoid caffeine on the morning of each test.2) was estimated from the circumference (cm), assuming circularity . In. In33]. Several dimensions of comfort were considered encompassing six domains: four domains of physical perceptions , and two domains of psychological perceptions (domains 1 and 6) of comfort. Domain-2 refers to nonharmful sensations of the device on the body; domain-3 refers to the harm caused by the device conveyed through sensations of pain; domain-4 refers to nonharmful feelings associated with the perception of being awkward, where the wearer makes conscious compensations or modifications to movements or actions; domain-5 refers to a direct impact of the device on normal movement patterns; domain-1 refers to psychological perceptions of discomfort; domain-6 refers to concerns related to the safety of wearing the device and its performance . Table 1Each domain was assessed using a 21-point scale, called CRS, anchored at each end with the labels “low” and “high”. A 21-point scale was used so that scoring on the scale would range from 0 at the far left to 20 at the far right .” AccordWe evaluated the wearability of the ACB based on the criteria defined in A summary of participant anthropometric measures and age is presented in The ACB mean applied pressure, wrapped and actuated, for the four test phases are presented in A representative example trace from one participant showing calf circumference changes throughout testing can be seen in The impact of the actuation and wrapped conditions on cardiovascular responses during the test phases can be seen in There were significant main effects of test condition, i.e. the difference between actuated and wrapped conditions, whereby the ΔSV (p = 0.008), and HR (p = 0.007) were reduced with ACB actuation, and the pulse pressure was larger with ACB actuation (p = 0.045) . BecauseThe cumulative AUC for SAP and SV are shown in Significant main effects between test phases, i.e. the differences between baseline, HUT1, HUT2 and walking phases, can be seen in There was no significant effect of the two tilting phases on CO compared to baseline. SV was significantly decreased during both HUT1 and HUT2 compared to baseline . HR was significantly increased during HUT1 and HUT2 compared to baseline . When considering the cumulative AUC for SAP and SV . there wConsiderable variability was noted between individual responses for change in SV (%) and HR (%). We evaluated whether this was related to anthropometric variables. During HUT1, the change in SV (%) was positively correlated with the height:calf circumference ratio . The chaThere was no significant relationship between the change in SV during HUT1 and the calf circumference measurements when expressed as average calf circumference, muscle cross-sectional area and height:muscle cross sectional area ratio. Similarly, there was no significant relationship between the change in HR during HUT1 and the calf circumference measurements when expressed as muscle cross-sectional areas and height:muscle cross sectional area ratio. However, there was a significant relationship between the change in HR (%) and height:calf circumference ratio ; further analysis showed that average calf circumference was negatively correlated to the height:calf circumference ratio . These relationships between anthropometric characteristics and haemodynamic control were no longer significant when considered after the walking phase.Most participants did not feel the ACB was causing “exertion” in either wrapped or actuated conditions . When thResults from the comfort evaluation can be seen in Most participants were unconcerned by the attachment of the ACB to their body . In termResults regarding any kind of harm such as pain, heat, itching, and irritation, caused by the ACB are illustrated in Perceived change: The feedback from the participants on the perceived change is presented in The concerns of the participants in terms of movement restriction are reflected in Answers to the questions related to anxiety arising because of wearing the ACB are shown in The overall level of effect of the ACB on participants is summarized in We have demonstrated that the prototyped ACB was effective at improving SV in a randomised, double-blind, placebo-controlled study on healthy participants. The test protocol was designed to investigate the efficacy of the ACB during passive head-up tilting, in which blood pooling occurs, and walking, in which the skeletal muscle pump increases venous return.The ACB can apply a desired wrapping compression similar to commercial compression stockings, 15 mmHg, and when altering the compression by actuation, can apply pressure up to 27.3±1.6 mmHg, in the supine resting position. In both HUT 1 and 2 phases applied pressures showed a significant increase compared to the baseline phase (p<0.05). This could be because of the muscle movements, contraction, and an increase in calf circumference. The maximum applied pressure was observed in HUT1 and HUT2 phases when the actuated ACB applied pressure of 46.3±2.2 and 44.8±2.1 mmHg respectively. The walk phase showed lower applied pressure as a result of a drop in calf circumference. This decrease could be because of an increase in venous return due to the muscle pump. It should be mentioned that walking also altered the performance of the ACB due to increased heat loss in the SMA wires. Walking increases the convective heat transfer coefficient because of the air flow, which decreases the degree of actuation (phase transformation) in the SMA wires. In fact, this alteration could potentially be useful as a self-regulatory factor of the ACB since during walking, the muscle pump mechanism is active and there might be less of a need for compression.In both HUT1 and HUT2 phases there was an initial rapid and secondary gradual increase in calf circumference that is thought to be due to venous pooling and capillary filtration respectively . In the CO was maintained throughout each test, except during walking, when it increased markedly. The maintenance of CO in the HUT1 and HUT2 phases likely reflects the intact baroreflex response in these healthy control volunteers, whereby reductions in SV were accompanied by compensatory increases in HR and vascular resistance. Indeed, the increases in HR during the tilted phases closely matched the decreases in SV. This is compatible with a reduced venous return when upright, secondary to venous pooling and plasma filtration , and a cThere were significant main effects of test condition on changes in SV and HR during tilting, whereby the SV was lower and HR higher in the wrapped than the actuated conditions. This effect was less clear when the walking phase was incorporated, presumably because in this case SV volume was mainly maintained because of the muscle pump mechanism and the impact of device actuation was reduced. These data highlight the need for compression garment paradigms that can be applied selectively, only during passive orthostasis, and not during active orthostatic manoeuvres such as walking when any deficits in cardiovascular reflex control may be offset by the action of the skeletal muscle pumps .There was no significant effect of the actuation condition on blood pressure responses or orthostatic burden (SAP AUC). This also likely reflects the intact baroreflex response in healthy volunteers, in whom blood pressure is well maintained during brief mild orthostatic stresses such as those encountered in the present study. However, the higher associated stroke volume and lower heart rates during orthostatic stress in the actuation condition suggest that this maintenance of blood pressure was achieved with a smaller baroreflex response, compatible with the actuation condition augmenting stroke volume, and presumably, venous return.When considering the possible relationships between SV, HR changes and anthropometric variables we first examined interactions between the main conditions (ACB wrapped/actuated) and each variable during initial passive orthostatic stress. Since we found no differences in the slopes of these relationships between the two test conditions, we combined data for the two ACB conditions. We showed that individuals with larger calf circumferences had higher heart rate responses to orthostatic stress, associated with larger reductions in SV. Therefore, is tempting to speculate that those with larger calf circumferences would be poised to benefit most from ACB actuation; however, because there were no differences in the slopes between the regressions for actuated and wrapped conditions, this is not the case. The relationships between haemodynamic parameters and anthropometric variables were no longer significant during the second tilt phase, which was preceded by walking. Presumably there is an effect of walking and associated autonomic and muscle activation on either orthostatic haemodynamic control or calf circumference that persists for some time (at least ten minutes) after termination of the activity. This has implications for the use of the device during activities of daily living–device actuation may not be necessary during walking because the enhanced skeletal muscle pumping and autonomic activity seem sufficient to maintain cardiovascular control. We suggest that actuation of the device upon cessation of activity would be of more benefit.Overall the ACB comfort and wearability evaluation showed a low level of concern in all the domains considered. Although overall the device was well tolerated, some participants expressed discomfort, and priority areas for improvement in this regard were identified .Our physiological tests were designed to be double-blind in the sense that the primary investigator was unaware of the test condition during data collection and analysis, and the participants were not told what to expect from the compression conditions. However, although participants were not informed whether the ACB was actuated or not on each test day, nor were they told the expected outcome of the experiment, it is possible that the study was not truly double-blinded. The ACB gets a bit warm when it is actuated, and participants may have been aware of a different sensation due to the higher compression.It is possible that we have underestimated the impact of ACB actuation, because we compared it to a wrapped condition, which also applied a low level of pressure, and may itself have reduced orthostatic fluid shifts and enhanced orthostatic cardiovascular control. Comparisons of ACB actuation with no pressure application might show even greater benefit. However, we wished to compare whether our device provided additional benefit over and above conventional strategies that employ a low level of calf compression similar to our wrapped condition. In addition, use of a wrapped condition had the benefit that for participants and experimenters the protocol was the same for both tests, enhancing our ability to blind the study. Additional considerations for future study might also include the incorporation of a true placebo condition in which no compression was applied.We tested healthy volunteers, and we can not be certain if the results would extend similarly to a patient population. For example, in healthy controls pooling and filtration is lower during orthostatic stress than in patient populations , and so We had a relatively small sample size in this preliminary study proof-of-concept study, with an obvious impact on statistical power. As a consequence, we only considered the main effects of the test condition and phase, and not the interaction effects. Future studies should further elucidate these interactions.It may be that the application of compression stockings prior to rising in the morning would have a greater effect, due to the ‘‘water jacket effect”, whereby oedema accumulating during the day restricts further venous pooling . HoweverWe evaluated the efficacy of the ACB on improvement of SV and calf volume changes, and accordingly our results may not extend to other compression garments. The existing literature suggests that compression garments extending to the thigh and abdomen may be more effective at preventing orthostatic intolerance ,11,13,14Our limited sample size in this preliminary evaluation precluded the evaluation of potential sex differences in terms of blood pooling and cardiovascular response to ACB actuation. Comparison between male and female participants’ responses and the efficacy of ACB should be considered in future, particularly given the known differences in venous pooling and capillary filtration between men and women  and incrThis paper showed the feasibility of an ACB to achieve the desired external calf pressure, and demonstrated an enhancement of stroke volume and reduction in orthostatic tachycardia during device actuation. In addition, evidence was provided on wearability, comfort, viability and ambulatory use of the ACB in human participants.


The aim of this study was to disclose the prevalence of myocardial ischemia, as detected by adenosine stress myocardial perfusion imaging (MPI) with hybrid single-photon emission computed tomography/computed tomography (SPECT/CT), in asymptomatic diabetic and pre-diabetic patients and to find out whether ischemia predicted the occurrence of adverse cardiac/cerebrovascular events (ACCE) at follow-up.Forty-three diabetic and thirty-five pre-diabetic asymptomatic patients without any history of coronary artery disease, underwent MPI and were followed-up for a 12.8±2.2 (8-19) months for the occurrence of ACCE. Baseline variables that would predict the presence of ischemia and the value of ischemia on MPI for predicting the occurrence of ACCE at follow-up were evaluated by logistic regression analysis.Ischemia was detected in ten (23.3%) of the diabetic and in four (11.4%) of the pre-diabetic patients. The presence of diabetes was the only independent predictor of myocardial ischemia . During 12.8±2.2 (8-19) months of follow-up, ACCE was observed in five out of 78 (6.4%) patients. Patients with ischemia were significantly more likely to have ACCE during follow-up as compared to those with normal MPI scans .Myocardial ischemia as detected by adenosine stress SPECT/CT in a population of asymptomatic patients with diabetes mellitus or pre-diabetes appeared to predict the occurrence of ACCE at follow-up. Type 2 diabetes mellitus (DM) is associated with an increased risk of coronary artery disease (CAD) and has long been considered a CAD equivalent ,2. CAD iWe enrolled 35 pre-diabetic and forty-three diabetic patients  without any history of CAD. The diagnosis of DM and pre-diabetes were made according to American Diabetes Association (ADA) criteria . DiabeteExclusion criteria were defined as follows;1- History of CAD ,2- Electrocardiogram (ECG) findings suggestive of Q wave-MI, ischemic ST-segment or T-wave changes, or complete left bundle branch block,3- Typical angina pectoris,4- Absolute contraindication for adenosine stress testing,5- Segmental wall motion abnormality (WMA) or left ventricular hypertrophy on transthoracic echocardiography,6- Comorbid conditions that might influence plasma glucose levels such as Cushing syndrome, acromegaly, pheochromocytoma,7- Use of drugs that may affect plasma glucose levels such as corticosteroids, neuroleptics, antiviral agents, beta agonists, interferon, diazoxide.After a detailed medical history and a thorough physical examination, a 12-lead ECG and a trans-thoracic echocardiogram were recorded for each patient. Age at onset of diabetes, duration of diabetes and recently used medications were recorded. Major cardiovascular risk factors including smoking, dyslipidemia, hypertension, and family history of CAD were also recorded. Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or any treatment with an antihypertensive drug. Microalbuminuria was evaluated on 24-hour urine samples in all patients. The fundoscopic examination was applied to patients with DM.Venous blood samples were drawn in the fasting state using vacutainer tubes. Plasma glucose, HbA1c, triglycerides, total and high-density lipoproteins (HDL) and cholesterol concentrations were measured by enzymatic assays . Albumin measurement in 24-hour urine samples was made by immunoradioturbimetric method , and levels ≥30 mg/day were defined as ‘microalbuminuria’.All patients underwent same-day rest/stress technetium-99m methoxy-isobutyl-isonitrile (99mTc-MIBI) gated-SPECT MPI by adenosine stress with hybrid SPECT/CT system . Pharmacologic stress with adenosine was chosen as the stress modality of choice to standardize the stress level and eliminate potential confounding that could arise from different levels of maximum achievable stress due to varying levels of exercise capacity in different patients. For adenosine stress test, patients were asked to refrain from consuming caffeinated beverages after midnight prior to testing. In the morning 296-370 MBq 99mTc-MIBI was injected intravenously at rest and imaging was performed 60 min after injection. Three or four hours after resting acquisition, stress protocol was started. One hundred forty µg/kg per minute adenosine  was infused intravenously over 4-6 min. 99mTc-MIBI of 888-1110 MBq) was administered 3 minutes after the beginning of adenosine infusion. After the radiotracer injection, adenosine infusion was continued for another 1-2 minutes. ECG was monitored continuously and blood pressure and heart rate were obtained at 1-min intervals. Stress images were acquired 30-45 minutes after radiotracer injection. The SPECT MPI acquisition was performed on a dual-head camera  with a low-energy, high-resolution collimator; a 20% symmetric window at 140 keV; a 64x64 matrix; and an elliptic orbit with step-and-shoot acquisition at 3° intervals over a 180° arc (45° right anterior oblique to 45° left posterior oblique) with 30 steps (60 views). Scan time was set to 20 s per frame for stressed and 25 s per frame for resting conditions. Gating included 16 frames per R-R cycle. For attenuation correction (AC), all patients underwent low-dose CT using a Hawkeye system . Single-slice non-spiral CT  with a slice thickness of 10 mm and a scan time of more than 5 min for a typical 13-cm field of view was obtained. After reconstruction and transfer to a Xeleris workstation , AC maps were generated. SPECT images were reconstructed into short and vertical and horizontal long axes using standard reconstruction-that is, filtered back projection-and iterative reconstruction with CT-AC. Visual interpretation of SPECT images was always performed side by side by 2 experienced nuclear medicine specialists. SPECT images were analyzed by using Emory Cardiac Toolbox software package. For semi-quantitative analysis, SPECT images were visually scored using a 20-segment model of the left ventricle and images with AC were evaluated visually and each segment was scored between 0 and 4. Zero was defined as normal perfusion, 1: equivocal, 2: moderate reduction, 3: severe reduction, and 4: lack of perfusion. Summed stress score (SSS) and summed rest scores were obtained by adding the scores of the 20 segments. The summed difference score (SDS) represents the difference between the stress and rest scores. In the semi-quantitative analysis done by using AC images, SSS >1 and SDS >1 were accepted as positive for ischemia ( MBq was The patients were followed up for a mean of 12.8±2.2 (8-19) months for the occurrence of ACCE defined as the occurrence of either typical angina pectoris, MI, myocardial revascularization (PCI or CABG), stroke, cardiovascular or cerebrovascular death, new cardiac arrhythmia or congestive heart failure. Predictors of ischemia in the whole group and in those with DM were evaluated using multiple logistic regression analysis.Data analysis was performed by using SPSS for Windows, version 11.5 . The distribution pattern of metric discrete and continuous variables was evaluated by Kolmogorov-Smirnov test. Metric discrete and continuous variables were shown as the mean ± standard deviation (SD) or median (minimum-maximum), where applicable. The mean value differences between groups were compared by Student’s t-test. Mann-Whitney U test was applied for comparisons of the median values. Nominal data were analyzed by Pearson’s chi-square or Fisher’s exact test, where appropriate. The predictors of ischemia on MPI were evaluated by Multiple Logistic Regression Analyses. Any variable found to be significant on univariate testing  was subjected to testing in the multivariate model. Odds ratios and 95% confidence intervals for each independent variable were also calculated. A p value less than 0.05 was considered statistically significant.We enrolled 43 diabetics and 35 pre-diabetic subjects. DM had been present for a median of 7 years in the diabetic group. Among the pre-diabetics, 20 had IFG, 6 had IGT and 9 had both. The demographic properties, risk factors and medications that were being used at study entry are shown in By using 20 segment model, attenuation corrected images, SSS and SDS scores, 4 out of 35 (11.4%) in the pre-diabetics and 10 out of 43 (23.3%) in the diabetic group were found to have ischemia on SPECT/CT MPI  Figure . Among tHypo-perfusion involving more than 5% of the left ventricle was detected only in two diabetic patients. Although no patient had WMA on echocardiography at study entry, we detected segmental WMA  on post-stress gated images in five diabetic patients on MPI. No patient in the pre-diabetic group had WMA on MPI. The mean LVEF by gated SPECT was 72±7.3% in the pre-diabetic and 70±7.7% in the diabetic group. High SSS and/or SDS scores before AC turned to normal values after AC in 25 patients (31.6%) in the whole group. Follow up: During 12.8±2.2 (8-19) months of patient follow-up, we observed ACCE in two (5.7%) pre-diabetic and three (7%) diabetic patients . One diaThe major findings of this study are;1- By using adenosine stress MPI with gated SPECT/CT, myocardial ischemia was detected in 23.3% and 11.4% of asymptomatic diabetic and pre-diabetic subjects, respectively,2- Although the population size and the event numbers are too small to draw any firm conclusions, subjects with ischemia on MPI were significantly more likely to experience ACCE as compared to those with normal scans.The presence of silent ischemia has been evaluated in diabetic patients utilizing different methods of ischemia detection. In studies using nuclear imaging modalities, perfusion abnormalities were detected in 6-57% of asymptomatic patients with DM ,14,15,16Routine screening for silent ischemia in asymptomatic diabetic patients has been a matter of debate for a long time. Guidelines recommend routine screening only for high-risk patients. Janand-Delenne et al.  found a MPI is a well-established method for the evaluation of CAD and has a high diagnostic accuracy ,24,25. IThere are some limitations in our study;1- No control group was included due to ethical reasons,2- The small population size precluded any meaningful discussion of IGT and IFG groups, even diabetics and pre-diabetics separately,3- The follow-up interval for cardiac events was rather short.In conclusion, although the population size and the event numbers are too small to draw any firm conclusions, subjects with ischemia on MPI were significantly more likely to experience ACCE as compared to those with normal scans.Ethics Committee Approval: The study was approved by the Ankara Atatürk Training and Research Hospital Local Ethics Committee, Informed Consent: Consent form was filled out by all participants.Peer-review: Externally peer-reviewed.Financial Disclosure: The authors declared that this study has received no financial support.


QT) is a non-invasive method for assessment of proarrhythmic risk. The aim of the study was to evaluate the STVQT in patients with impaired glucose tolerance (IGT). 18 IGT patients  and 18 healthy controls  were enrolled into the study. ECGs were recorded, processed, and analyzed off-line. The RR and QT intervals were expressed as the average of 30 consecutive beats, the temporal instability of beat-to-beat repolarization was characterized by calculating STVQT as follows: STVQT = Σ|QTn + 1 − QTn| (30x√2)−1. Autonomic function was assessed by means of standard cardiovascular reflex tests. There were no differences between IGT and control groups in QT (411 ± 43 vs 402 ± 39 ms) and QTc (431 ± 25 vs 424 ± 19 ms) intervals or QT dispersion (44 ± 13 vs 42 ± 17 ms). However, STVQT was significantly higher in IGT patients . The elevated temporal STVQT in patients with IGT may be an early indicator of increased instability of cardiac repolarization during prediabetic conditions.Prediabetic states and diabetes are important risk factors for cardiovascular morbidity and mortality. Determination of short-term QT interval variability (STV Prediabetic states and diabetes are important risk factors for cardiovascular morbidity and mortality –3. CardiThe prevalence of confirmed cardiovascular autonomic neuropathy (AN), an impairment of autonomic control of the cardiovascular system during diabetes, was between 16 and 20% in unselected type 1 and type 2 diabetic patients . CardiovQT) was introduced as an early and sensitive indicator of repolarization instability  ectopic atrial or ventricular beats, were in a rhythm other than normal sinus, had repolarization abnormalities , had a permanent pacemaker or any other disorders such as serious retinopathy, symptomatic cardiac and pulmonary disease, and acute metabolic disease, had excessive noise on the electrocardiographic signal that precluded analysis of the ECG waveform, were on any medication likely to affect the investigated ECG parameters, or consumed significant amount of food within 3 h or drank alcohol, coffee, or smoked within 10 h.We studied 18 IGT patients, 9 males and 9 females with the age of 63 ± 11 years . A total of 18 age- and sex-matched volunteers (mean age 56 ± 9 years) without a history or evidence of heart disease were enrolled in the study as controls. All of the control individuals and IGT patients were of Caucasian origin.The studies described here were carried out in accordance with the Declaration of Helsinki (2000) of the World Medical Association and were approved by the Scientific and Research Ethical Committee of the Medical Research Council at the Hungarian Ministry of Health (ETT-TUKEB), under ethical approval No. 4987-0/2010-1018EKU (338/PI/010). All subjects have given written informed consent of the study.Before the ECG recording, all IGT patients and controls were at rest, in the supine position for 10 min. Then, 12-lead electrocardiograms were continuously recorded for 5 min at rest, also in the supine position to obtain signals with the least amount of motion artifact. In all leads, the ECG signals were digitized at 2,000 Hz sampling rate with a multichannel data acquisition system  connected to a personal computer and stored for later off-line analysis.peak − Tend) and the short-term variability of QT interval (STVQT).Out of the repolarization parameters, we analyzed the frequency corrected QT interval (QTc) using Bazett’s (QTc = QT/√RR), Fridericia , Framingham  and the Hodges formulas , the QTd, the PQ and QRS intervals, the duration of terminal part of T waves (Tpeak − Tend) intervals were measured semi-automatically in 30 consecutive beats  and were calculated as the average of 30 beats. The QT intervals were analyzed by conventional computerized QT measurement technique, all QT intervals were checked in a blinded manner by the same expert investigator of the team and fiducial cursor positions set by the software were manually corrected if needed −1, where D represents the duration of the QT and RR intervals. This calculation defines the STV as the mean distance of points perpendicular to the line of identity in the Poincaré plot and relies on previous mathematical analysis  and repolarization, Poincaré plots of the QT and RR intervals were constructed, where each QT and RR value is plotted against its former value. STV+1 − Dn| x√2−1, whAutonomic function was assessed by means of five standard cardiovascular reflex tests: the HR responses to deep breathing and to standing up (30/15 ratio), the Valsalva maneuver, the systolic blood pressure response to standing up, and the diastolic pressure change during a sustained handgrip . A scoreFasting venous blood samples were obtained from each patient and controls for the determination of serum glucose and hemoglobin A1c (HbA1c) levels. Oral glucose tolerance test (OGTT) was carried out with 75 g glucose to confirm the diagnosis of IGT according to the World Health Organization recommendation .t-test for normally distributed parameters , and linear regression for revealing correlations. The statistical analyses were performed using the Statistica 12 software package. Statistical significance was defined by P < 0.05 level.All data are expressed as mean ± SD. Comparisons between IGT patients and controls for the study variables were done using the unpaired Student’s P < 0.05) than among age- and sex-matched healthy volunteers. Mean systolic blood pressure did not differ significantly between control subjects and IGT patients; however, IGT patients had lower diastolic blood pressure . Significant differences were seen between IGT and control groups in mean serum glucose , HbA1c , and serum glucose 120 min level during OGTT . Clinical data of IGT patients and control subjects are shown in Table In 18 IGT patients studied, mean body mass index (BMI) was significantly higher  was calculated by the Bazett’s, Fridericia, Framingham and Hodges formulas. QTc values calculated with all the four formulas showed no significant differences between IGT patients and controls. Electrocardiographic parameters in study subjects are presented in Table Comparison of the two groups (IGT patients vs controls) revealed no significant differences in HR, the PQ, QRS, QT and TQT (P = 0.882).As it has been shown that T wave amplitude may affect STVQT , we haveQT can be, at least in part, influenced by the short-term variability of the RR interval, the STVRR was also calculated in both groups . No significant correlation was found between STVQT and STVRR values in IGT patients .To characterize the instability of cardiac ventricular repolarization, the short-term beat-to-beat variability of the QT interval was calculated in IGT patients and age-matched controls. Since it is reasonable to assume that STVh groups . PatientQT was significantly increased by 36% in IGT patients compared to controls .As individual representative examples (Poincaré plots) illustrate Figure  and grouP < 0.0001) and the HR responses to deep breathing among IGT subjects compared to controls (P = 0.033). However, no significant differences in 30/15 ratio, systolic blood pressure response after standing up, diastolic blood pressure response after sustained handgrip, and AN score were detected between the two groups. Autonomic parameters of IGT patients and age-matched control subjects are shown in Table Standard cardiovascular reflex tests indicated significant deteriorations in Valsalva ratio .Pearson correlation coefficient values indicated that neither laboratory data nor autonomic parameters correlated with STVQT, an early and sensitive parameter of repolarization instability, is increased even before QTc prolongation or enhanced QTd could be detected in patients with IGT.Cardiac autonomic dysfunction present in prediabetes may lead to repolarization disturbances and may increase the risk of ventricular arrhythmias and sudden cardiac death. In this study, we show for the first time that beat-to-beat STVPatients with prediabetic conditions or diabetes have higher risk for sudden cardiovascular death , 5–7. CaQT has been suggested as an early and sensitive indicator of temporal repolarization instability based on previous experimental and clinical studies  dysfunction in the endo/sarcoplasmic reticulum leading to altered intracellular calcium homeostasis, glucose intolerance, and impaired insulin secretion in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT)  were found in pancreatic β-cells to cause reduced insulin secretion and consequently, IGT  , 37. Thea2+ leak . In knoctly, IGT . In additivation  and constivation . Interestic dogs . Althougtic dogs , cardiactic dogs , 43, IGTtic dogs , 44, howRepolarization instability can be a long-standing risk factor for cardiovascular morbidity and mortality in prediabetic states and during development of diabetes. However, the role of additional cardiovascular risk factors cannot be excluded in early prediabetic conditions. Early sympathetic nerve dysfunction and insulin resistance may also play a role in the development of decreased coronary flow reserve in patients with normoglycemia . In thisQT in our study. The significantly lower STVRR values observed also represent this parasympathetic dysinnervation and subsequent relative sympathetic predominance in patients with IGT. Sympathetic predominance acutely evoked by graded head-up tilt test resulted in similar changes, such as decreased variance of HR and increased variance of repolarization duration  were unchanged, whereas two of three parasympathetic parameters measured  were significantly decreased. In addition, a significant negative correlation was seen between the values measured in the third parasympathetic test (30/15 ratio) and STVduration , 48.P = 0.004) and abnormal Valsalva maneuver  were significantly more frequent in patients with IGT than in control subjects; however, the frequency of abnormal postural test was not different in these two groups (P = 0.334)  . Insulin= 0.334) . However= 0.334) . IGT ind= 0.334) .Putz et al.  describeP < 0.0003) even after adjustments for other confounders (P < 0.006) correlated with adrenergic autonomic dysfunction when age, an important confounder, was removed from the model  of the World Medical Association and were approved by the Scientific and Research Ethical Committee of the Medical Research Council at the Hungarian Ministry of Health (ETT-TUKEB), under ethical approval No. 4987-0/2010-1018EKU (338/PI/010). All subjects have given written informed consent of the study.The authors listed below gave the following contributions: IB, AN, TV, LB, GÁ, PK, JP, AV, and CL had substantial contributions to the conception of the work and design of the paper; AO, SN, AK, ZP, RT, LB, and CL contributed to the measurements and analyses of data; AO, IB, PK, JP, AV, and CL drafted the paper or revised it critically for important intellectual content. All authors  have read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Aldosterone is elevated in chronic kidney disease (CKD) and may be involved in hypertension. Surprisingly, the determinants of the plasma aldosterone concentration (PAC) and its role in hypertension are not well studied in CKD. Therefore, we studied the determinants of aldosterone and its association with blood pressure in CKD patients. We also studied this during renin-angiotensin-aldosterone system inhibition (RAASi) to establish clinical relevance, as RAASi is the treatment of choice in CKD with albuminuria.n = 33, creatinine clearance (CrCl) 85 (75–95) ml/min, proteinuria 3.2 (2.5–4.0) g/day). Patients were treated with losartan 100 mg (ARB), and ARB + hydrochlorothiazide 25 mg (HCT), during both a regular (200 ± 10 mmol Na+/day) and low (89 ± 8 mmol Na+/day) dietary sodium intake, in 6-week study periods. PAC data at the end of each study period were analyzed. The association between PAC and blood pressure was analyzed continuously, and according to PAC above or below the median.We performed a post-hoc analysis on data from a randomized controlled double blind cross-over trial in non-diabetic CKD patients . Higher PAC was not explained by high renin, illustrated by a comparable association between CrCl and the aldosterone-to-renin ratio. The association between lower CrCl and higher PAC was also found in a second study with single RAASi with ACE inhibition , and dual RAASi . Higher PAC was associated with a higher systolic blood pressure (P = 0.010) during different study periods. Only during maximal treatment with ARB + HCT + dietary sodium restriction, blood pressure was no longer different in subjects with a PAC above and below the median.Lower CrCl was correlated with higher PAC during placebo as well as during ARB .The online version of this article (10.1186/s12882-017-0789-x) contains supplementary material, which is available to authorized users. Aldosterone is involved in sodium and volume homeostasis, and consequently regulation of extracellular volume and blood pressure. It has a main role in the homeostatic response to volume depletion, where higher aldosterone levels contribute to renal retention of sodium and water, and followingly restoration of the extracellular volume. In chronic kidney disease (CKD), derangement of volume status and hypertension are common. Several studies indicate an inverse association between plasma aldosterone levels and creatinine clearance –4.Inappropriately high aldosterone levels in CKD have been suggested to contribute to CKD-associated hypertension, as well as to progressive kidney damage by direct profibrotic effects of aldosterone –7. InhibTherefore, we aim to investigate, first, the determinants of the plasma aldosterone concentration (PAC) and aldosterone-to-renin ratio (ARR) in non-diabetic CKD, both without and with RAAS inhibition (RAASi). Second, we aim to investigate whether in CKD, high aldosterone is associated with blood pressure.To this purpose, we studied the association between PAC, ARR and renal function during different treatment conditions in a previously performed randomized controlled trial. Here, ARB losartan 100 mg/day) and placebo were compared in combination with dietary sodium restriction and HCT (hydrochlorothiazide 25 mg/day) in non-diabetic proteinuric CKD patients . In this0 mg/day +/day; approximately 1200 mg Na+/day or 3 g NaCl/day) or a regular sodium diet . Dietary counselling was aimed at avoiding salty foods while keeping other dietary habits unchanged. Patients remained on the assigned diet for 18 weeks, consisting of three consecutive 6-week study periods. Placebo was always as the first treatment, followed by ARB (losartan 100 mg/day), and ARB + HCT (losartan 100 mg/day + hydrochlorothiazide 25 mg/day), where ARB and ARB + HCT were given in random order. After 18 weeks, the patients changed their diet and the three 6-week periods were repeated in the same order as the first three 6-week periods. Therefore, in total there were 4 possible treatment sequences. Additional antihypertensive drugs were allowed if required; these were kept constant during the study.This is a post-hoc analysis of a previously performed randomized controlled cross-over trial, the protocol is described in detail elsewhere . For alln = 45) the 6-week study periods consisted of single RAASi (lisinopril 40 mg/day) and dual RAASi , both during a regular sodium diet (target 200 mmol Na+/day) and a low sodium diet (target 50 mmol Na+/day), in random order. As 7 patients participated in both trials, we excluded them from the second analysis, to avoid duplication of the results.We assessed the effect of single RAASi with ACEi vs dual RAASi with ACEi + ARB, respectively, on the association between PAC, ARR and creatinine clearance in an independent second study, with a comparable cross-over design during different sodium intakes. The protocol is described in detail elsewhere . PatientProteinuria was measured by the pyrogallol red-molybdate method in 24-h urine samples. Blood pressure was determined at 1 min intervals with an automatic device  with the patient in a supine position. After 15 min of measurements, we used the mean of the last three readings for further analyses. Dietary sodium intake was assessed from 24-h urinary sodium excretion. We calculated creatinine clearance from creatinine concentrations in plasma and in 24-h urine samples. Peripheral blood was drawn by venipuncture, and aliquots from serum were stored (−80 °C) until plasma aldosterone concentration (PAC) and active plasma renin concentration (APRC) analysis. Samples were taken in a standardized manner, with the patient in a supine position, and were directly put on ice. Aldosterone was measured with a commercially available RIA kit . Plasma renin activity was measured as described previously with a RIA that detects the amount of angiotensin I produced per hour in the presence of excess angiotensinogen (nanograms of angiotensin I produced per millilitre of plasma per hour) . This asIn the second study, renin was determined using direct renin measurements, in this respect, data regarding the aldosterone-to-renin ratio in both studies could not be pooled. The remaining measurements and calculations in the second study used for the independent analysis were performed equally .All 33 patients were included in our data analysis, and are presented here. Skewed variables were natural log (LN) transformed in order to achieve a normal distribution for linear regression and linear mixed model analyses. Data is given as mean with standard deviation when normally distributed, and geometric mean with 95% confidence interval when data is skewed. SPSS 22.0 for Windows was used for all analyses.To assess the determinants of PAC and ARR, linear regression analyses were performed. The log transformed PAC and ARR were used as the dependent factors. Analysed variables are: age, gender, body mass index, serum sodium, 24-h urinary sodium excretion, serum potassium, 24-h urinary potassium excretion, log transformed plasma renin activity, log transformed proteinuria and log transformed creatinine clearance. This analysis was equally performed in data from the second study.P < 0.100 were included in the multivariate mixed model.Treatment effects were determined using linear mixed model analyses, with Sidak post-hoc analyses to localize the differences. Statistical significance was assumed at the 5% level of probability. The covariance structure for all mixed model analyses was based on Akaike’s information criterion. The association between PAC, and systolic blood pressure (SBP) was studied using linear mixed model analyses. First the association between aldosterone and SBP, and possible confounders , were tested univariately. In univariate analysis, SBP was the dependent variable, and sodium diet, ARB, HCT, their interaction (sodium diet x ARB x HCT), and log transformed PAC  were fixed factors. Subjects was used as a random factor. Covariates with a To ensure there were no carryover effects from the different treatment regimens, we performed linear mixed model analyses. Log transformed PAC was the dependent factor, and treatment and sequence as well as their interaction (treatment x sequence) were fixed factors. We did similar analyses with log transformed ARR, and systolic blood pressure as the dependent factors. Carry-over effects were not detected , and for the sake of conciseness these data are not shown.+/day (approximately 4600 mg Na+/day or 12 g NaCl/day), and during low dietary sodium intake (LS) this was 92 ± 46 mmol Na+/day , illustrating reduction of extracellular fluid volume. Dietary sodium restriction was associated with a higher PAC during ARB and ARB + HCT, but not during placebo treatment.PAC did not change during ARB as compared to placebo, neither during the regular nor during low sodium intake , nor serum potassium  were significant determinants of PAC in either treatment condition. During low dietary sodium intake results were virtually similar. In multivariate analysis, when adjusting for age and gender, creatinine clearance remained the only significant predictor of PAC in both treatment conditions . During ARB, the association was similarly present , although the regression line was shifted downwards, illustrating pharmacological inhibition of the RAAS by ARB treatment  were similar to those of PAC Table , Fig. 1.P = 0.543). During dual RAASi the PAC did not change (71 (59–86) ng/L, P = 0.993). Also in this second study, creatinine clearance was significantly and negatively correlated with PAC during single RAASi, albeit with lisinopril . With ARR it did not quite reach statistical significance . During dual RAASi treatment with lisinopril and valsartan, creatinine clearance was significantly and negatively correlated with both PAC and ARR .In a second study, we assessed the effect of single RAASi with ACEi (lisinopril 40 mg/day) and dual RAASi  on the negative association between creatinine clearance and PAC and ARR during a standardized regular sodium intake . PatientTo study the association between PAC and systolic blood pressure (SBP) in different treatment conditions, we performed linear mixed model analyses. Sodium diet ARB, HCT, gender and log transformed aldosterone were significant predictors of SBP Table , demonstP = 0.001). This difference was also seen during placebo + LS , ARB , during ARB + LS  and during ARB + HCT . Only during the most extensive treatment regimen of ARB + HCT + LS, there was no statistical significant SBP difference between the groups, while the mean blood pressure is still higher is patients with a high PAC .To visualize the association between PAC and SBP, we dichotomized the group in subjects with a baseline PAC above the median and a baseline PAC below the median, also shown in Fig. In this study, we found that pharmacological effective RAASi did not affect the correlation between worse renal function and higher aldosterone. This was true for single RAASi with either ARB or ACEi, as well as for dual RAASi. This indicates that the association between creatinine clearance and aldosterone levels is not susceptible to RAASi, not even with dual inhibition. Furthermore, higher PAC was associated with a higher systolic blood pressure, independent of age, gender and creatinine clearance. During stepwise treatment with losartan, hydrochlorothiazide and dietary sodium restriction this difference decreased to the point where this difference was no longer statistically significant at the final treatment step .The association between lower creatinine clearance and higher PAC and ARR we observed is consistent with older data . HoweverTo our knowledge, the association we describe between high aldosterone and blood pressure has not been described before in CKD patients under RAASi. These data suggest that treatment with MRA is efficacious to treat hypertension in CKD. Indeed, a meta-analysis of patients with mild or moderate CKD has shown that intervention with a mineralocorticoid receptor antagonist (MRA) as adjunct to RAASi reduces blood pressure . In resiThe mechanism underlying the consistent association between lower renal function and high PAC during RAASi is unknown. The parallel association between worse renal function and ARR, and the persistence of both associations during RAASi, with either ARB or ACEi, suggest that the higher aldosterone with lower renal function is not due to renin activation. This is further supported by the persistence during dual RAASi, which makes it unlikely that the association persists due insufficient pharmacological blockade of angiotensin II and the RAAS. Furthermore, the association between worse renal function and PAC was similarly present during ARB and ACEi, which differ in various pharmacological aspects; i.e. during ARB there is a compensatory rise in angiotensin II and increased angiotensin II type 2 receptor activation, and during ACEi bradykinin levels may increase. This renders it unlikely that pharmacologically different modes of RAASi play a role in the association between renal function and PAC. The consistent association between renal function and PAC during different modes of RAASi may suggest other mechanisms and pathways are involved, which are not susceptible to RAASi. Recent data show a link between aldosterone and the calcium-phosphate-PTH-FGF23 axis . There iWhat are the implications of our study? Our data show that patients with renal function impairment, over a range from mild to moderately impaired, have high aldosterone, which is associated with higher blood pressure, even despite RAASi. Thus, aldosterone might play a role in volume derangement and hypertension, even in early CKD. One might wonder whether there is a further rise in aldosterone as renal function declines, and if so, whether this translates into hypertension. Future research is imperative to investigate the link between creatinine clearance and high aldosterone across all spectra of renal function impairment, and what would be the implications for blood pressure treatment, in particular the role of MRA treatment on top of RAASi.The primary limitation to our study was the post-hoc design. However, the robustness of our findings is supported by the independent study in which we found that the correlation between renal function and PAC was similarly present during RAASi with ACEi, and during dual RAASi. Furthermore, in our study the addition of MRA was not investigated.Our data show a consistent association between worse renal function and higher plasma aldosterone concentration, related to a higher ARR, during RAASi with either ARB, ACEi or both. Consequently, our data support the involvement of high aldosterone levels in hypertension in CKD with mildly impaired renal function – and show that a treatment regimen of RAASi combined with stepwise sodium intervention might be effective in correcting blood pressure.Additional file 1: Table S1.Patient characteristics. This Table depicts the patients characteristics of patients included in the study. (DOCX 19 kb)Additional file 2: Table S2.Multivariate analysis on the determinants of the plasma aldosterone concentration during placebo and during losartan treatment. In this table we illustrate the association between creatinine clearance and the plasma aldosterone concentration during placebo and losartan treatment, while adjusting for age and gender. (DOCX 13 kb)


Epicardial adipose tissue (EAT) is an emerging cardio-metabolic risk factor and has been shown to correlate with adverse cardiovascular (CV) outcome; however the underlying pathophysiology of this link is not well understood. The aim of this study was to evaluate the relationship between EAT and a comprehensive panel of cardiovascular risk biomarkers and pulse wave velocity (PWV) and indexed left ventricular mass (LVMI) in a cohort of patients with cardiovascular disease (CVD) and diabetes compared to controls.One hundred forty-five participants  were evaluated. All patients underwent cardiovascular magnetic resonance (CMR) examination and PWV. EAT measurements from CMR were performed on the 4-chamber view. Blood samples were taken and a range of CV biomarkers was evaluated.2 vs. group 4 EAT 11.8 ± 4.1 cm2, p = 0.001; group 3 EAT 15.1 ± 4.3 cm2 vs. group 4 EAT 11.8 ± 4.1 cm2, p = 0.024). EAT was independently associated with IL-6 . When added to clinical variables, both EAT  and IL-6  were independently associated with PWV. EAT was significantly associated with LVMI in a univariable analysis but not when added to significant clinical variables.EAT measurements were significantly higher in the groups with CVD, with or without T2DM compared to patients without CVD or T2DM  contains supplementary material, which is available to authorized users. The distribution of body fat appears to be important in cardiovascular disease (CVD) risk . With reRecent studies have shown that EAT is related to atherosclerotic disease in other vascular beds. In the population based Rotterdam Study, EAT was associated with multiple vessel beds and was independent of CV risk factors . This obThe aim of this study was to assess the association between EAT, metabolic and inflammatory biomarkers, peripheral arterial stiffness (as measured by PWV) and left ventricular mass (LVM) in a cohort of patients with a spectrum of cardio-metabolic disease compared to controls to provide an understanding of the underlying local and systemic pathophysiological process by which EAT might lead to adverse CVD outcome.2), and therapy for any chronic inflammatory disease or malignancy. The study protocols were approved by The East of Scotland Research Ethics Committee, and were conducted in accordance with the Declaration of Helsinki. All volunteers who participated in this study provided written informed consent. Informed consent was obtained from each patient and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.This study was a single centre observational cross sectional sub-study of the multicentre SUMMIT (SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools) study. Recruitment strategy and the imaging protocol have been described in detail previously . In summCardiovascular magnetic resonance (CMR) images were acquired on a 32 RF receiver channel, 3.0 T Tesla MRI scanner . Full details of the CMR protocol and intra-observer reproducibility of LV analysis in this cohort have been as previously described in detail .2) after a careful examination of the cine 4 chamber view image to outline the fat at the end-diastolic image as described in other studies [http://segment.heiberg.se) [n = 29) selected at random to assess inter-observer variability.EAT area was defined as the fat located between the outer wall of the myocardium and the visceral layer of the pericardium . We chos studies –19. EAT berg.se) . A repreArterial stiffness was assessed by calculating PWV using a Sphygmocor device  as described previously . In brie, Science for Life Laboratory, Uppsala. The full list of biomarkers measured is shown in Additional file Fifty-one biomarkers were analysed by the Proximity Extension Assay technique using the Proseek Multiplex CVD96*96 reagent kit  at the Clinical Biomarkers Facilityp < 0.05 was considered statistically significant.All analyses were performed using SPSS . Continuous variables are shown as mean ± standard deviation. Categorical variables are reported as number with percentage in brackets. To compare the four groups, ANOVA was applied as a parametric test with post-hoc Bonferroni correction to account for multiple testing. In the investigation of associations among continuous variables, a Pearson correlation test was used for parametric data and a Spearman test for non-parametric data. Univariate and multivariable linear regressions were used for determining factors associated with EAT and PWV and LVM. Firstly, linear regression was performed to determine the association between biomarkers and EAT and PWV and LVM. Then, regression was performed to determine the independent association between clinical variables and EAT with PWV and LVM. Finally, biomarkers were added to the clinical variables and EAT to determine their association with PWV and LVM. To build the multivariable models, significant baseline clinical variables were first included. Following this, EAT and significant biomarkers were added to significant clinical variables in order to build a final multivariable model for association with PWV and LVMI. For all tests a In total 145 participants were included in study. Full demographic details are shown in Table 2 vs. group 4 EAT 11.8 ± 4.1 cm2, p = 0.001; group 3 EAT 15.1 ± 4.3 cm2 vs. group 4 EAT 11.8 ± 4.1 cm2, p = 0.024). A significant correlation was found between EAT and PWV . LVMI was also significantly higher in group 1 compared to group 4 . There was no significant difference in PWV amongst any of the four groups.PWV, EAT and LV measurements are presented in Table p = 0.003) (CD40L: beta − 0.21 p = 0.014)  .The full list of 51 CV biomarkers evaluated is reported in Additional file p < 0.001), systolic BP  and lower extremity arterial disease (LEAD) (beta 0.17 p = 0.025) remained significantly associated with PWV (Table p = 0.026). Finally, when IL-6 and CD40L were added to the model both EAT (beta 0.16 p = 0.035) and IL-6 (beta 0.20 p = 0.005) remained independently associated with PWV in addition to age and systolic blood pressure however CD40L was not. The stepwise additions of both EAT and IL-6 added significant independent power to model association with PWV.In univariate analysis for association with PWV we found that age, systolic blood pressure, history of smoking, lower extremity arterial disease, AF and EAT were all significantly associated with PWV . In multivariable analysis, only male gender and history of hypertension remained significantly associated with LVMI .In univariable analysis there were several significant clinical variables associated with LVMI,  and both EAT and IL-6 were significantly associated with PWV independent of clinical variables, suggesting potential inflammatory pathophysiological link. Additionally, both EAT and IL-6 had significant incremental association with PWV. EAT may be associated with systemic inflammation and could be a therapeutic target in cardio-metabolic disease.Additional file 1:Table S1. Correlations between cardiovascular biomarkers and epicardial adipose tissue (EAT), pulse wave velocity (PWV) and left ventricular mass index (LVMI). Table S2. Univariable Linear Regression of Clinical Variables and EAT with Pulse Wave Velocity and LV Mass Index. Table S3. Multivariable Associations with LV Mass Index. Figure S1. Correlations between EAT, IL-6 and CD40L. (DOCX 88 kb)