The renal vasodilatation from ß-adrenergic activation in vivo in rats is not driven by KV7 and BKCa channels.

The mechanisms behind renal vasodilatation elicited by stimulation of ß-adrenergic receptors are not clarified. As several classes of K channels are potentially activated, we tested the hypothesis that KV7 and BKCa channels contribute to the decreased renal vascular tone in vivo and in vitro. Changes in renal blood flow (RBF) during ß-adrenergic stimulation were measured in anaesthetized rats using an ultrasonic flow probe. The isometric tension of segmental arteries from normo- and hypertensive rats and segmental arteries from wild-type mice and mice lacking functional KV7.1 channels was examined in a wire-myograph. The ß-adrenergic agonist isoprenaline increased RBF significantly in vivo. Neither activation nor inhibition of KV7 and BKCa channels affected the ß-adrenergic RBF response. In segmental arteries from normo- and hypertensive rats, inhibition of KV7 channels significantly decreased the ß-adrenergic vasorelaxation. However, inhibiting BKCa channels was equally effective in reducing the ß-adrenergic vasorelaxation. The ß-adrenergic vasorelaxation was not different between segmental arteries from wild-type mice and mice lacking KV7.1 channels. As opposed to rats, inhibition of KV7 channels did not affect the murine ß-adrenergic vasorelaxation. Although inhibition and activation of KV7 channels or BKCa channels significantly changed baseline RBF in vivo, none of the treatments affected ß-adrenergic vasodilatation. In isolated segmental arteries, however, inhibition of KV7 and BKCa channels significantly reduced the ß-adrenergic vasorelaxation, indicating that the regulation of RBF in vivo is driven by several actors in order to maintain an adequate RBF. Our data illustrates the challenge in extrapolating results from in vitro to in vivo conditions.

Cardiovascular autonomic nervous function in children conceived by assisted reproductive technology with frozen or fresh embryo transfer.

As a result of epigenetic changes, children conceived by assisted reproduction may be at risk of premature cardiovascular aging with notably increased blood pressures. Their cardiovascular autonomic nervous function is unknown. Therefore, this study investigated the cardiovascular autonomic nervous function in 8-12-yr-old children (51% girls) conceived naturally (n = 33) or by assisted reproduction with frozen (n = 34) or fresh (n = 38) embryo transfer by evaluating heart rate variability, during rest; from provocation maneuvers; and from baroreflex function. Heart rate and blood pressure response to provocation maneuvers and baroreflex function were comparable between children conceived naturally or by assisted reproduction. The mean RR-interval and high-frequency component of heart rate variability were lower in children conceived by assisted reproduction than in children conceived naturally. Children conceived by fresh embryo transfer had ∼17% lower heart rate-corrected standard deviation of normal-to-normal R-R intervals; ∼22% lower heart rate-corrected square root of the mean of the squared difference between successive R-R intervals; and ∼37% higher low-frequency/high-frequency ratio than naturally conceived children. Children conceived by assisted reproduction still had lower heart rate variability and vagal modulation than naturally conceived children after adjustment for confounders. Thus, these results raise the possibility of sympathetic predominance in children conceived by assisted reproduction. Therefore, it is important to reproduce these results in larger and older cohorts as sympathetic predominance relates with cardiovascular and metabolic diseases.NEW & NOTEWORTHY We observed that children conceived by assisted reproductive technology (both frozen and fresh embryo transfer) had lowered heart rate variability during rest as compared with children conceived naturally. During physiological stress maneuvers, however, the cardiovascular autonomic nervous regulation was comparable between children conceived by assisted reproductive technologies and naturally. Our findings highlight the potential that lowered heart rate variability during rest in children conceived by assisted reproductive technologies may precede premature hypertension.

Interacting information streams on the nephron arterial network.

Blood flow and glomerular filtration in the kidney are regulated by two mechanisms acting on the afferent arteriole of each nephron. The two mechanisms operate as limit cycle oscillators, each responding to a different signal. The myogenic mechanism is sensitive to a transmural pressure difference across the wall of the arteriole, and tubuloglomerular feedback (TGF) responds to the NaCl concentration in tubular fluid flowing into the nephron's distal tubule,. The two mechanisms interact with each other, synchronize, cause oscillations in tubular flow and pressure, and form a bimodal electrical signal that propagates into the arterial network. The electrical signal enables nephrons adjacent to each other in the arterial network to synchronize, but non-adjacent nephrons do not synchronize. The arteries supplying the nephrons have the morphologic characteristics of a rooted tree network, with 3 motifs characterizing nephron distribution. We developed a model of 10 nephrons and their afferent arterioles in an arterial network that reproduced these structural characteristics, with half of its components on the renal surface, where experimental data suitable for model validation is available, and the other half below the surface, from which no experimental data has been reported. The model simulated several interactions: TGF-myogenic in each nephron with TGF modulating amplitude and frequency of the myogenic oscillation; adjacent nephron-nephron with strong coupling; non-adjacent nephron-nephron, with weak coupling because of electrical signal transmission through electrically conductive arterial walls; and coupling involving arterial nodal pressure at the ends of each arterial segment, and between arterial nodes and the afferent arterioles originating at the nodes. The model predicted full synchronization between adjacent nephrons pairs and partial synchronization among weakly coupled nephrons, reproducing experimental findings. The model also predicted aperiodic fluctuations of tubular and arterial pressures lasting longer than TGF oscillations in nephrons, again confirming experimental observations. The model did not predict complete synchronization of all nephrons.

Renoprotective effects of GLP-1 receptor agonists and SGLT-2 inhibitors-is hemodynamics the key point?

Two novel treatments for diabetic kidney disease have emerged after decades with little progression. Both agents were developed for improved glycemic control in patients with type-2 diabetes. However, large clinical trials showed renoprotective effects beyond their ability to lower plasma glucose levels, body weight, and blood pressure. How this renal protection occurs is unknown. We will discuss their physiological effects, with special focus on the renal effects. We discuss how these drugs affect the function of the diabetic and nondiabetic kidneys to elucidate mechanisms by which the renoprotection could arise. Diabetic kidney disease affects the glomerular capillaries, which are usually protected by the renal autoregulatory mechanisms, the myogenic response, and the tubuloglomerular feedback mechanism. Animal models with reduced renal autoregulatory capacity develop chronic kidney disease. Despite different cellular targets, both drugs are suspected to affect renal hemodynamics through changes in the renal autoregulatory mechanisms. The glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert a direct vasodilatory effect on the afferent arteriole (AA) positioned just before the glomerulus. Paradoxically, this effect is expected to increase glomerular capillary pressure, causing glomerular injury. In contrast, the sodium-glucose transporter-2 inhibitors (SGLT2i) are believed to activate the tubuloglomerular feedback mechanism to elicit vasoconstriction of the afferent arteriole. Because of their opposing effects on the renal afferent arterioles, it appears unlikely that their renoprotective effects can be explained by common effects of renal hemodynamics, but both drugs appear to add protection to the kidney beyond what can be obtained with classical treatment targeted at lowering blood glucose levels and blood pressure.

A hybrid approach to full-scale reconstruction of renal arterial network.

The renal vasculature, acting as a resource distribution network, plays an important role in both the physiology and pathophysiology of the kidney. However, no imaging techniques allow an assessment of the structure and function of the renal vasculature due to limited spatial and temporal resolution. To develop realistic computer simulations of renal function, and to develop new image-based diagnostic methods based on artificial intelligence, it is necessary to have a realistic full-scale model of the renal vasculature. We propose a hybrid framework to build subject-specific models of the renal vascular network by using semi-automated segmentation of large arteries and estimation of cortex area from a micro-CT scan as a starting point, and by adopting the Global Constructive Optimization algorithm for generating smaller vessels. Our results show a close agreement between the reconstructed vasculature and existing anatomical data obtained from a rat kidney with respect to morphometric and hemodynamic parameters.

Synchronization in renal microcirculation unveiled with high-resolution blood flow imaging.

Internephron interaction is fundamental for kidney function. Earlier studies have shown that nephrons signal to each other, synchronize over short distances, and potentially form large synchronized clusters. Such clusters would play an important role in renal autoregulation, but due to the technological limitations, their presence is yet to be confirmed. In the present study, we introduce an approach for high-resolution laser speckle imaging of renal blood flow and apply it to estimate the frequency and phase differences in rat kidney microcirculation under different conditions. The analysis unveiled the spatial and temporal evolution of synchronized blood flow clusters of various sizes, including the formation of large (>90 vessels) and long-lived clusters (>10 periods) locked at the frequency of the tubular glomerular feedback mechanism. Administration of vasoactive agents caused significant changes in the synchronization patterns and, thus, in nephrons' co-operative dynamics. Specifically, infusion of vasoconstrictor angiotensin II promoted stronger synchronization, while acetylcholine caused complete desynchronization. The results confirm the presence of the local synchronization in the renal microcirculatory blood flow and that it changes depending on the condition of the vascular network and the blood pressure, which will have further implications for the role of such synchronization in pathologies development.

Diet-induced hypertension in rats is associated with increased renal vasoconstrictor response to angiotensin II after imitated endothelial dysfunction.

The mechanisms behind development of diet-induced hypertension remain unclear. The kidneys play a paramount role in blood volume and blood pressure regulation. Increases in renal vascular resistance lead to increased mean arterial blood pressure (MAP) due to reduced glomerular filtration rate and Na+ excretion. Renal vascular resistance may be increased by several factors, e.g. sympathetic output, increased activity in the renin-angiotensin system or endothelial dysfunction. We examined if a 14-week diet rich in fat, fructose or both led to increased renal vascular resistance and blood pressure. Sixty male Sprague-Dawley rats received normal chow (Control), high-fat chow (High Fat), high-fructose in drinking water (High Fructose), or a combination of high-fat and high-fructose diet (High Fat + Fruc) for 14 weeks from age 4-weeks. Measurements included body weight (BW), telemetry blood pressures, renal blood flow in anesthetized rats, plasma concentrations of atrial natriuretic peptide and glucose, as well as vessel myography in renal segmental arteries. Body weight increased in both groups receiving high fat, whereas MAP increased only in the High Fat + Fruc group. Renal blood flow did not differ between groups showing that renal vascular resistance was not increased by the diets. After inhibiting nitric oxide and prostacyclin production, renal blood flow reductions to Angiotensin II infusions were exaggerated in the groups receiving high fructose. MAP correlated positively with heart rate in all rats tested. Our data suggest that diet-induced hypertension is not caused by an increase in renal vascular resistance. The pathophysiological mechanisms may include altered signaling in the renin-angiotensin system and increases in central sympathetic output in combination with reduced baroreceptor sensitivity leading to increased renal vasoconstrictor responses.

DeepFake electrocardiograms using generative adversarial networks are the beginning of the end for privacy issues in medicine.

Recent global developments underscore the prominent role big data have in modern medical science. But privacy issues constitute a prevalent problem for collecting and sharing data between researchers. However, synthetic data generated to represent real data carrying similar information and distribution may alleviate the privacy issue. In this study, we present generative adversarial networks (GANs) capable of generating realistic synthetic DeepFake 10-s 12-lead electrocardiograms (ECGs). We have developed and compared two methods, named WaveGAN* and Pulse2Pulse. We trained the GANs with 7,233 real normal ECGs to produce 121,977 DeepFake normal ECGs. By verifying the ECGs using a commercial ECG interpretation program (MUSE 12SL, GE Healthcare), we demonstrate that the Pulse2Pulse GAN was superior to the WaveGAN* to produce realistic ECGs. ECG intervals and amplitudes were similar between the DeepFake and real ECGs. Although these synthetic ECGs mimic the dataset used for creation, the ECGs are not linked to any individuals and may thus be used freely. The synthetic dataset will be available as open access for researchers at OSF.io and the DeepFake generator available at the Python Package Index (PyPI) for generating synthetic ECGs. In conclusion, we were able to generate realistic synthetic ECGs using generative adversarial neural networks on normal ECGs from two population studies, thereby addressing the relevant privacy issues in medical datasets.

Explaining deep neural networks for knowledge discovery in electrocardiogram analysis.

Deep learning-based tools may annotate and interpret medical data more quickly, consistently, and accurately than medical doctors. However, as medical doctors are ultimately responsible for clinical decision-making, any deep learning-based prediction should be accompanied by an explanation that a human can understand. We present an approach called electrocardiogram gradient class activation map (ECGradCAM), which is used to generate attention maps and explain the reasoning behind deep learning-based decision-making in ECG analysis. Attention maps may be used in the clinic to aid diagnosis, discover new medical knowledge, and identify novel features and characteristics of medical tests. In this paper, we showcase how ECGradCAM attention maps can unmask how a novel deep learning model measures both amplitudes and intervals in 12-lead electrocardiograms, and we show an example of how attention maps may be used to develop novel ECG features.

Vascular function in adults with cyanotic congenital heart disease.

BACKGROUND: Patients with cyanotic congenital heart disease (CCHD) may have a low burden of atherosclerosis. Endothelial dysfunction is an early stage of atherosclerosis and endothelial function is previously studied in smaller CCHD groups with different techniques and variable results. We aimed to examine endothelial function and carotid atherosclerosis in a larger group of CCHD patients. METHODS: This multicentre study assessed endothelial function in adults with CCHD and controls by measuring the dilatory response of the brachial artery to post-ischemic hyperaemia (endothelium-dependent flow-mediated-vasodilatation (FMD)), and to nitroglycerin (endothelium-independent nitroglycerin-induced dilatation (NID)). Flow was measured at baseline and after ischaemia (reactive hyperaemia). Carotid-intima-media-thickness (CIMT), prevalence of carotid plaque and plaque thickness (cPT-max) were evaluated ultrasonographically. Lipoproteins, inflammatory and vascular markers, including sphingosine-1-phosphate (S1P) were measured. RESULTS: Forty-five patients with CCHD (median age 50 years) and 45 matched controls (median age 52 years) were included. The patients presented with lower reactive hyperaemia (409 ± 114% vs. 611 ± 248%, p < 0.0001), however preserved FMD response compared to controls (106.5 ± 8.3% vs. 106.4 ± 6.1%, p = 0.95). In contrast, NID was lower in the patients (110.5 ± 6.1% vs. 115.1 ± 7.4%, p = 0.053). There was no difference in CIMT, carotid plaque or cPT-max. The patients presented with lower high-density-lipoprotein cholesterol, and higher level of inflammatory markers and S1P. CONCLUSION: Adults with CCHD had preserved FMD in the brachial artery, but impaired NID response and lower reactive hyperaemia than controls. The preserved FMD and the comparable prevalence of carotid atherosclerosis indicate that CCHD patients have the same risk of atherosclerosis as controls.

Lack of Connexins 40 and 45 Reduces Local and Conducted Vasoconstrictor Responses in the Murine Afferent Arterioles.

The juxtaglomerular apparatus (JGA) is an essential structure in the regulation of renal function. The JGA embodies two major functions: tubuloglomerular feedback (TGF) and renin secretion. TGF is one of the mechanisms mediating renal autoregulation. It is initiated by an increase in tubular NaCl concentration at the macula densa cells. This induces a local afferent arteriolar vasoconstriction and a conducted response that can be measured several 100 µm upstream from the juxtaglomerular segment. This spread of the vasomotor response into the surrounding vasculature likely plays a key role in renal autoregulation, and it requires the presence of gap junctions, intercellular pores based on connexin (Cx) proteins. Several Cx isoforms are expressed in the JGA and in the arteriolar wall. Disruption of this communication pathway is associated with reduced TGF, dysregulation of renin secretion, and hypertension. We examine if the absence of Cx40 or Cx45, expressed in the endothelial and vascular smooth muscle cells respectively, attenuates afferent arteriolar local and conducted vasoconstriction. Afferent arterioles from wildtype and Cx-deficient mice (Cx40 and Cx45) were studied using the isolated perfused juxtamedullary nephron preparation. Vasoconstriction was induced via electrical pulse stimulation at the glomerular entrance. Inner afferent arteriolar diameter was measured locally and upstream to evaluate conducted vasoconstriction. Electrical stimulation induced local vasoconstriction in all groups. The local vasoconstriction was significantly smaller when Cx40 was absent. The vasoconstriction decreased in magnitude with increasing distance from the stimulation site. In both Cx40 and Cx45 deficient mice, the vasoconstriction conducted a shorter distance along the vessel compared to wild-type mice. In Cx40 deficient arterioles, this may be caused by a smaller local vasoconstriction. Collectively, these findings imply that Cx40 and Cx45 are central for normal vascular reactivity and, therefore, likely play a key role in TGF-induced regulation of afferent arteriolar resistance.

Influence of connexin45 on renal autoregulation.

Renal autoregulation is mediated by the myogenic response and tubuloglomerular feedback (TGF) working in concert to maintain renal blood flow and glomerular filtration rate despite fluctuations in renal perfusion pressure. Intercellular communication through gap junctions may play a role in renal autoregulation. We examine if one of the building blocks in gap junctions, connexin45 (Cx45), which is expressed in vascular smooth muscle cells, has an influence on renal autoregulatory efficiency. The isolated perfused juxtamedullary nephron preparation was used to measure afferent arteriolar diameter changes in response to acute changes in renal perfusion pressure. In segmental arteries, pressure myography was used to study diameter changes in response to pressure changes. Wire myography was used to study vasoconstrictor and vasodilator responses. A mathematical model of the vascular wall was applied to interpret experimental data. We found a significant reduction in the afferent arteriolar constriction in response to acute pressure increases in Cx45 knockout (KO) mice compared with wild-type (WT) mice. Abolition of TGF caused a parallel upward shift in the autoregulation curve of WT animals but had no effect in KO animals, which is compatible with TGF providing a basal tonic contribution in afferent arterioles whereas Cx45 KO animals were functionally papillectomized. Analysis showed a shift toward lower stress sensitivity in afferent arterioles from Cx45 KO animals, indicating that the absence of Cx45 may also affect myogenic properties. Finally, loss of Cx45 in vascular smooth muscle cells appeared to associate with a change in both structure and passive properties of the vascular wall.

Interactions between renal vascular resistance and endothelium-derived hyperpolarization in hypertensive rats in vivo.

Endothelium derived signaling mechanisms play an important role in regulating vascular tone and endothelial dysfunction is often found in hypertension. Endothelium-derived hyperpolarization (EDH) plays a significant role in smaller renal arteries and arterioles, but its significance in vivo in hypertension is unresolved. The aim of this study was to characterize the EDH-induced renal vasodilation in normotensive and hypertensive rats during acute intrarenal infusion of ACh. Our hypothesis was that the increased renal vascular resistance (RVR) found early in hypertension would significantly correlate with reduced EDH-induced vasodilation. In isoflurane-anesthetized 12-week-old normo- and hypertensive rats blood pressure and renal blood flow (RBF) was measured continuously. RBF responses to acute intrarenal ACh infusions were measured before and after inhibition of NO and prostacyclin. Additionally, RVR was decreased or increased using inhibition or activation of adrenergic receptors or by use of papaverine and angiotensin II. Intrarenal infusion of ACh elicited a larger increase in RBF in hypertensive rats compared to normotensive rats suggesting that endothelial dysfunction is not present in 12-week-old hypertensive rats. The EDH-induced renal vasodilation (after inhibition of NO and prostacyclin) was similar between normo- and hypertensive rats. Reducing RVR by inhibition of α1 -adrenergic receptors significantly increased the renal EDH response in hypertensive rats, but a similar increase was found after activating α-adrenergic receptors using norepinephrine. The results show that renal EDH is present and functional in 12-week-old normo- and hypertensive rats. Interestingly, both activation and inactivation of α1 -adrenergic receptors elicited an increase in the renal EDH-induced vasodilation.

Acute intramyocardial lipid accumulation in rats does not slow cardiac conduction per se.

Diabetic patients suffer from both cardiac lipid accumulation and an increased risk of arrhythmias and sudden cardiac death. This correlation suggests a link between diabetes induced cardiac steatosis and electrical abnormalities, however, the underlying mechanism remains unknown. We previously showed that cardiac conduction velocity slows in Zucker diabetic fatty rats and in fructose-fat fed rats, models that both exhibit prominent cardiac steatosis. The aim of this study was to investigate whether acute cardiac lipid accumulation reduces conduction velocity per se. Cardiac lipid accumulation was induced acutely by perfusing isolated rat hearts with palmitate-glucose buffer, or subacutely by fasting rats overnight. Subsequently, longitudinal cardiac conduction velocity was measured in right ventricular tissue strips, and intramyocardial triglyceride and lipid droplet content was determined by thin layer chromatography and BODIPY staining, respectively. Perfusion with palmitate-glucose buffer significantly increased intramyocardial triglyceride levels compared to perfusion with glucose (2.16 ± 0.17 (n = 10) vs. 0.92 ± 0.33 nmol/mg WW (n = 9), P < 0.01), but the number of lipid droplets was very low in both groups. Fasting of rats, however, resulted in both significantly elevated intramyocardial triglyceride levels compared to fed rats (3.27 ± 0.43 (n = 10) vs. 1.45 ± 0.24 nmol/mg WW (n = 10)), as well as a larger volume of lipid droplets (0.60 ± 0.13 (n = 10) vs. 0.21 ± 0.06% (n = 10), P < 0.05). There was no significant difference in longitudinal conduction velocity between palmitate-glucose perfused and control hearts (0.77 ± 0.025 (n = 10) vs. 0.75 m/sec ± 0.029 (n = 9)), or between fed and fasted rats (0.75 ± 0.042 m/sec (n = 10) vs. 0.79 ± 0.047 (n = 10)). In conclusion, intramyocardial lipid accumulation does not slow cardiac longitudinal conduction velocity per se. This is true for both increased intramyocardial triglyceride content, induced by palmitate-glucose perfusion, and increased intramyocardial triglyceride and lipid droplet content, generated by fasting.

The nephron-arterial network and its interactions.

Tubuloglomerular feedback and the myogenic mechanism form an ensemble in renal afferent arterioles that regulate single-nephron blood flow and glomerular filtration. Each mechanism generates a self-sustained oscillation, the mechanisms interact, and the oscillations synchronize. The synchronization generates a bimodal electrical signal in the arteriolar wall that propagates retrograde to a vascular node, where it meets similar electrical signals from other nephrons. Each signal carries information about the time-dependent behavior of the regulatory ensemble. The converging signals support synchronization of the nephrons participating in the information exchange, and the synchronization can lead to formation of nephron clusters. We review the experimental evidence and the theoretical implications of these interactions and consider additional interactions that can limit the size of nephron clusters. The architecture of the arterial tree figures prominently in these interactions.

Intravascular assessment of coronary arteries in patients with cyanotic congenital heart disease.

AIMS: Patients with cyanotic congenital heart disease (CCHD) have been suggested to develop less atherosclerosis than the general population. This study aimed to evaluate the extent of coronary atherosclerosis in patients with CCHD using intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS). METHODS AND RESULTS: Fifteen patients with CCHD (women, 9; median age, 53 years) and 14 acyanotic controls (women, 6; median age, 53 years) were examined with IVUS-NIRS of the right coronary artery (RCA). The patients with CCHD presented with a larger RCA diameter than the controls (external elastic membrane diameter, 6.1 [4.8-6.7] vs. 4.7 [4.1-5.1] mm, respectively; p=0.01). No difference in area stenosis was found between the patients and the controls (15.8% [12.3-19.7] vs. 15.2% [9.5-18.8]; p=0.87). The presence of lipid by NIRS was noted in 43% of patients with CCHD and in 92% of the controls; however, no differences in total or max 4 mm lipid core burden index (LCBI) or in plasma lipid profile were found. CONCLUSIONS: Patients with CCHD presented with larger coronary arteries than acyanotic controls. No difference in the degree of area stenosis in the coronary arteries was found between the cyanotic and acyanotic patients; however, a lower proportion of patients with CCHD showed a positive LCBI.

Subclinical atherosclerosis in patients with cyanotic congenital heart disease.

INTRODUCTION: Survival in patients with cyanotic congenital heart disease (CCHD) has improved dramatically. The result is an ageing population with risk of acquired heart disease. Previous small uncontrolled studies suggested that these patients are protected against the development of atherosclerosis. To test this hypothesis, we sought to determine the prevalence of subclinical atherosclerosis in a larger population of patients with CCHD. METHOD: We compared the prevalence of subclinical atherosclerosis in adult CCHD patients from Denmark, Sweden, Norway and Australia, with that in age-, sex-, smoking status-, and body mass index matched controls. Coronary artery atherosclerosis was assessed on computed tomography with coronary artery calcification (CAC) score. Subclinical atherosclerosis was defined by CAC-score > 0. Carotid artery atherosclerosis was evaluated using ultrasound by measuring carotid plaque thickness (cPT-max) and carotid intima media thickness (CIMT). Lipid status was evaluated as an important atherosclerotic risk factor. RESULTS: Seventy-four patients with CCHD (57% women, median age 49.5 years) and 74 matched controls (57% women, median age 50.0 years) were included. There were no differences between the groups in: CAC-score > 0 (21% vs. 19%, respectively; p = 0.8), carotid plaques (19% vs. 9%, respectively; p = 0.1), cPT-max (2.3 mm vs. 2.8 mm, respectively; p = 0.1) or CIMT (0.61 mm vs. 0.61 mm, respectively; p = 0.98). And further no significant differences in lipoprotein concentrations measured by ultracentrifugation. CONCLUSION: Young adults with CCHD have similar cardiovascular risk factor profiles and measures of subclinical atherosclerosis, compared with controls. Given their increasing life expectancies, athero-preventive strategies should be an important part of their clinical management.

Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system.

The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt intake, according to instructions from a dietitian. Renal clearance studies were done for measurements of renal plasma flow, glomerular filtration rate (GFR) and the segmentel tubular handling of sodium and water (lithium clearance). rhEPO increased arterial blood pressure, total peripheral resistance, and renal vascular resistance, and decreased renal plasma flow in the high-dose rhEPO intervention and tended to decrease GFR. In spite of the decrease in renal perfusion, rhEPO tended to decrease reabsorption of sodium and water in the proximal tubule and induced a prompt decrease in circulating levels of renin and aldosterone, independent of changes in red blood cell mass, blood volumes, and blood pressure. We also found changes in biomarkers showing evidence that rhEPO induced a prothrombotic state. Our results suggest that rhEPO causes a direct downregulation in proximal tubular reabsorption that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system.

Long-term diet-induced hypertension in rats is associated with reduced expression and function of small artery SKCa, IKCa, and Kir2.1 channels.

Abdominal obesity and/or a high intake of fructose may cause hypertension. K+ channels, Na/K-ATPase, and voltage-gated Ca2+ channels are crucial determinants of resistance artery tone and thus the control of blood pressure. Limited information is available on the role of K+ transporters in long-term diet-induced hypertension in rats. We hypothesized that a 28-week diet rich in fat, fructose, or both, will lead to changes in K+ transporter expression and function, which is associated with increased blood pressure and decreased arterial function. Male Sprague-Dawley (SD) rats received a diet containing normal chow (Control), high-fat chow (High Fat), high-fructose in drinking water (High Fructose), or a combination of high-fat and high-fructose diet (High Fat/Fruc) for 28 weeks from the age of 4 weeks. Measurements included body weight (BW), systolic blood pressure (SBP), mRNA expression of vascular K+ transporters, and vessel myography in small mesenteric arteries (SMAs). BW was increased in the High Fat and High Fat/Fruc groups, and SBP was increased in the High Fat/Fruc group. mRNA expression of small conductance calcium-activated K+ channel (SKCa), intermediate conductance calcium-activated K+ (IKCa), and Kir2.1 inward rectifier K+ channels were reduced in the High Fat/Fruc group. Reduced endothelium-derived hyperpolarization (EDH)-type relaxation to acetylcholine (ACh) was seen in the High Fat and High Fat/Fruc groups. Ba2+-sensitive dilatation to extracellular K+ was impaired in all the experimental diet groups. In conclusion, reduced expression and function of SKCa, IKCa, and Kir2.1 channels are associated with elevated blood pressure in rats fed a long-term High Fat/Fruc. Rats fed a 28-week High Fat/Fruc provide a relevant model of diet-induced hypertension.

[Cardiovascular changes in childhood obesity].

Over the last 35 years there has been an almost 50% increase in childhood obesity worldwide. Childhood obesity is associated with increased cardiovascular morbidity and mortality in adulthood, and in children with overweight or obesity pathologic changes have been found down to the age of two years. These changes are present in vasculature, heart and autonomic nervous system and affect blood pressure control. Overweight and obesity must be prevented, detected and treated at an early age, as even a small weight loss reduces the risk of cardiovascular disease significantly.