[Baroreceptor activation therapy for therapy-resistant hypertension: indications and patient selection : Recommendations of the BAT consensus group 2017]. / Barorezeptorakivierungstherapie bei therapierefraktärer Hypertonie: Indikation und Patientenselektion : Empfehlungen der BAT-Konsensusgruppe 2017.

Baroreceptor activation therapy (BAT) has been available for several years for treatment of therapy-refractory hypertension (trHTN). This procedure is currently being carried out in a limited number of centers in Germany, also with the aim of offering a high level of expertise through sufficient experience; however, a growing number of patients who are treated with BAT experience problems that treating physicians are confronted with in routine medical practice. In order to address these problems, a consensus conference was held with experts in the field of trHTN in November 2016, which summarizes the current evidence and experience as well as the problem areas in handling BAT patients.

[Sympathetic nerve activity in chronic renal failure - what are the therapeutic options?]. / Sympathikusaktivität bei Niereninsuffizienz - Therapieoptionen.

Patients with chronic renal failure are characterized by a tonic elevation of sympathetic tone. This factor largely contributes to their increased cardiovascular risk. The increased sympathetic drive is caused by activiation of renal afferent fibers in the diseased kidneys. Therapeutic options for hypertensive patients with chronic renal failure with respect to their sympathetic overactivity are inhibitors of the renin-angiotensin-system and central sympatholytic drugs. The role of catheter-based renal denervation in these patients is currently under investigation.

[Expert consensus statement on interventional renal sympathetic denervation for hypertension treatment]. / Interventionelle renale Sympathikusdenervation zur Behandlung der therapieresistenten Hypertonie.

This commentary summarizes the expert consensus and recommendations of the working group 'Herz und Niere' of the German Society of Cardiology (DGK), the German Society of Nephrology (DGfN) and the German Hypertension League (DHL) on renal denervation for antihypertensive treatment. Renal denervation is a new, interventional approach to selectively denervate renal afferent and efferent sympathetic fibers. Renal denervation has been demonstrated to reduce office systolic and diastolic blood pressure in patients with resistant hypertension, defined as systolic office blood pressure ≥ 160 mm Hg and ≥ 150 mm Hg in patients with diabetes type 2, which should currently be used as blood pressure thresholds for undergoing the procedure. Exclusion of secondary hypertension causes and optimized antihypertensive drug treatment is mandatory in every patient with resistant hypertension. In order to exclude pseudoresistance, 24-hour blood pressure measurements should be performed. Preserved renal function was an inclusion criterion in the Symplicity studies, therefore, renal denervation should be only considered in patients with a glomerular filtration rate > 45 ml/min. Adequate centre qualification in both, treatment of hypertension and interventional expertise are essential to ensure correct patient selection and procedural safety. Long-term follow-up after renal denervation and participation in the German Renal Denervation (GREAT) Registry are recommended to assess safety and efficacy after renal denervation over time.

[The kidneys and hypertension]. / Nieren und Hochdruck.

In patients with severe hypertension a search for a renal cause, particularly for a renal artery stenosis, needs to be undertaken with 24-hour blood pressure measurement, urinary examination, determination of renal function and duplex sonography of the kidneys.--Sympathetic hyperactivity, which is associated with an increased cardiovascular risk, may already be found in an early stage of renal diseases. There is evidence that administration of an ACE inhibitor or an angiotensin receptor antagonist (ARB) may induce a decrease of sympathetic hyperactivity as well as a reduced rate of adverse cardiovascular events in patients in renal failure.--In patients with renal disease and high proteinuria antihypertensive therapy with ACE-inhibitors or ARB delays the progression of chronic renal failure. Combined therapy of ACE-inhibitors plus ARB may reduce proteinuria more than that would be the case with either of these drugs alone. However, there is no evidence that combination of these two drugs improves renal function more than monotherapy.--Renal artery stenosis of > 70% should be treated by dilatation, if there is evidence of fibromuscular dysplasia. Dilatation and/or stent implantation in an atherosclerotic renal artery stenosis of > 70% should be performed if indicated by the patient's clinical state. i.e. severe hypertension has proved to be resistant to triple drug antihypertensive therapy or pulmonary edema has occurred frequently. Preservation of renal function by angioplasty of an atherosclerotic renal artery stenosis remains a challenge. However, exact criteria for such intervention need to be established. But so far there have not been adequate data from controlled prospective trials.

Increased inorganic phosphate induces human endothelial cell apoptosis in vitro.

Chronic kidney disease with hyperphosphatemia is associated with accelerated atherosclerosis and endothelial dysfunction. However, the contribution of high serum phosphate levels to endothelial injury is incompletely understood. The aim of this work was to evaluate the responses of endothelial cells to elevated levels of extracellular phosphate in vitro. High phosphate in concentrations similar to those observed in uremia-associated hyperphosphatemia (>2.5 mM) induced apoptosis in two endothelial cell lines (EAhy926 cells and GM-7373 cells). This effect was enhanced when cells were incubated for 24 h in the presence of 2.8 mM calcium instead of 1.8 mM. By treating cells with 0.5 or 1.0 mM phosphonoformic acid, an inhibitor of the phosphate transporter, death was completely prevented. The process of phosphate-induced apoptosis was further characterized by increased oxidative stress, as detected by increased ROS generation and disruption of the mitochondrial membrane potential at approximately 2 h after treatment, followed by caspase activation. These findings show that hyperphosphatemia causes endothelial cell apoptosis, a process that impairs endothelial integrity. Endothelial cell injury induced by high phosphate concentrations may be an initial event leading to vascular complications in patients with chronic kidney disease.

Increased arterial vascular tone during the night in patients with essential hypertension.

The time-dependent incidence of cardiovascular events points to an important role of chronobiology for arterial properties. To evaluate arterial properties in patients with essential hypertension, we assessed arterial vascular tone during sleep at night in patients with essential hypertension and normotensive control subjects. Vascular tone was continuously quantified by the reflective index obtained by non-invasive digital photoplethysmography and an algorithm for continuous, investigator-independent, automatic analysis of digital volume pulse. During the first half of the night, the reflective index was significantly higher in 31 patients with essential hypertension compared to 30 normotensive control subjects (30.0+/-0.2 vs 28.8+/-0.2; P=0.001). In patients with essential hypertension, the reflective index significantly increased from 30.0+/-0.2 in the first half (from 2301 to 0230) to 30.7+/-0.2 in the second half (from 0231 to 0600) of the night (n=31; P=0.027). In normotensive control subjects the reflective index also significantly increased from 28.8+/-0.2 in the first half of the night to 30.2+/-0.2 in the second half of the night (n=30; P=0.001). An increase of the reflective index tone indicated systemic vasoconstriction as confirmed by cold pressure tests and a significant correlation between arterial vascular tone and sympathetic nerve activity measured by microneurography from the peroneal nerve. Photoplethysmographic determination of arterial vascular tone demonstrated a significant increase of systemic arterial vascular tone in patients with essential hypertension during the first half of the night compared to normotensive control subjects.

Aldosterone remodels human endothelium.

AIM: In response to aldosterone endothelial cells swell and stiffen. Although amiloride-sensitive sodium and water uptake is known to be involved, the underlying mechanisms are yet unclear. We tested the hypothesis whether the intracellular accumulation of water or organic matter is responsible for the structural and functional alterations. METHODS: Atomic force microscopy was used as an imaging tool and a mechanical nanosensor. Cell water, organic cell matter and cell pressure was measured at single cell level in human umbilical vein endothelial cells (HUVEC). Furthermore, we tested by means of a miniature perfusion chamber in vitro the physical robustness to blood flow of the aldosterone-treated endothelium. RESULTS: In response to a three-day treatment with 1 nM aldosterone HUVEC swell. To our surprise, cell water decreased from 82+/-6% to 71+/-5% while intracellular organic matter increased from 18+/-1.8% to 29+/-3.0%. These changes were paralleled by a rise in cell pressure of 114%, measured in living HUVEC in vitro. Blood flow across the endothelium was found significantly altered after aldosterone treatment. Imaging the endothelial monolayer after blood perfusion disclosed large gaps between cells treated with aldosterone. The mineralocorticoid receptor blockers, spironolactone and eplerenone could prevent the aldosterone actions. CONCLUSION: Mild aldosteronism causes intracellular accumulation of organic matter at the cost of cell water. This makes endothelium stiff and vulnerable to shear stress. The measurements could explain clinical observations that high blood pressure combined with high plasma aldosterone concentration may damage the endothelium of blood vessels.

17beta-estradiol increases volume, apical surface and elasticity of human endothelium mediated by Na+/H+ exchange.

OBJECTIVE: 17beta-estradiol is known to delay the onset of atherosclerosis in women but cellular mechanisms are still unclear. Estrogens bind to specific receptors and initiate a signaling cascade that involves the activation of plasma membrane Na(+)/H(+) exchange. We hypothesized that estrogens interfere with ion transport across the plasma membrane and thus control endothelial structure and function. Therefore, we investigated the effects of the sex steroids 17beta-estradiol, progesterone, and testosterone on volume, apical surface and elasticity in human endothelium. METHODS: The atomic force microscope was used as an imaging tool and as an elasticity sensor. We applied the antiestrogen tamoxifen, the Na(+)/H(+) exchange blocker cariporide and the epithelial Na(+)channel blocker amiloride to elucidate the role of transmembrane ion transport in hormone-treated human umbilical vein endothelial cells (HUVEC). RESULTS: Incubation with 17beta-estradiol for 72 h led to a dose-dependent increase of endothelial cell volume (41%), apical cell surface (22%), and cell elasticity (53%) as compared to non-17beta-estradiol treated controls. Block of the 17beta-estradiol receptor by tamoxifen and of plasma membrane Na(+)/H(+) exchange by cariporide prevented the hormone-induced changes. Progesterone and testosterone were ineffective. CONCLUSIONS: 17beta-estradiol increases HUVEC water content and HUVEC elasticity mediated by activated estrogen receptors. The estrogen response depends on the activation of plasma membrane Na(+)/H(+) exchange. The increase in endothelial cell elasticity could be one of the vasoprotective mechanisms postulated for 17beta-estradiol.

[Large artery wall properties -- what is relevant for the classic management of hypertension?]. / Gefässwandeigenschaften grosser Arterien -- was ist wichtig für das klassische Hypertoniemanagement?

Decisions about the management of patients with hypertension should not be based on the level of blood pressure alone but also on the presence of target organ damage. Apart of classical sites of target organ damage - kidney and heart - the assessment of functional and structural alterations of large arteries is of increasing clinical importance. Modern non-invasive procedures allow the assessment of large artery wall properties within the clinical routine. Hypertension associated large artery damage may present as structural and functional alterations. Structural alterations comprise intima-media thickening, plaque formation, stenosis of the artery and formation of aneurysms. Functional alterations comprise endothelial dysfunction and alterations of the mechanical properties of the arterial wall with increasing stiffness and loss of the Windkessel function. Loss of central artery elastic properties will ensue an early reflection of the pulse wave with a resulting increase in central systolic and central diastolic pressure. This causes an increase in left ventricular afterload and a reduction in diastolic perfusion of the myocardium. In the last decade the relevance of large artery structural alterations, endothelial dysfunction and arterial stiffness for the risk of cardiovascular morbidity and mortality in hypertensive patients could be demonstrated convincingly. Measurement of intima-media-thickness therefore is part of the standard evaluation of hypertensive patients. Because of the equal prognostic relevance of functional properties of the arterial wall, assessment of large artery functional alterations is helpful for the risk stratification of hypertensive patients. Modern antihypertensive drugs have favourable effects on arterial wall properties. Therefore, the quantification of large artery wall properties should be part of the management of hypertensive patients.

Arterial distensibility, intima media thickness and pulse wave velocity after renal transplantation and in dialysis normotensive patients.

AIM: Structural and mechanical properties of the arterial wall are altered in patients with renal failure. The ageing process of the arterial wall appears to be accelerated in patients with end-stage renal failure. The mechanisms responsible for reduced arterial compliance and distensibility in dialysis patients and renal transplant recipients without hypertension remain to be evaluated. METHODS: Thirty-five normotensive dialysis patients (D), 35 normotensive renal transplant recipients (T) and 35 healthy volunteers (N) matched for age, sex and blood pressure as controls were enrolled into the study. The arterial blood pressure of all patients was < 140/90 mmHg. The dialysis patients and renal transplant recipients were eligible for the study if the serum creatinine level was < 2 mg/dL. In all subjects, fasting concentrations of serum creatinine, total cholesterol, HDL-cholesterol, LDL-cholesterol and hemoglobin and glucose were determined at enrollment to the study. Blood pressure was measured using an automatic sphygmomanometer. Pulse wave velocity (PWV) was evaluated using non invasive automatic Complior device. The vessel wall properties of the left common carotid artery were studied using multigate pulsed Doppler system. With this method, the end-diastolic diameter (d) and the systolic increase of vessel diameter (distension DELTAd) were measured. From these data the relative systolic increase of vessel diameter (DELTAd/d) and the arterial wall distensibility coefficient (DC) were calculated. RESULTS: Systolic blood pressure (SBP) and central pulse pressure (CPP) were significantly higher in T than in D and N group, respectively 138 +/- 18 mmHg and 59 +/- 16 mmHg vs 128 +/- 13 mmHg and 49 +/- 12 mmHg and 132.12 mmHg and 51 +/- 10 mmHg. The d did not change significantly between all groups. The distension DELTAd was significantly lower in patients group D and T, respectively 466 +/- 38 microm and 511 +/- 37 microm than in controls. Similarly DELTAd/d was in these groups significantly lower than in healthy volunteers, respectively D 6.33 +/- 0.5%, T 6.9 +/- 0.4% vs N 9.15 +/- 0.5%. DC was also significantly lower in D and T than in N groups, respectively D 17.91 +/- 1.5 10-3/kPa and T 18.92 +/- 1.3 10-3/kPa and N 24.28 +/- 0.51-3/kPa. Significant differences were found in the increase of the intima-media thickness (IMT) of carotid artery for dialyzed patients and renal transplant recipients in contrast to the control group, but there were no differences between the patients. PWV in both patient groups was statistically significant higher than in control group correspondingly D 11.1 +/- 1.03 m/s and T 13.3 +/- 1.13 m/s, N 9.4 +/- 0.89 m/s. There was a significant correlation between the change of DC, PWV and CPP in T group (n = 35; r = -0.43; P < 0.01 and n = 35; r = 0.48; P < 0.05). In the T group also an important correlation between PWV and IMT complex (n = 35; r = 0.49, P < 0.001) was found. CONCLUSIONS: The elastic and structural properties of arterial wall in dialysis patients and renal recipients are decreased. End-stage renal disease accelerates arterial stiffening despite of arteriosclerosis and hypertension. Renal transplantation does not reverse loss of elastic and morphologic properties of arteries found in patients with end-stage renal insufficiency.

Early onset of a decreased intracellular magnesium and phosphate concentration in smooth muscle cell of SHR.

A decrease in total magnesium content is not a direct proof of a decreased magnesium ion concentration. It could reflect a phosphate alteration or an ATP metabolism disorder. Plasma phosphate levels are lower in spontaneously hypertensive rats (SHRs) than in Wistar-Kyoto rats (WKYs), and defects in membrane regulation or mitochondrial ATP synthase occur. Only sparse data exist concerning cellular magnesium and phosphate concentrations in hypertensive cells. In aortic smooth muscle cells from 10 SHRs of the Münster strain and 10 age-matched normotensive WKY rats, the intracellular phosphate and magnesium content was measured by electron probe X-ray microanalysis (Camscan CS 24 apparatus, Cambridge, U.K.). The Mg++ content was 0.09 +/- 0.15 g/kg dry weight in SHRs versus 1.15 +/- 0.10 g/kg dry weight in WKY rats (p < 0.01). Vascular smooth muscle phosphate content was 23.6 +/- 0.79 g/kg dry weight in WKY rats versus 15.81 +/- 1.22 g/kg dry weight in SHRs (p < 0.01). In aortic smooth muscle cells of one month old SHRs intracellular magnesium was measured as 1.05 +/- 0.08 versus 1.09 +/- 0.09 g/kg dry weight in WKYs. Intracellular phosphate concentration in one month old SHRs was 18.71 +/- 2.41 versus 21.36 +/- 1.25 g/kg dry weight in WKYs (eight animals in each group). Aortic smooth muscle cells of SHRs are caracterized by markedly lowered intracellular phosphate and magnesium concentrations, resulting in an altered ATP-metabolism, as described earlier. Possibly a membrane defect or a magnesium deficiency or disturbed magnesium channels are responsible for the early onset in the pathogenesis of primary hypertension.

Early-onset increased calcium and decreased magnesium concentrations and an increased calcium/magnesium ratio in SHR versus WKY.

Alterations in the metabolism of calcium and magnesium have been implicated in the pathogenesis of primary hypertension. Calcium influx across the external cellular membrane in smooth muscle cells and cardiomyocytes plays a crucial role in the control of cellular excitation contraction and impulse propagation. Intracellular calcium and magnesium concentrations are controlled by reversible binding to specific calcium binding proteins. The calcium and magnesium flux across the external membrane is regulated by a calcium pump (calcium-magnesium-ATPase), calcium channels and binding to the membrane. In cell membranes and in lymphocytes of essential hypertensives, our group showed increased calcium and decreased magnesium and an increased calcium/magnesium ratio in hypertensive cells. In this context, in aortic smooth muscle cells from 13 spontaneously hypertensive rats (SHR) of the Münster strain (systolic blood pressure 188.4+/-9.8 mmHg) and 13 normotensive rats (NT, systolic blood pressure 118.5+/-7.2 mmHg) aged 9 months, the intracellular calcium and magnesium contents were measured under nearly in vivo conditions by electron-probe microanalysis. Measurements were performed in aortic cryosections 3 microm thick. The calcium content was 124.7+/-4.5* mmol/kg dry weight in SHR versus 110.3+/-4.1 mmol/kg dry weight in NT (Means+/-SD, p < 0.01), the magnesium content was 35.5+/-3.9* in SHR versus 50.1+/-4.9 mmol/kg dry weight in NT /p < 0.01). The calcium/magnesium ratio was significantly increased in SHR versus NT (3.56+/-0.39* versus 2.23+/-0.27, p < 0.01). In hypertensive one month old animals the increase in the calcium/magnesium ratio was not as pronounced as in 9 month old animals. The calcium/magnesium ratio was measured 3.3+/-0.42 in SHR (n = 8) as compared to 2.51+/-0.39 in normotensive animals (n = 8, p < 0.01). Aortic smooth muscle cells from SHR are characterized by markedly elevated intracellular calcium and decreased intracellular magnesium contents compared with normotensive cells. The increased calcium/magnesium ratio in hypertensive cells may be a pathogenetic factor for the development of arteriosclerosis and hypertension.