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Atherosclerotic renovascular disease (ARVD) is the most common type of renal artery stenosis. It represents a common health clinical problem with clinical presentations relevant to many medical specialties and carries high risk for future cardiovascular and renal events, as well as overall mortality. The available evidence regarding the management of ARVD is conflicting. Randomized controlled trials failed to demonstrate superiority of percutaneous transluminal renal artery angioplasty (PTRA) with or without stenting in addition to standard medical therapy compared with medical therapy alone in lowering blood pressure levels or preventing adverse renal and cardiovascular outcomes in patients with ARVD, but they carried several limitations and met important criticism. Observational studies showed that PTRA is associated with future cardiorenal benefits in patients presenting with high-risk ARVD phenotypes (i.e. flash pulmonary oedema, resistant hypertension, or rapid loss of kidney function). This clinical practice document prepared by experts from the European Renal Best Practice (ERBP) board of the European Renal Association (ERA) and from the Working Group on Hypertension and the Kidney of the European Society of Hypertension (ESH) summarizes current knowledge in epidemiology, pathophysiology and diagnostic assessment of ARVD and presents, following a systematic literature review, key evidence relevant to treatment, with an aim to support clinicians in decision-making and everyday management of patients with this condition.

Background: Accurate blood pressure (BP) measurement is critical for optimal cardiovascular risk management. Age-related trajectories for cuff-measured BP accelerate faster in women compared with men, but whether cuff BP represents the intraarterial (invasive) aortic BP is unknown. This study aimed to determine the sex differences between cuff BP, invasive aortic BP, and the difference between the 2 measurements. Methods: Upper-arm cuff BP and invasive aortic BP were measured during coronary angiography in 1615 subjects from the Invasive Blood Pressure Consortium Database. This analysis comprised 22 different cuff BP devices from 28 studies. Results: Subjects were 64±11 years (range 40–89) and 32% women. For the same cuff systolic BP (SBP), invasive aortic SBP was 4.4 mm Hg higher in women compared with men. Cuff and invasive aortic SBP were higher in women compared with men, but the sex difference was more pronounced from invasive aortic SBP, was the lowest in younger ages, and the highest in older ages. Cuff diastolic blood pressure overestimated invasive diastolic blood pressure in both sexes. For cuff and invasive diastolic blood pressure separately, there were sex*age interactions in which diastolic blood pressure was higher in younger men and lower in older men, compared with women. Cuff pulse pressure underestimated invasive aortic pulse pressure in excess of 10 mm Hg for both sexes in older age. Conclusions: For the same cuff SBP, invasive aortic SBP was higher in women compared with men. How this translates to cardiovascular risk prediction needs to be determined, but women may be at higher BP-related risk than estimated by cuff measurements.

Background: Statin therapy is effective for the prevention of atherosclerotic cardiovascular disease and is widely prescribed, but there are persisting concerns that statin therapy might frequently cause muscle pain or weakness. We aimed to address these through an individual participant data meta-analysis of all recorded adverse muscle events in large, long-term, randomised, double-blind trials of statin therapy. Methods: Randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years, and involved a double-blind comparison of statin versus placebo or of a more intensive versus a less intensive statin regimen. We analysed individual participant data from 19 double-blind trials of statin versus placebo (n=123 940) and four double-blind trials of a more intensive versus a less intensive statin regimen (n=30 724). Standard inverse-variance-weighted meta-analyses of the effects on muscle outcomes were conducted according to a prespecified protocol. Findings: Among 19 placebo-controlled trials (mean age 63 years [SD 8], with 34 533 [27·9%] women, 59 610 [48·1%] participants with previous vascular disease, and 22 925 [18·5%] participants with diabetes), during a weighted average median follow-up of 4·3 years, 16 835 (27·1%) allocated statin versus 16 446 (26·6%) allocated placebo reported muscle pain or weakness (rate ratio [RR] 1·03; 95% CI 1·01–1·06). During year 1, statin therapy produced a 7% relative increase in muscle pain or weakness (1·07; 1·04–1·10), corresponding to an absolute excess rate of 11 (6–16) events per 1000 person-years, which indicates that only one in 15 ([1·07–1·00]/1·07) of these muscle-related reports by participants allocated to statin therapy were actually due to the statin. After year 1, there was no significant excess in first reports of muscle pain or weakness (0·99; 0·96–1·02). For all years combined, more intensive statin regimens (ie, 40–80 mg atorvastatin or 20–40 mg rosuvastatin once per day) yielded a higher RR than less intensive or moderate-intensity regimens (1·08 [1·04–1·13] vs 1·03 [1·00–1·05]) compared with placebo, and a small excess was present (1·05 [0·99–1·12]) for more intensive regimens after year 1. There was no clear evidence that the RR differed for different statins, or in different clinical circumstances. Statin therapy yielded a small, clinically insignificant increase in median creatine kinase values of approximately 0·02 times the upper limit of normal. Interpretation: Statin therapy caused a small excess of mostly mild muscle pain. Most (>90%) of all reports of muscle symptoms by participants allocated statin therapy were not due to the statin. The small risks of muscle symptoms are much lower than the known cardiovascular benefits. There is a need to review the clinical management of muscle symptoms in patients taking a statin. Funding: British Heart Foundation, Medical Research Council, Australian National Health and Medical Research Council.

ZusammenfassungBasierend auf neuen Erkenntnissen und Leitlinien wird die orale Dreifachtherapie des Typ-2-Diabetes am Beispiel der Kombination aus Metformin, Empagliflozin und Linagliptin diskutiert. Der SGLT-2-Hemmstoff Empagliflozin verbessert im Vergleich zu Placebo den kombinierten Endpunkt aus kardiovaskulärem Tod oder nicht tödlichem Myokardinfarkt oder Schlaganfall (MACE-3) und reduziert die Wahrscheinlichkeit einer Klinikaufnahme wegen Herzinsuffizienz sowie die Gesamtsterblichkeit. Eine neu auftretende oder sich verschlechternde Nephropathie wird ebenfalls seltener beobachtet. Der DPP-4-Hemmstoff Linagliptin senkt Blutzucker und HbA1c und hat keine Wirkungen auf den kardiovaskulären Endpunkt MACE-3, während die Progression der Albuminurie im Vergleich zu Placebo vermindert wird. Im Vergleich zum Sulfonylharnstoff Glimepirid sind die kardiovaskulären Wirkungen ähnlich, Hypoglykämien aber deutlich seltener. Die Kombination des insulinotropen Linagliptin mit dem insulinunabhängigen Glukose ausscheidenden Wirkprinzip von Empagliflozin verbessert im Vergleich zu Placebo bei mit Metformin unzureichend behandelten Patienten die metabolische Situation. Bei solchen Patienten ist die Fixkombination aus Empagliflozin und Linagliptin die erste, bei der Langzeitwirkungen der Einzelkomponenten in drei kardiovaskulären Endpunktstudien bestätigt wurden.

Contains fulltext : 286841.pdf (Publisher’s version ) (Closed access) BACKGROUND: Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. METHODS: PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. FINDINGS: The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was -15·3 (SE 0·9) mm Hg for aprocitentan 12·5 mg, -15·2 (0·9) mm Hg for aprocitentan 25 mg, and -11·5 (0·9) mm Hg for placebo, for a difference versus placebo of -3·8 (1·3) mm Hg (97·5% CI -6·8 to -0·8, p=0·0042) and -3·7 (1·3) mm Hg (-6·7 to -0·8; p=0·0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was -4·2 mm Hg (95% CI -6·2 to -2·1) and -5·9 mm Hg (-7·9 to -3·8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 to 7·9, p

Since the current guidelines were published in 2018, a total of 5 sham-controlled high-quality studies evaluating renal denervation have been conducted and the results were published. These five studies clearly confirmed the efficacy and safety of renal denervation, which correspond to the knowledge of the Clinical Consensus Conference. Thus, an update of the guidelines for the treatment of arterial hypertension regarding the clinical significance of renal denervation is urgently necessary. For this reason, the position paper of the working group of the European Society of Hypertension on the current state of renal denervation was reviewed. An approval of this procedure can soon be expected. In Germany there is a diagnosis-related group (DRG) for the reimbursement of renal denervation, which was suspended due to the erroneous Symplicity 3 study. This DRG should be revived in practice by a structured process of the implementation of renal denervation. It will then be a joint task of treating physicians and specialists in certified centers to identify eligible patients. In the future, antihypertensive treatment will consist of three pillars: lifestyle measures, pharmacotherapy and interventional treatment. These three treatment options should not be regarded as competitive (which is better) but alternative (patient preference) and additive (the aim is blood pressure control). It is the task of the treating physician to provide the patient with the ideal treatment concept. Clearly, renal denervation will not replace antihypertensive pharmacotherapy; however, it can lead to a reduction of the drug burden and increase of patient adherence to medication. It represents an option of modern antihypertensive treatment and will also become increasingly more important in special patient groups.Seit der Veröffentlichung der aktuellen Leitlinien im Jahr 2018 wurden insgesamt 5 Sham-kontrollierte Studien mit hoher Qualität zur renalen Denervation durchgeführt und die Ergebnisse veröffentlicht. Diese 5 Studien belegen die Wirksamkeit und Sicherheit der renalen Denervation, die den Kenntnissen der Clinical Consensus Conference entsprechen, eindeutig. Somit ist eine Anpassung des Stellenwerts der renalen Denervation in der leitliniengerechten Blutdrucktherapie dringend erforderlich. Aus diesem Grund wurde das Positionspapier der Arbeitsgruppe der europäischen Bluthochdruckliga zum aktuellen Stand der renalen Denervation erarbeitet. Es kann mit einer zeitnahen Zulassung dieses Verfahrens gerechnet werden. In Deutschland gibt es eine DRG für die renale Denervation, die wegen der fehlerhaften Symplicity-3-Studie ausgesetzt wurde. Durch einen strukturierten Prozess der Einführung der renalen Denervation in die Praxis soll diese DRG wiederbelebt werden. Es wird dann gemeinsame Aufgabe der behandelnden Ärzte und der zertifizierten Zentren sein, hierfür geeignete Patienten zu identifizieren. Die Bluthochdrucktherapie wird auch in Zukunft aus den 3 Säulen Lifestyle-Maßnahmen, medikamentöse Therapie und interventionelle Therapie bestehen. Dies sollte nicht kompetitiv (Was ist besser?), sondern alternativ (Patientenpräferenz) und additiv (Blutdruckkontrolle ist das Ziel) betrachtet werden. Es ist Aufgabe der behandelten Ärzte, dem Patienten das ideale Therapiekonzept anzubieten. Die renale Denervation wird die medikamentöse Therapie dabei nicht ersetzen können, aber zur Reduktion der Medikamentenlast führen und die Adhärenz der Patienten erhöhen. Sie wird in der modernen Bluthochdrucktherapie auch bei speziellen Patientengruppen zunehmend an Bedeutung gewinnen.

ZusammenfassungDie Wirksamkeit der renalen Denervation zur Blutdrucksenkung war lange umstritten. Die anfängliche Euphorie nach einer Reihe vielversprechender unkontrollierter Pilotstudien wurde durch die Veröffentlichung der Symplicity-HTN-3-Studie 2014 zunächst getrübt. Hier hatte sich im Vergleich zur Scheinbehandlung keine signifikante Differenz in der Blutdruckreduktion gegenüber der renalen Denervation gezeigt. Die Ergebnisse dreier größerer randomisierter Studien dokumentieren nun den Wirkungsnachweis: Die interventionelle renale Denervation bewirkt eine signifikante Senkung des 24-Stunden- und Praxisblutdrucks im Vergleich zur Scheinbehandlung. Die aus diesen Studien gewonnenen Erkenntnisse bieten zukünftig spannende Perspektiven hinsichtlich der Anwendung des Verfahrens bei anderen Erkrankungen sowie hinsichtlich der Patienten, die am besten für die renale Denervation geeignet sind.

Background: Control of serum phosphate over the long term is essential in patients with end-stage renal disease. Six-month and 2-year extensions to a 6-month study evaluated the long-term safety, tolerability and efficacy of the new phosphate binder lanthanum carbonate. Methods: Patients who participated in a 6-month, randomized trial comparing lanthanum carbonate with calcium carbonate were eligible for a 24-week, open-label extension. Lanthanum carbonate-treated patients continued taking their established maintenance dose (‘continued-lanthanum group’) and calcium carbonate-treated patients switched to lanthanum carbonate, 375–3,000 mg/day (‘switch group’). Patients could also enter a further 2-year extension. Efficacy parameters, including serum phosphate, were monitored. Results: Mean serum phosphate was ∼1.80 mmol/l throughout the trial. The percentage of patients with controlled serum phosphate (≤1.80 mmol/l) after the 6-month extension was 63.3 and 58.4% in the continued-lanthanum and switch groups, respectively; after the 2-year extension, 54.4% of patients had controlled serum phosphate. After discontinuation of calcium carbonate and initiation of lanthanum carbonate, the hypercalcemia incidence was 2.7%, compared with 20.2% during the double-blind phase. Calcium × phosphate product was maintained at an acceptable level. Lanthanum carbonate was well tolerated; adverse events were mild/moderate and mainly gastrointestinal. Conclusions: Lanthanum carbonate maintains effectiveness with continued tolerability for up to 3 years.

Background Recent reports suggest that existing antihypertensive agents may not have sufficient efficacy to control blood pressure (BP) in many patients. Omapatrilat, an agent under development, has been shown to have significantly greater antihypertensive efficacy than existing agents, but may also carry increased risk of angioedema. We compared the efficacy and safety of omapatrilat to a representative angiotensin-converting enzyme (ACE) inhibitor, enalapril. Methods The Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial is a multicenter, randomized, double-blind, active-controlled, 24-week trial in 25,302 patients with untreated or uncontrolled hypertension conducted in 3298 office-based sites in 12 countries. Subjects were randomized to omapatrilat 10 mg or enalapril 5 mg as initial therapy for hypertension (group 1, n = 9292), replacement for existing antihypertensive therapy (group 2, n =11,224), or in addition to existing antihypertensive therapy (group 3, n = 4751). Study drug was force-titrated at week 2 and electively titrated at weeks 4 and 6 to a maximum of omapatrilat 80 mg or enalapril 40 mg once daily. At weeks 8 and 16, adjunctive antihypertensive medications were added electively to achieve target BP. Results Omapatrilat reduced systolic BP 3.6 mm Hg more than enalapril at week 8, and was associated with less use of adjunctive antihypertensive therapy by week 24 (19% v 27%; P < 0.001 for both comparisons). Subjects randomized to omapatrilat were more likely to reach BP target, regardless of demographics or comorbid conditions and whether omapatrilat was used as initial therapy, replacement for existing therapy, or in addition to existing therapy. Angioedema was more frequent with omapatrilat than enalapril (2.17% v 0.68%). Two omapatrilat-treated subjects experienced angioedema with airway compromise, which was successfully treated. Conclusions Omapatrilat provided broadly superior antihypertensive efficacy when used in a setting resembling clinical practice. Angioedema was more common than with enalapril but life-threatening angioedema was rare. The risk–benefit profile for omapatrilat in clinical use therefore appears likely to be favorable in appropriate patients.

Background: The family of aquaporin water channels contributes to water and salt homeostasis. AQP5 is an ubiquitously expressed exocrine-type water channel. Functional single nucleotide polymorphisms in AQP5 which alter gene transcription have not yet been described. We, therefore, sequenced the human AQP5 promoter to detect novel sequence variants which could impact upon AQP5 expression and contribute to the phenotypic variability of the renin-angiotensin-aldosterone system (RAAS). Method and Results : Sequencing of the whole AQP5 promoter revealed a novel -1364A/C polymorphism. Substitution of C for A was associated with increased transcription factor binding as tested by electrophoretic mobility shift assay, but significantly reduced transcriptional activation of the AQP5 gene by cAMP and serum. The C allele was associated with significantly decreased mRNA in human heart and with decreased protein expression in erythrocyte membranes. Finally, we investigated the phenotypic variability of the RAAS in two different independent study cohorts. First, we studied the phenotypic variability of the RAAS in 103 young (26 ± 3 years) healthy males under an increased salt diet. Increasing dietary salt intake decreased plasma angiotensin II by 25% in AC/CC genotypes but only by 2% in AA genotypes (p=0.012), and decreased serum aldosterone by 34% in subjects with AC/CC genotypes but only by 19% in the AA genotypes (p =0.005). Both genotypes had increased blood pressure under salt diet (p Conclusion: A novel single nucleotide polymorphism in the AQP5 gene promoter evokes an alteration of both AQP5 expression in different in vitro systems and cells, and the regulation of the Renin-Angiotensin-Aldosterone System.

The inhibition of the renin-angiotensin system is one of the most commonly utilized ways to lower blood pressure in patients with arterial hypertension. Up till now, angiotensin-converting enzyme inhibitors as well as angiotensin receptor blockers are the established inhibitors of this system, and both classes are used in clinical routine. There is a wealth of information about those classes, which are known not only to lower blood pressure, but also to prevent end-organ damage and, ultimately, reduce mortality in patients. Direct renin inhibition was already targeted 30 years ago to inhibit the renin-angiotensin system, but low bioavailability and short duration of action of the first generations of renin inhibitors withheld their clinical success. With the new generation of non-peptide orally available renin inhibitors, a third substance to inhibit the renin-angiotensin system is on the market, and the prototype of this class, aliskiren, has now been tested in various clinical trials in arterial hypertension. We review the studies of aliskiren and discuss its current role in the contemporary treatment of arterial hypertension as well as the possible new fields of action for aliskiren in treating heart failure and diabetic nephropathy.

Eigenwerte, Eigenvektoren, charakteristisches Polynom und charakteristische Gleichung, Eigenraum, Spur einer Matrix, ahnliche Matrizen, Eigenschaften und Anwendungen

Definition n-reihiger Determinanten, Eigenschaften und Bezeichnungen, Berechnung zwei- und dreireihiger Determinanten, Berechnung n-reihiger Determinanten nach dem Entwicklungssatz und nach dem Gauβschen Algorithmus, Anwendungen

Parameterintegrale mit variablen und uneigentlichen Grenzen, Differentiation von Parameterintegralen $$I = \{ x\left| {a \leqslant x \leqslant b\} ;B = \{ (x,y)} \right|x \in I,\varphi (x) \leqslant y \leqslant \psi )\} ;f(x,y)$$ stetig auf B