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Background/Introduction The win ratio is a new methodology which utilizes multiple hierarchical endpoints to evaluate clinical outcomes in trials. The win ratio may have added benefit in device therapy trials like renal denervation (RDN) where anti-hypertensive medication burden can influence blood pressure (BP) changes. Purpose In this analysis, we applied the win ratio to patients in the Global SYMPLICITY Registry (GSR) to quantify potential differences in RDN efficacy according to different comorbidities, specifically atrial fibrillation and obstructive sleep apnea. Methods All patients in GSR had an RDN procedure with the Symplicity Flex or Symplicity Spyral catheter. For the win ratio analysis, ambulatory systolic BP (ASBP) measurements, office systolic BP (OSBP) measurements and the number of prescribed anti-hypertensive medications at 6 months were included as hierarchical endpoints. Patients were divided into 1 of 2 groups: with or without atrial fibrillation (AF) at baseline. Each patient was compared with every other patient in the opposing group first according to ASBP to determine “win”, “lose” or “tie” with a threshold of 5 mmHg. Then, ties from the ASBP comparison underwent the comparison using OSBP with a threshold of 10 mmHg. Any tie for a pair comparing OSBP resulted in comparison of number of anti-hypertensive medications with a threshold of 1. Comparisons of ASBP and OSBP were adjusted for baseline SBPs by using residuals from a linear regression. The analysis was repeated for patients grouped according to history of obstructive sleep apnea (OSA) at baseline. Results In March 2020, 336 patients with AF at baseline and 2,394 patients with no AF were compared in GSR, resulting in 336 x 2394 = 804,384 pairwise comparisons for the win ratio analysis. A total of 285,709 “wins”, indicating greater ASBP reduction, OSBP reduction, and/or fewer number of anti-hypertensive medications occurred in the AF group compared to the no AF group. Conversely, 256,511 “losses”, meaning greater BP reduction and/or number of medications occurred in the no AF group. The win ratio was thus calculated as 1.11 (95% CI: 0.98, 1.28, p=0.081) indicating similar BP reduction and medication burden after RDN in patients with or without AF in GSR (Figure). Using these methods, the win ratio for patients with and without OSA was calculated to be 0.98 (95% CI: 0.85, 1.13, p=0.81), also indicating similar RDN efficacy regardless of presence of OSA at baseline (Figure). Previously published results of the win ratio analysis of RDN and sham control patients in the SPRYAL HTN-ON MED trial reported a win ratio in favor of RDN of 2.78 (95% CI: 1.58, 5.48, p Conclusions Application of the win ratio methodology to patients in GSR demonstrated similar efficacy of RDN to patients regardless of whether they had comorbidities of atrial fibrillation or obstructive sleep apnea. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Medtronic

Background The principle of initial value (Wilder's law of initial value) proposes that the “direction of response of body function to any agent depends to a large degree on the initial value of that function”. Indeed, in several trials on renal denervation (RDN), pre-treatment blood pressure (BP) has been consistently and repeatedly found to predict the decrease in BP after RDN. Efforts to discover further statistically significant and clinically meaningful predictors of BP response to RDN failed. Objective By use of a new methodological approach, we aimed to determine predictors of BP response after RDN in patients with resistant hypertension. Methods The study population comprised 266 patients with resistant hypertension (mean age 62 years, 34% females, mean BMI 30.5 kg/m2, 27% had coronary heart disease, 42% had diabetes mellitus and 61% had hypercholesterolaemia) who underwent radiofrequency RDN with the Symplicity catheter at the Universities of Homburg and Erlangen. Clinical data including 24h ambulatory BP (ABP) were obtained prior to, and 3, 6 and 12 months after RDN. The primary parameter of response was defined as change in 24-hour systolic ABP after 6 months from pre-treatment values. As expected, change in 24h systolic ABP correlated with pre-treatment 24h systolic ABP (r2 linear = 0.225, p Results Neither pre-treatment 24h systolic or diastolic ABP, nor office systolic or diastolic BP differed between the two groups (all p>0.20). Following RDN, 24h systolic ABP decreased in the responders by −23.3±16 vs non-responders +1.4±11 mmHg at 6 month, and 24h systolic ABP values were also significantly lower in responders at 3 and 12 months (all p Conclusion In patients with resistant hypertension, lower HbA1c and office HR were identified as predictors of BP response in addition to pre-treatment BP. This finding may help to identify hypertensive patients who benefit most from RDN. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Extramural grant provided vy Medtronic INc

Background and purpose The optimal choice of antidiabetic medication in patients that need combined therapy is under debate. The aim of this study was to analyze whether beyond glucose control the combination of empagliflozin (E) and linagliptin (L) improves blood pressure (BP) and vascular function in patients with type 2 diabetes (T2DM) as opposed to the combination of metformin (M) and insulin glargine (I). Methods This was a prospective, randomized, controlled, single center study including 101 patients with T2DM, who were randomized 1:1 to E 10–25mg combined with L 5mg once daily or M 850 or 1000mg twice daily combined with I once daily. All patients underwent BP measurement and vascular function analysis by validated systems at baseline and after 12 weeks of treatment. Results In comparison to baseline, office, 24-hour ambulatory BP as well as central blood and pulse pressure (PP) values decreased significantly after 12 weeks of treatment with E+L, whereas there was no change in the M+I group (see table). Twenty-four-hour peripheral systolic (mean difference: −5.2±1.5mmHg, p=0.004) and diastolic BP (−1.9±1.0mmHg, p=0.036), central clinical systolic BP (−5.56±1.9mmHg, p=0.009), forward pressure pulse height (−2.0±0.9mmHg, p=0.028), 24-h central systolic BP (−3.6±1.4mmHg, p=0.045) and 24-h pulse wave velocity (−0.14±0.05m/s, p=0.043) were reduced to a greater extent in the E+L than in the M+I group. Empagliflozin+Linagliptin Metformin+Insulin Baseline 12 weeks p value Baseline 12 weeks p value Peripheral ambulatory BP values 24-h SBP [mmHg] 131.0±10.9 127.0±8.8 Conclusion The combination of E+L significantly improves BP and vascular function in contrast to the combination of M+I. Acknowledgement/Funding This IIS was supported by a research grant from Boehringer Ingelheim International GmBH

Background Lowering blood pressure (BP) reduces clinical events. Renal denervation (RDN) is under investigation for treatment of uncontrolled hypertension and might represent a particularly attractive option for patients with high cardiovascular (CV) risk. To evaluate this proposal, it is important to determine whether baseline CV risk impacts the efficacy of RDN in lowering BP. Purpose We evaluated whether BP changes after RDN were dependent on baseline CV risk. Methods AHA/ACC Atherosclerosis CV Disease (ASCVD) risk score was calculated for patients in the Global Symplicity Registry (GSR; NCT01534299), a global registry of RDN in patients with uncontrolled hypertension, using baseline office systolic BP, total/HDL cholesterol measurements, diabetic and smoking status, gender, age, and number of baseline anti-hypertensive medications. Patients were separated into 3 groups based on ASCVD risk scores: Results Individual ASCVD risk scores were calculated for 1,434 patients in GSR. The median ASCVD risk score was 19.4% and 403 patients had a risk score of Adverse events at 3 years ASCVD risk score Conclusions BP changes after RDN were similar for patients with varying baseline ASCVD risk scores, suggesting uniform BP-lowering efficacy of RDN regardless of patients' baseline CV risk. The impact of baseline risk on clinical event reduction by RDN-induced BP reduction will need to be evaluated in further studies. Acknowledgement/Funding The Global SYMPLICITY Registry is funded by Medtronic.

Background Studies describe a linkage between greater sodium intake and higher incidence of organ damage and cardiovascular end points. Sodium intake is usually assessed by measuring 24-hour urinary sodium excretion, which is prone to high fluctuation. For the assessment of tissue sodium a new technique (23Na-MRI) has been developed. We analyzed whether tissue sodium is linked to vascular remodeling of small resistance vessels in patients with type-2 diabetes. Methods In patients with type 2 diabetes we assessed tissue sodium content and vascular structural parameters of the retinal arterioles, since structural changes of resistance vessels (150–300 μm) can be non-invasively and reliably assessed in the retinal circulation by Scanning Laser Doppler Flowmetry (SLDF). Patients with antidiabetic medication were off the therapy (antihypertensives were kept constant) for 4 weeks. The structural parameters of retinal arterioles assessed were outer- and inner diameter (OD & ID), wall thickness (WT), wall-to-lumen ratio (WLR) and wall cross sectional area (WCSA). Tissue sodium content was assessed non-invasively with a 3.0 T clinical MRI system in each patient. Subject placed their lower legs in the center of a 23Na knee coil and sodium content in skin and muscle (musculus triceps surae) were measured. Results In patients with type 2 diabetes (N=52) we observed a significant correlation between tissue sodium content (muscle and skin) and OD, WT and WCSA and a trend has been noticed between muscle sodium content and ID and WLR. Multiple linear regression analysis demonstrated that tissue sodium content is a significant determinant of hypertrophic vascular remodeling as indicated by increased WT and WCSA, independent of age, gender and 24-hour ambulatory diastolic blood pressure. Correlation coefficients Muscle sodium content (mmol/l) Skin sodium content (mmol/l) OD (μmol) r=0.402, p=0.003 r=0.299, p=0.033 ID (μmol) r=0.265, p=0.058 r=0.202, p=0.154 WT (μm) r=0.402, p=0.003 r=0.313, p=0.026 WLR r=0.247, p=0.078 r=0.171, p=0.230 WCSA (μm2) r=0.417, p=0.002 r=0.322, p=0.021 Conclusion With the novel 23Na-MRI technology, we could demonstrate that high tissue sodium concentration is linked to with hypertrophic vascular remodeling of retinal arterioles. Thus, the reduction of tissue sodium content may emerge as a therapeutic target.

Objective:Detailed analysis of retinal capillary flow (RCF) and vascular parameters in the retinal circulation allows us to differentiate between eutrophic and hypertrophic remodeling. In previous studies, we found that hypertensive patients with type 2 diabetes mellitus (T2DM) mostly suffer from hy

Objective:Results from the prospective, randomized, sham-controlled SPYRAL HTN-ON MED trial to assess blood pressure (BP) reduction post-renal denervation (RDN) have been previously published. We wished to examine the impact of RDN on individual patterns of BP during the critical “morning surge” per

Objective:The aim of the study was to test the hypothesis if arterial stiffness is linked to reduction of retinal capillary blood flow and development of retinal microvascular remodelling.Design and method:The study group comprised of 88 patients with essential hypertension (n = 88, 54.3 ± 8.3 years

Objective:Flow-mediated vasodilation (FMD) has become one of the most widely assessed parameter to analyze endothelial function. However, some techniques used to measure FMD have limitations. Recently, finger plethysmography (EndoPAT) failed to show any kind of reproducibility. A semi-automatic devi

Objective:The Global Symplicity Registry (GSR) is a prospective clinical study to evaluate the long-term safety and efficacy of renal denervation. In order to better characterize the safety and efficacy profile of renal denervation, post-hoc analyses of several subgroups within GSR were conducted.De

Objective:Retinal microvascular structural abnormalities mirror cerebrovascular structural changes and are related to an increased risk of cerebrovascular morbidity. Endothelial dysfunction is described as a key pathological condition associated with established cardiovascular disease. Endothelial d

Objective:The aim of the study was to establish the relationship between structural and functional abnormalities of retinal microcirculation and cardiac damage defined as the presence of left ventricle hypertrophy and/or diastolic dysfunction.Design and method:The study consisted of 88 patients with

Objective:Activity of the sympathetic nervous system (SNS) is increased in hypertensive patients with chronic kidney disease (CKD). In this updated version, we tested the hypothesis whether hypertensive patients with CKD enrolled in the Global Symplicity Registry (GSR) showed different responses in

Objective:Epidemiological evidence suggests a link between noise exposure and increased incidence of arterial hypertension and cardiovascular disease. The kidney as long-term regulator of blood pressure might play a role in the underlying pathophysiological mechanism. The aim of this study is to inv

Objective:The tetrahydrobiopterin-analogue VAS203, an in vivo inhibitor of predominantly the inducible nitric oxide synthase (iNOS), was developed to reduce secondary damage in patients with severe traumatic brain injury. However, its effect on micro- and macrocirculation is less well established. T

Objective:Spectral-domain optical coherence tomography (SD-OCT) of the eye has become a valuable high-resolution imaging technique for the evaluation of retinal layer volumes in a variety of diseases such as glaucoma and age-related macular degeneration, but also neurodegenerative diseases such as m

In der Diagnostik der Hypertonie ist die ambulante 24-h-Blutdruckmessung unverzichtbar. Sie ist eng mit hypertensiven Endorganschaden assoziiert. Dies gilt auch fur die Herzfrequenz, deren prognostische Wertigkeit unter Behandlung nachgewiesen wurde. Kombinationstherapien, auch deren fruher Einsatz, haben eine klare Uberlegenheit gegenuber einer Dosisverdopplung bei Monotherapie bewiesen, sowohl bezuglich der Blutdrucksenkung, der Compliance als auch der Kardioprotektion. Die therapieresistente arterielle Hypertonie geht mit einer sehr hohen kardiovaskularen Komplikationsrate einher. Die Basistherapie, bestehend aus einem Angiotensinkonversionsenzym(ACE)-Hemmer oder Angiotensinrezeptorblocker, Kalziumantagonisten und Diuretikum, wird bei kardialer Komorbiditat durch einen β-Rezeptoren-Blocker erganzt. Weitergehende pharmakologische Therapieprinzipien mussen sich zunehmend mit der renalen Denervierung messen. Fur beide Strategien gilt: Harte Endpunktstudien fehlen, und deren Sicherheit und Vertraglichkeit sind sorgfaltig zu uberwachen. Interessant ist, dass die Antidiabetika wie Exenatid und „Sodium-glucose-cotransporter-2“(SGLT-2)-Inhibitoren eine Blutdrucksenkung als additiven Effekt zur antidiabetogenen Wirkung aufweisen.

Der SCORE wird von der Europaischen Gesellschaft fur Kardiologie zur Berechnung des Mortalitatsrisikos uber einen Zeitraum von 10 Jahren bei asymptomatischen Erwachsenen empfohlen. Er berucksichtigt die Risikofaktoren Alter, Geschlecht, systolischer Blutdruck, Cholesterin und Rauchen. Das so bestimmte Risiko ist aber nicht immer hinreichend prazise und wird durch die Berucksichtigung renaler Variablen prognostisch erheblich aufgewertet. Im diesem Kontext von besonderer Bedeutung ist sowohl die errechnete glomerulare Filtrationsrate als auch die Albuminausscheidung im Urin. Fur beide Parameter lasst sich eine Steigerung in der Abschatzung des Risikos unabhangig von der eigentlichen SCORE-Klassifizierung belegen. Sie fuhrt oberhalb eines Risikos von 1% zu einer Zuordnung der Patienten zur nachsthoheren Risikostufe im SCORE.

Die Ergebnisse neuer Studien haben eine Uberarbeitung der Leitlinien der Europaischen Gesellschaften fur Hypertonie und Kardiologie (ESH/ESC) fur die Behandlung der arteriellen Hypertonie notwendig gemacht. In den Leitlinien 2007 wird die Relevanz des gesamten kardiovaskularen Risikos betont, und die Einteilung der Hypertonie erfolgt jetzt anhand einer anderen Graduierung (Stadien 1–3 an Stelle von „mild“ oder „masig“). Hinsichtlich der Endorganschaden werden die Testung auf Mikroalbuminurie und die Messung der Nierenfunktion hervorgehoben. Das metabolische Syndrom wird als Risikofaktor dem Diabetes mellitus gleichgestellt und spielt eine grosere Rolle bei der Auswahl der Antihypertensiva, da durch ACE-Hemmer und Angiotensinrezeptor-Antagonisten das Risiko fur die Entwicklung eines Diabetes mellitus gunstig beeinflusst werden kann. Eine neue Indikation fur diese Substanzen ist die Pravention des Vorhofflimmerns. Insgesamt wird der Stellenwert einer initialen Kombinationstherapie betont, insbesondere bei hohem kardiovaskularem Gesamtrisiko und niedrigem Zielblutdruck.

Stimulation of renal sympathetic nerves causes reduced renal blood flow. To elucidate whether renal denervation (RDN) affects renal perfusion, we analysed renal blood flow of parenchymal areas perfused by arteries that were non-treated versus treated with RDN. In a pilot study 8 patients with treatment-resistant hypertension that had multiple renal arteries in either kidney were included. All patients underwent catheter-based RDN using the Symplicity FlexTM RDN System of the main renal arteries, but not of accessory renal arteries. Renal perfusion was measured noninvasively by magnetic resonance imaging on a 1.5-T scanner with arterial spin labelling before (day-1), after (day + 1) and again after 3 months (3 M) of RDN. Renal parenchyma was divided into areas that were perfused by renal arteries which were treated with RDN versus those areas perfused by accessory renal arteries not treated with RDN. Hence, every patient could serve at its own control with respect to changes of renal blood flow in the same kidney. In addition renal function was assessed by eGFR according CKD-Epi formula. There was an acute increase of renal perfusion in areas supplied by arteries not undergoing RDN (day-1: 242.3 [229.2-263.2] vs. day + 1: 260.0 [243.5-296.6] ml/min/100 g, p = 0.008), which returned to baseline values after 3 M (257.0 [240.5-277.8] ml/min/100 g, p = 0.260). In contrast, renal perfusion did not change in areas supplied by arteries undergoing RDN in acute (day-1: 263.5 [245.9-273.6] vs. day + 1: 256.5 [242.9-273.5] ml/min/100 g, p = 0.953) and 3 M (245.4 [235.5-269.7] ml/min/100 g, p = 0.594). Accordingly, the acute change in renal perfusion between day-1 and day + 1 was significantly greater in parenchymal areas supplied by arteries without compared to areas with RDN (p = 0.014), but not after 3 M. Renal function assessed by eGFR did not change between day-1 and day + 1 (80.3 ± 20 versus 79.8 ± 20 ml/min/1.73m, p = 0.885) as well as after 3 M of RDN (80.8 ± 18 ml/min/1.73m, p = 0.889). Despite an average of 7.0 ± 1.5 antihypertensive drugs, baseline office BP was 157/85mmHg, and was reduced by -11/-7mmHg after 3 M of RDN. Our data indicate an acute increase of renal perfusion in renal parenchymal areas perfused by arteries with intact renal nerves, whereas no change occurred in parenchymal areas perfused by arteries after RDN.