Aims:To determine the effects of empagliflozin on blood pressure (BP) and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes mellitus (T2DM). Methods:We conducted a post hoc analysis of data from a phase III trial in patients with T2DM and hypertension receiving 12 weeks' empagliflozin and four phase III trials in patients with T2DM receiving 24 weeks' empagliflozin (cohort 1, n = 823; cohort 2, n = 2477). BP was measured using 24-h BP monitoring (cohort 1) or seated office measurements (cohort 2).Results: Empagliflozin reduced systolic BP (SBP) and diastolic BP in both cohorts (p < 0.001 vs placebo), without increasing heart rate. Empagliflozin reduced pulse pressure (PP; adjusted mean difference vs placebo cohort 1: −2.3 mmHg; cohort 2: −2.3 mmHg), mean arterial pressure (MAP; cohort 1, −2.3 mmHg; cohort 2, −2.1 mmHg) and double product (cohort 1, −385 mmHg × bpm; cohort 2, −369 mmHg × bpm) all p < 0.001 vs placebo. There was a trend towards a reduction in the ambulatory arterial stiffness index (AASI) with empagliflozin in cohort 1 (p = 0.059 vs placebo). AASI was not measured in cohort 2. Subgroup analyses showed that there were greater reductions in PP with increasing baseline SBP in cohort 1 (p = 0.092). In cohort 2, greater reductions in MAP were achieved in patients with higher baseline SBP (p = 0.027) and greater reductions in PP were observed in older patients (p = 0.011). Conclusions IntroductionCardiovascular (CV) disease is the major cause of morbidity and mortality in patients with type 2 diabetes (T2DM) [1]. The risk of CV disease in adults with diabetes is double that in adults without diabetes, and diabetes is estimated to account for 10-12% of all vascular deaths [2]. Patients with T2DM often have numerous CV risk factors and a multifactorial approach to addressing CV risk, including controlling glycaemia, blood pressure (BP) and body weight, is recommended in these patients [1,3].The metabolic abnormalities that are characteristic of diabetes, such as hyperglycaemia, excess free fatty acids and insulin resistance, can lead to suppression of nitric oxide production and activation of the renin-angiotensin system, leading to oxidative stress, endothelial dysfunction and activation of the receptor for advanced glycation end products (RAGE) [4][5][6]. These may contribute to hypertension [7] or to increased arterial stiffness related to vascular calcification or accumulation ofCorrespondence to: Odd Erik Johansen, Boehringer Ingelheim Norway KS, Asker, Norway. E-mail: odd_erik.johansen@boehringer-ingelheim.com This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.collagen [8,9] that could partly explain the increased risk of vascular complications associated with T2DM [4].Arterial stiffness is a strong predictor of CV events, heart failure and death [10][11][12]...

Neuroendocrine activity was studied in 60 consecutive untreated patients with dyspnoea and a clinical suspicion of heart failure. On the basis of the socalled Boston clinical criteria the diagnosis of heart failure was regarded as unlikely in 26 patients, possible in 15 patients, and definite in 19 patients. These groups were studied before any drug treatment was started and were compared with a control group of 69 healthy individuals. Plasma atrial natriuretic peptide concentration was clearly raised in patients with definite heart failure and slightly raised in patients with possible heart failure.Plasma adrenaline concentration was somewhat raised in patients with definite or possible heart failure, whereas plasma noradrenaline concentration was raised only in patients with definite heart failure. Plasma renin activity was not increased in any of the patient groups and plasma aldosterone concentration was slightly increased only in patients with definite heart failure. In the total patient series there were significant correlations between plasma atrial natriuretic peptide concentration and markers of the severity of left ventricular dysfunction.There was some evidence of neuroendocrine activation in untreated heart failure: plasma concentrations of atrial natriuretic peptide and catecholamines were increased but the renin-angiotensinaldosterone system showed little or no activation. Most studies of the hormonal changes in heart failure have included patients treated with diuretics; there is little information on the activation of the neuroendocrine system in untreated heart failure,9-2 especially on concentrations of atrial natriuretic peptide. We studied neuroendocrine activation in patients in whom the diagnosis of heart failure was suspected for the first time and in whom treatment for the condition had not been started. We used the Boston diagnostic criteria"3 to confirm the clinical diagnosis of heart failure. Patients and methods PATIENTSWe studied 88 patients (37 men and 51 women) with a clinical suspicion of previously unrecognised heart failure and 82 controls (36 men and 46 women), all aged 45-74 years.Patients were identified by 32 primary health care physicians working in community health centres in a defined area in eastern Finland. These physicians had agreed to refer to the university clinic all patients who had presented with symptoms or signs suggestive of heart failure and in whom this condition had not been previously diagnosed. Patients with acute pulmonary oedema complicating myocardial infarction were not included. Those 24 patients who had severe symptoms were referred immediately and studied on the day of referral, whereas the remaining 64 patients with milder symptoms were examined within two weeks of their visit to the primary health care centre. A detailed description of the patient series has been published elsewhere.'4

Background: The Covid-19 pandemic caused a shutdown of healthcare systems in many countries. We explored the impact on hypertension care in the Excellence Center (EC) network of the European Society of Hypertension.Methods: We conducted a 17-question electronic survey among ECs.Results: Overall, 52 ECs from 20 European and three non-European countries participated, providing hypertension service for a median of 1500 hypertensive patients per center per year. Eighty-five percent of the ECs reported a shutdown lasting for 9 weeks (range 0-16). The number of patients treated per week decreased by 90%: from a median of 50 (range 10-400) before the pandemic to a median of 5.0 (range 0-150) during the pandemic (P < 0.0001). 60% of patients (range 0-100%) declared limited access to medical consultations. The majority of ECs (57%) could not provide 24-h ambulatory BP monitoring, whereas a median of 63% (range 0-100%) of the patients were regularly performing home BP monitoring. In the majority (75%) of the ECs, hypertension service returned to normal after the first wave of the pandemic. In 66% of the ECs, the physicians received many questions regarding the use of renin-angiotensin system (RAS) blockers. Stopping RAS-blocker therapy (in a few patients) either by patients or physicians was reported in 27 and 36.5% of the ECs. Conclusion:Patient care in hypertension ECs was compromised during the Covid-19-related shutdown. These data highlight the necessity to develop new strategies for hypertension care including virtual clinics to maintain services during challenging times.

We describe a new principle for the determination of enzymes, here applied to angiotensin-converting enzyme (ACE, EC 3.4.15.1) in human serum. The enzyme inhibitor binding assay is based on specific binding of labeled inhibitor to the active center of the enzyme. Serum (10-15 microL) is incubated with 125I-labeled ACE inhibitor (" 351A ," a p- hydroxybenzamidine derivative of N-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline) at pH 7.0 at 37 degrees C for 2 h in a non-equilibrated system. Inhibitor bound to ACE is separated by adsorption to coated charcoal, the radioactivity remaining in the supernate is counted, and the ACE value is calculated from a standard curve. Sensitivity for ACE in serum is 200 U/L, corresponding to 5.0 ng of ACE purified from human lung. The coefficient of variation was 3.9% within assay, and 6.4% between assays for normal ACE activities. Correlation with a comparison spectrophotometric method (Am J Med 59: 363-372, 1975) for ACE assay was excellent (r = 0.98) in 59 samples from healthy subjects and from patients with various diseases including active sarcoidosis. The novel assay principle presented here is simple and specific, and can be extended to use with various biological fluids and tissues, and to other enzymes as well.

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Eleven patients on haemodialysis were treated with erythropoietin (EPO), 50-200 U kg-1 once to three times a week, for up to 1 year. After outset of EPO all patients became transfusion-independent. Four patients did not reach the target haemoglobin (Hb) level 100 g l-1 in 5 months. These patients had higher serum concentrations of aluminium (225 +/- 87 micrograms l-1, mean +/- SD) than the responding patients (55 +/- 56 micrograms l-1). Addition of desferrioxamine to treatment with EPO resulted in a rapid rise in Hb values in these patients. Thus, aluminium may inhibit EPO responsiveness. All patients were iron overloaded. Serum ferritin levels declined in all but one patient with secondary haemochromatosis. In exercise tests the aerobic capacity and oxygen uptake increased during EPO therapy. Peak oxygen consumption (Vo2 peak), oxygen pulse, oxygen uptake at anaerobic threshold (AT) and total work output (W max) increased 19%, 36%, 26% and 24%, respectively. Lean body mass (LBM) increased by 8%. Taken together, all clinical EPO effects measured appeared clinically favourable.

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We assessed the antihypertensive and hormonal effects of two new angiotensin converting enzyme (ACE) inhibitors. enalapril (MK-421) and lisinopril (MK-521) in 22 patients with renovascular hypertension. All patients had angiographically verified renal artery lesions, 3 had bilateral renal artery stenosis and one a stenosis in a single kidney, and the rest had unilateral renal artery stenosis. After placebo treatment for 3 days in hospital, increasing doses from 5 to 40 mg daily, of both ACE-inhibitors were given. Both drugs induced a significant fall in blood pressure (BP). Significant BP reductions were seen after 2 h with a maximum fall for the enalapril group at a dose of 40 mg 4 h after drug intake (mean supine BP decrease-31/24 mm Hg, standing-29/16 mmHg). The corresponding maximal BP reductions were for the lisinopril group at a dose of 40 mg o.d. at 6 h: mean supine BP fall-25/28 mmHg and standing-33/31 mm Hg. Both drugs significantly inhibited serum ACE to about 5 to 10% of initial values and with a duration for more than 24 h. Both drugs also caused a decrease in plasma All levels and also in plasma aldosterone concentrations. There were no toxic effects and no serious side effects. Careful monitoring of biochemical variables showed no significant changes. We conclude that both enalapril and lisinopril are effective and very Safe agents for the treatment of renovascular hypertension and with a long duration of action and with very good tolerance.