DOCUMENT REVIEWERS
Luis Alcocer (Mexico), Christina Antza (Greece), Mustafa Arici (Turkey), Eduardo Barbosa (Brazil), Adel Berbari (Lebanon), Luís Bronze (Portugal), John Chalmers (Australia), Tine De Backer (Belgium), Alejandro de la Sierra (Spain), Kyriakos Dimitriadis (Greece), Dorota Drozdz (Poland), Béatrice Duly-Bouhanick (France), Brent M. Egan (USA), Serap Erdine (Turkey), Claudio Ferri (Italy), Anthony Heagerty (UK), Slavomira Filipova (Slovak Republic), Michael Hecht Olsen (Denmark), Dagmara Hering (Poland), Uday Jadhav (India), Manolis Kallistratos (Greece), Kazuomi Kario (Japan), Vasilios Kotsis (Greece), Adi Leiba (Israel), Patricio López-Jaramillo (Colombia), Hans-Peter Marti (Norway), Terry McCormack (UK), Paolo Mulatero (Italy), Dike B. Ojji (Nigeria), Sungha Park (South Korea), Priit Pauklin (Estonia), Sabine Perl (Austria), Arman Postadzhian (Bulgaria), Aleksander Prejbisz (Poland), Venkata Ram (India), Ramiro Sanchez (Argentina), Markus Schlaich (Australia), Alta Schutte (Australia), Cristina Sierra (Spain), Sekib Sokolovic (Bosnia and Herzegovina), Jonas Spaak (Sweden), Dimitrios Terentes-Printzios (Greece), Bruno Trimarco (Italy), Thomas Unger (The Netherlands), Bert-Jan van den Born (The Netherlands), Anna Vachulova (Slovak Republic), Agostino Virdis (Italy), Jiguang Wang (China), Ulrich Wenzel (Germany), Paul Whelton (USA), Jiri Widimsky (Czech Republic), Jacek Wolf (Poland), Grégoire Wuerzner (Switzerland), Eugene Yang (USA), Yuqing Zhang (China).

2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension Endorsed by the European Renal Association (ERA) and the International Society of Hypertension (ISH).

Abstract Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays a prominent role in cardiovascular diseases. From the research history and milestone events related to hypoxia in cardiovascular development and diseases, The "hypoxia-inducible factors (HIFs) switch" can be observed from both temporal and spatial perspectives, encompassing the occurrence and progression of hypoxia (gradual decline in oxygen concentration), the acute and chronic manifestations of hypoxia, and the geographical characteristics of hypoxia (natural selection at high altitudes). Furthermore, hypoxia signaling pathways are associated with natural rhythms, such as diurnal and hibernation processes. In addition to innate factors and natural selection, it has been found that epigenetics, as a postnatal factor, profoundly influences the hypoxic response and progression within the cardiovascular system. Within this intricate process, interactions between different tissues and organs within the cardiovascular system and other systems in the context of hypoxia signaling pathways have been established. Thus, it is the time to summarize and to construct a multi-level regulatory framework of hypoxia signaling and mechanisms in cardiovascular diseases for developing more therapeutic targets and make reasonable advancements in clinical research, including FDA-approved drugs and ongoing clinical trials, to guide future clinical practice in the field of hypoxia signaling in cardiovascular diseases. 

Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets.

Hypertension is the leading modifiable cause of premature death and hence one of the global targets of World Health Organization for prevention. Hypertension also affects the great majority of patients with chronic kidney disease (CKD). Both hypertension and CKD are intrinsically related, as hypertension is a strong determinant of worse renal and cardiovascular outcomes and renal function decline aggravates hypertension. This bidirectional relationship is well documented by the high prevalence of hypertension across CKD stages and the dual benefits of effective antihypertensive treatments on renal and cardiovascular risk reduction. Achieving an optimal blood pressure (BP) target is mandatory and requires several pharmacological and lifestyle measures. However, it also requires a correct diagnosis based on reliable BP measurements (eg, 24-hour ambulatory BP monitoring, home BP), especially for populations like patients with CKD where reduced or reverse dipping patterns or masked and resistant hypertension are frequent and associated with a poor cardiovascular and renal prognosis. Even after achieving BP targets, which remain debated in CKD, the residual cardiovascular risk remains high. Current antihypertensive options have been enriched with novel agents that enable to lower the existing renal and cardiovascular risks, such as SGLT2 (sodium-glucose cotransporter-2) inhibitors and novel nonsteroidal mineralocorticoid receptor antagonists. Although their beneficial effects may be driven mostly from actions beyond BP control, recent evidence underline potential improvements on abnormal 24-hour BP phenotypes such as nondipping. Other promising novelties are still to come for the management of hypertension in CKD. In the present review, we shall discuss the existing evidence of hypertension as a cardiovascular risk factor in CKD, the importance of identifying hypertension phenotypes among patients with CKD, and the traditional and novel aspects of the management of hypertensives with CKD.

Hypertension as Cardiovascular Risk Factor in Chronic Kidney Disease

Background In patients with chronic kidney disease, SGLT2 inhibitors and endothelin A receptor antagonists (ERAs) can reduce albuminuria and glomerular filtration rate (GFR) decline. We assessed the albuminuria-lowering efficacy and safety of the ERA zibotentan combined with the SGLT2 inhibitor dapagliflozin. Methods ZENITH-CKD was a multicentre, randomised, double-blind, active-controlled clinical trial, done in 170 clinical practice sites in 18 countries. Adults (≥18 to ≤90 years) with an estimated GFR (eGFR) of 20 mL/min per 1·73 m2 or greater and a urinary albumin-to-creatinine ratio (UACR) of 150–5000 mg/g were randomly assigned (2:1:2) to 12 weeks of daily treatment with zibotentan 1·5 mg plus dapagliflozin 10 mg, zibotentan 0·25 mg plus dapagliflozin 10 mg, or dapagliflozin 10 mg plus placebo, as adjunct to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers if tolerated. The primary endpoint was a change from baseline in log-transformed UACR (zibotentan 1·5 mg plus dapagliflozin vs dapagliflozin plus placebo) at week 12. Fluid retention was an event of special interest, defined as an increase in bodyweight of at least 3% (at least 2·5% must have been from total body water) from baseline or an increase of at least 100% in B-type natriuretic peptide (BNP) and either a BNP concentration greater than 200 pg/mL if without atrial fibrillation or BNP greater than 400 pg/mL if with atrial fibrillation. This trial is registered with ClinicalTrials.gov, NCT04724837, and is completed. Findings Between April 28, 2021, and Jan 17, 2023, we assessed 1492 participants for eligibility. For the main analysis, we randomly assigned 449 (30%) participants, 447 (99%) of whom (mean age 62·8 years [SD 12·1], 138 [31%] female, 309 [69%] male, 305 [68%] White, mean eGFR 46·7 mL/min per 1·73 m2 [SD 22·4], and median UACR 565·5 mg/g [IQR 243·0–1212·6]) received treatment with zibotentan 1·5 mg plus dapagliflozin (n=179 [40%]), zibotentan 0·25 mg plus dapagliflozin (n=91 [20%]), or dapagliflozin plus placebo (n=177 [40%]). Zibotentan 1·5 mg plus dapagliflozin and zibotentan 0·25 mg plus dapagliflozin reduced UACR versus dapagliflozin plus placebo throughout the treatment period of the study. At week 12, the difference in UACR versus dapagliflozin plus placebo was –33·7% (90% CI –42·5 to –23·5; p<0·0001) for zibotentan 1·5 mg plus dapagliflozin and –27·0% (90% CI –38·4 to –13·6; p=0·0022) for zibotentan 0·25 mg plus dapagliflozin. Fluid-retention events were observed in 33 (18%) of 179 participants in the zibotentan 1·5 mg plus dapagliflozin group, eight (9%) of 91 in the zibotentan 0·25 mg plus dapagliflozin group, and 14 (8%) of 177 in the dapagliflozin plus placebo group. Interpretation Zibotentan combined with dapagliflozin reduced albuminuria with an acceptable tolerability and safety profile and is an option to reduce chronic kidney disease progression in patients already receiving currently recommended therapy. Funding AstraZeneca. 

Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): a multicentre, randomised, active-controlled, phase 2b, clinical trial

Endothelin (ET) is found to be increased in kidney disease secondary to hyperglycaemia, hypertension, acidosis, and the presence of insulin or proinflammatory cytokines. In this context, ET, via the endothelin receptor type A (ETA) activation, causes sustained vasoconstriction of the afferent arterioles that produces deleterious effects such as hyperfiltration, podocyte damage, proteinuria and, eventually, GFR decline. Therefore, endothelin receptor antagonists (ERAs) have been proposed as a therapeutic strategy to reduce proteinuria and slow the progression of kidney disease. Preclinical and clinical evidence has revealed that the administration of ERAs reduces kidney fibrosis, inflammation and proteinuria. Currently, the efficacy of many ERAs to treat kidney disease is being tested in randomized controlled trials; however, some of these, such as avosentan and atrasentan, were not commercialized due to the adverse events related to their use. Therefore, to take advantage of the protective properties of the ERAs, the use of ETA receptor-specific antagonists and/or combining them with sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been proposed to prevent oedemas, the main ERAs-related deleterious effect. The use of a dual angiotensin-II type 1/endothelin receptor blocker (sparsentan) is also being evaluated to treat kidney disease. Here, we reviewed the main ERAs developed and the preclinical and clinical evidence of their kidney-protective effects. Additionally, we provided an overview of new strategies that have been proposed to integrate ERAs in kidney disease treatment.

/pdf/endothelin-receptor-antagonists-in-kidney-disease-3ofquxyz.pdf

Endothelin Receptor Antagonists in Kidney Disease

24-hour ECG Holter monitoring - detection of asymptomatic stimulationdisturbances in patients with artificial pacemakers

Background: Acute myocardial infarction (AMI) is one of the main causes of death in the elderly, however, the optimal therapy of AMI in this age-group has not yet been established. Aim: To compare the early outcome of patients with AMI aged ≥75 years who underwent primary percutaneous coronary interventions (PCI) or were treated conservatively. Methods: In-hospital outcome of 180 patients aged ≥75 years, hospitalised due to AMI, was retrospectively analysed. Ninety two consecutive patients, admitted with AMI between May 2001 and October 2002, underwent primary PCI whereas 88 patients, treated for AMI between 1993 and 2002, received standard pharmacological therapy without thrombolysis. Conclusions: Primary PCI in the elderly with AMI is significantly more effective than conservative therapy, except with patients with cardiogenic shock in whom mortality is similar regardless of the therapy used.

Acute myocardial infarction in the elderly. Is primary coronary angioplasty the treatment of choice? In-hospital follow-up results.

/pdf/sirtuin-1-and-sirtuin-2-plasma-concentrations-in-patients-154boyxj.pdf

Sirtuin 1 and Sirtuin 2 Plasma Concentrations in Patients with Ascending Aortic Dissection and Ascending Aortic Aneurysm

We present the case of a 49-year-old male patient with hypertension, coronary artery disease, diabetes mellitus type 2, hyperuricemia and dyslipidaemia. The patient had a history of multiple coronary stenting and previous ischaemic stroke. Despite chronic therapy with six antihypertensive drugs (metoporolol succinate 100 mg, valsartan 160 mg, torasemide 10 mg, spironolactone 25 mg, doxazosinum 8 mg, nitrindipine 20 mg) his arterial blood pressure (BP) remained still elevated (Table 1). He presented frequent episodes of headache, dizziness, and syncope and was also hospitalised due to episodes of hypertensive crisis. The set of endocrinology tests and renal angiography excluded secondary causes of hypertension. Additionally, the scan revealed anatomy of renal arteries favourable for catheter-based renal denervation. Due to highly symptomatic and drug resistant hypertension, the patient was referred for an invasive treatment option as an adjunctive therapy. The procedure was performed in the electrophysiological laboratory. Arterial BP was continuously monitored with a Finometer Pro device (Finapres Medical Systems BV, Amsterdam, The Netherlands). Initially an angiography of the right and left renal arteries was performed through transfemoral access (Fig. 1). Subsequently, the patient underwent 3D electroanatomical mapping (CARTO 3 electroanatomical mapping system, Biosense Webster, Inc., Johnson & Johnson, Diamond Bar, CA, USA) of the aorta and both renal arteries (Fig. 2). Before radiofrequency (RF) current application, we paced 10 s 20 Hz (10 mA/2 ms) burst sequence using a mapping catheter (Navistar Thermocool, Johnson & Johnson) at the ostia of each renal artery as described by Pokushalov et al. (J Am Coll Cardiol, 2012; 60: 1163–1170). Immediately after pacing, a rise of arterial BP was observed (Fig. 3). Afterwards, under intravenous analgesia (midasolam and fentanyl), applications of RF energy (7–8 W; 95–120 s) were delivered in two points in the left renal artery and in four points in the right renal artery (Fig. 2). Subsequent renal arteriography revealed neither stenosis nor dissection. The further in-hospital observation was uneventful. Herein, we present the first Polish experience with renal denervation performed with the electrophysiological method using 3D electroanatomical mapping. This procedure was part of a research project approved by the Ethics Committee, Medical University of Lodz, Poland.

/pdf/an-electrophysiological-approach-using-3d-electroanatomical-t545pe93wa.pdf

An electrophysiological approach using 3D electroanatomical mapping system for catheter-based renal denervation: the first Polish experience.

Patent ductus arteriosus - generally an anomaly of childhood, but is it always? Clinical implications in an adult patient.

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24-hour ECG Holter monitoring - detection of asymptomatic stimulationdisturbances in patients with artificial pacemakers

Acute myocardial infarction in the elderly. Is primary coronary angioplasty the treatment of choice? In-hospital follow-up results.

Sirtuin 1 and Sirtuin 2 Plasma Concentrations in Patients with Ascending Aortic Dissection and Ascending Aortic Aneurysm

An electrophysiological approach using 3D electroanatomical mapping system for catheter-based renal denervation: the first Polish experience.

Patent ductus arteriosus - generally an anomaly of childhood, but is it always? Clinical implications in an adult patient.