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In this recent publication review the authors aimed to collect evidence of impact of nonsynonymous single nucleotide polymorphisms (nsSNP) in the renin–angiotensin–aldosterone system on patients’ phenotype not only regarding arterial hypertension and its complications, but also the impact on other diseases of interest outside the field of cardiovascular medicine. PubMed database records published between 2017–2020 were searched and all positive case-control studies or positive studies with human DNA were selected. The search identified 104 articles, of which 22 were included on the basis of the inclusion criteria. This paper presents the impact of 44 nsSNPs in panels for genes of renin, angiotensinogen, angiotensin-converting enzyme, angiotensin receptor and aldosterone on the clinical picture of investigated cohorts or on the peptide-protein interactions as consequence of nsSNPs. Genetic variability in nsSNPs of the RAAS is involved in the pathogenesis of arterial hypertension and its complications, and surprisingly also in the pathogenesis of conditions not associated with elevated blood pressure, like neoplasms or inflammatory diseases.

In the last five years, the medical community was astonishingly surprised by the sequential large outcome trials that displayed the renal effects of sodium glucose co-transporter inhibitors (SGLT2Is) in type 2 diabetes mellitus (T2DM) patients with or without chronic kidney disease (CKD). This favorable effect was later disclosed in non-diabetic CKD patients. The EMPA-REG OUTCOME trial was the first trial that showed a reduction for the need for dialysis in patients suffering diabetic kidney disease (DKD) by 55%. This figure is double the score achieved by the angiotensin receptor blocker, Losartan, in RENAAL trial. The need for dialysis in DAPA-CKD trial was reduced in diabetic and non-diabetic CKD patients by 33%. The renal-specific composite outcome was reduced by 39% in EMPA-REG trial, 40% in CANVAS study, 47% in DECLARE-TIMI 58 study, 34% in CREDENCE trial, and 44% in DAPA-CKD trial. The greater surprise is the significant favorable effect of SGLT2Is on overall mortality in CKD patients with or without T2DM. Similar survival benefit was not previously encountered with any of the medications used in CKD patients with or without diabetes. In this review, we disclose the results of the DAPA-CKD trial, the CREDENCE trial and those of several cardiovascular outcome trials (CVOT) that used different SGLT2Is and showed that patients with lower eGFR levels may have greater benefit with respect to cardiovascular morbidity than patients with normal kidney function. In addition, we discuss the different mechanisms of action that explain the renal beneficial effects of SGLT2Is.

Background : Recent studies suggested that patients with coronavirus disease 2019 (COVID-19) who use renin-angiotensin system (RAS) inhibitors have an increased risk of respiratory failure and death. The hypothesis was that angiotensin-converting enzyme inhibitor (ACEIs) or angiotensin receptor blocker (ARBs) may up-regulate ACE2 expression that is used as receptor for viral entry into cells. Objective: The purpose of this review is to discuss the existing evidence on the interaction between COVID-19 infection, ACE2 and ACEIs or ARBs and to examine the main implications for clinical practice. In addition, novel therapeutic strategies for blocking ACE2-mediated COVID-19 infection will be displayed. Methods : We performed a comprehensive review of the literature to identify data from clinical and experimental studies for the association between COVID-19 infection, ACE2 and RAS inhibition. Results: The current clinical and experimental evidence for ACEIs or ARBs to facilitate severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) is insufficient to suggest discontinuing these drugs. Several observational studies arrive at the conclusion that the continued use of RAS inhibitors is unlike to be harmful in COVID-19-positive patients. Conclusions: Further randomized trials are needed to answer definitely the question of whether RAS inhibitors are harmful or beneficial to patients with COVID-19.

Огляд присвячено питанням лікування артеріальної гіпертензії (АГ) у пацієнтів з гострими ураженнями нирок та хронічною хворобою нирок з протеїнурією та без неї. Підкреслено, що лікування АГ у пацієнтів із хворобами нирок призначається після уточнення типу ураження нирок, наявності протеїнурії, набрякового синдрому, швидкості клубочкової фільтрації. АГ при гострому захворюванні клубочків з набряками потребує видалення рідини сечогінними засобами або, при необхідності, діалізом. У хворих із хронічною хворобою нирок та протеїнурією як терапія першої лінії для лікування АГ використовуються інгібітори ангіотензинперетворюючого ферменту або блокатори рецепторів ангіотензину. Доведено, що олмесартану медоксоміл має найбільш виражені ренопротекторні властивості серед усіх препаратів — блокаторів рецепторів ангіотензину.

Majority of patients with hypertension and chronic kidney disease (CKD) undergoing renal denervation (RDN) are maintained on antihypertensive medication. However, RDN may impair compensatory responses to hypotension induced by blood loss. Therefore, continuation of antihypertensive medications in denervated patients may exacerbate hypotensive episodes. This study examined whether antihypertensive medication compromised hemodynamic responses to blood loss in normotensive (control) sheep and in sheep with hypertensive CKD at 30 months after RDN (control-RDN, CKD-RDN) or sham (control-intact, CKD-intact) procedure. CKD-RDN sheep had lower basal blood pressure (BP; ≈9 mm Hg) and higher basal renal blood flow (≈38%) than CKD-intact. Candesartan lowered BP and increased renal blood flow in all groups. 10% loss of blood volume alone caused a modest fall in BP (≈6–8 mm Hg) in all groups but did not affect the recovery of BP. 10% loss of blood volume in the presence of candesartan prolonged the time at trough BP by 9 minutes and attenuated the fall in renal blood flow in the CKD-RDN group compared with CKD-intact. Candesartan in combination with RDN prolonged trough BP and attenuated renal hemodynamic responses to blood loss. To minimize the risk of hypotension-mediated organ damage, patients with RDN maintained on antihypertensive medications may require closer monitoring when undergoing surgery or experiencing traumatic blood loss.

© 2021 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), Heart failure (HF) with reduced ejection fraction (HFrEF) is associated with high rates of hospitalization and death. It also has a negative impact on patients' functional capacity and quality of life, as well as on healthcare costs. In recent years, new HFrEF prognosis-modifying drugs have emerged, leading to intense debate within the international scientific community toward a paradigm shift for the management of HFrEF. In this article, we report the contribution of a Portuguese HF expert panel to the ongoing debate. Based on the most recently published clinical evidence, and the panel members' clinical judgment, three key principles are highlighted: (i) sacubitril/valsartan should be preferred as first-line therapy for HFrEF, instead of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; (ii) the four foundation HFrEF drugs are the angiotensin receptor/neprilysin inhibitor, beta-adrenergic blocking agents, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors, regardless of the presence of type-2 diabetes mellitus; (iii) these four HFrEF drug classes should be introduced over a short-term period of four to six weeks, guided by a safety protocol, followed by a dose up-titration period of 8 weeks., A insuficiência cardíaca (IC) com fração de ejeção reduzida (ICFEr) está associada a níveis elevados de hospitalização e mortalidade. A ICFEr também tem um impacto negativo na capacidade funcional e na qualidade de vida dos doentes, bem como na despesa em saúde. Nos últimos anos, surgiram novos medicamentos modificadores do prognóstico da ICFEr, originando um intenso debate na comunidade científica internacional em relação a uma mudança de paradigma para o tratamento da ICFEr. Neste artigo, relatamos a contribuição de um painel de especialistas portugueses em IC para o debate em curso. Com base na evidência clínica publicada mais recentemente e no julgamento clínico dos membros do painel, três princípios-chave são destacados: (i) sacubitril/valsartan deve ser preferido como terapia de primeira linha para a ICFEr, em vez de um inibidor da enzima de conversão da angiotensina ou um bloqueador do recetor da angiotensina; (ii) os quatro medicamentos básicos para a ICFEr são o inibidor do recetor da angiotensina e da neprilisina, os agentes bloqueadores beta-adrenérgicos, os antagonistas do recetor mineralocorticoide e os inibidores do cotransportador sódio-glucose 2, independentemente da presença de diabetes mellitus tipo 2; (iii) essas quatro classes de medicamentos para a ICFEr devem ser rapidamente introduzidas num período curto de 4-6 semanas, seguindo um protocolo de segurança, e depois tituladas durante as oito semanas seguintes.

Aims The angiotensin receptor–neprilysin inhibitor (ARNI), sacubitril/valsartan, confers additional protective effects compared with angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers (ACEIs/ARBs) in terms of reversed left ventricular (LV) remodelling and improves the prognosis of patients with heart failure (HF). However, few studies have examined the effects of ARNI on the left atrium. Accordingly, this study compared the effects of ARNI and ACEI/ARB on left atrial (LA) remodelling in heart failure with reduced ejection fraction (HFrEF). Methods and results This was a single‐centre retrospective study of patients with HFrEF hospitalized at the First Affiliated Hospital of Dalian Medical University between 26 February 2016 and 8 July 2020. Patients were classified into ARNI and ACEI/ARB groups and further subgroups based on the left atrial volume index (LAVI): mildly abnormal (29 mL/m2 ≤ LAVI

WHAT IS KNOWN AND OBJECTIVE Reduction in skeletal muscle mass is the most important component in diagnosing sarcopenia. Ageing and chronic heart failure due to cardiovascular diseases (CVDs) accelerate the reduction of skeletal muscles. However, there are no currently available drugs that are effective for sarcopenia. The purpose of this study was to explore the association between prescribed medications and skeletal muscle mass in patients with CVD. METHODS This was a single-centre, retrospective, cross-sectional study. The subjects were 636 inpatients with CVD who took prescribed medicines for at least 4 weeks at the time of admission. Skeletal muscle volume was assessed using a bioelectrical impedance assay. RESULTS AND DISCUSSION Single regression analysis showed that 10 and 3 medications were positively and negatively associated with skeletal muscle index (SMI), respectively. Stepwise multivariate regression analysis revealed that angiotensin II receptor blocker (ARB)/statin combination, dipeptidyl peptidase-4 inhibitor, and antihyperuricemic agents were positively associated with SMI while diuretics and antiarrhythmic agents were negatively associated with SMI. After adjustment using propensity score matching, the SMI was found to be significantly higher in ARB/statin combination users than in non-users. WHAT IS NEW AND CONCLUSION Combination use of ARB/statin was associated with a higher SMI in patients with CVD. A future randomised, controlled trial is warranted to determine whether the ARB/statin combination will increase the SMI and prevent sarcopenia in patients with CVD.

Previous reports demonstrated a bleeding avoidance potential of angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) and β-blocker. It remains unclear whether early guideline-directed medical therapy [GDMT, i.e., the combined use of β-blocker, angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) and statin] confers protection against bleeding in the setting of high-intensity antithrombotic therapy. We assessed associations between the use of early (within the first 24 h) GDMT and in-hospital major bleeds, ischemic events and mortality among ST-elevation myocardial infarction (STEMI) patients treated with percutaneous coronary intervention (PCI) in the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project. Among 34,538 STEMI patients without contra-indications to GDMT and eligible for analysis, 35.5% received early GDMT. In a 1-to-2 propensity-score matched cohort, compared with non-early GDMT, early GDMT was associated with a 25% reduction in major bleeds [odds ratio (OR) 0.75, 95% confidence interval (CI) 0.60–0.94], with parallel reductions in ischemic events (OR 0.60, 95%CI 0.45–0.78) and in-hospital mortality (OR 0.43, 95%CI 0.31–0.61). Early GDMT-associated reduction in major bleeds was generally consistently observed across different major bleeding definitions and in sensitivity analyses. Additionally, no significant interaction was observed in subgroup analyses. In a large nationwide registry, early initiation of GDMT was associated with reduced risk for in-hospital major bleeds in STEMI patients treated with PCI. To improve the outcome of STEMI, further effort should be made to reinforce the early use of GDMT in this patient population.

Background The mechanisms underlying angiotensin receptor-neprilysin inhibitor (ARNi) suppression of ventricular arrhythmia (VA) are unclear. This study aimed to investigate the mechanism of ARNi-related suppression of VA in a heart failure (HF) model. Methods New Zealand white rabbits (n = 6 per group) were assigned to normal, HF [4 weeks of left ascending artery (LAD) ligation], angiotensin receptor blocker (ARB, valsartan at 27 mg/kg/day for 3 weeks after 1 week of LAD ligation), and ARNi (sacubitril at 34 mg/kg/day and valsartan at 27 mg/kg/day for 3 weeks after 1 week of LAD ligation) groups. Experiments involving echocardiogram, optical mapping, histological of trichrome stain and immunostain, and flow cytometry were performed. Results HF group had larger left ventricular (LV) internal dimensions in diastole and systole, and lower LV ejection fraction and fractional shortening than normal, ARB, and ARNi groups. HF group had a prolonged action potential duration (APD) and decreased conduction velocity (CV), which was mitigated in ARB and ARNi groups. HF group had a prolonged QRS duration, QT and QTc intervals, which was reversed in ARB and ARNi groups. HF group had a steeper maximum slope of APD restitutions, which was attenuated in normal, ARB, and ARNi groups. HF group had increased number of phase singularities (PSs) and VA inducibility than normal, ARB, and ARNi groups. A higher content of fibrosis was found in HF group than that in normal, ARB, and ARNi groups. Compared to ARB group, ARNi had a lower context of fibrosis. HF group had more peripheral blood CD4+ and CD8+ cells count than normal, ARB, and ARNi group. Conclusions In a rabbit model of ischemic HF, ventricular arrhythmogenesis could be suppressed by ARNi treatment. This appears to be mediated by reversing changes in the APD, CV, maximum slope of the APDR, PSs, fibrosis, and inflammation.

Objective: A cardinal feature of Marfan syndrome is thoracic aortic aneurysm. The contribution of the renin-angiotensin system via AT1aR (Ang II [angiotensin II] receptor type 1a) to thoracic aortic aneurysm progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacological modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on thoracic aortic aneurysm in mice with fibrillin-1 haploinsufficiency ( Fbn1 C1041G/+ ). Approach and Results: Thoracic aortic aneurysm in Fbn1 C1041G/+ mice was found to be strikingly sexual dimorphic. Males displayed aortic dilation over 12 months while aortic dilation in Fbn1 C1041G/+ females did not differ significantly from wild-type mice. To determine the role of AT1aR, Fbn1 C1041G/+ mice that were either +/+ or −/− for AT1aR were generated. AT1aR deletion reduced expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen was administered to male Fbn1 C1041G/+ mice to determine the effects of Ang II depletion. Antisense oligonucleotide against angiotensinogen administration attenuated dilation of the ascending aorta and aortic root and reduced extracellular remodeling. Aortic transcriptome analyses identified potential targets by which inhibition of the renin-angiotensin system reduced aortic dilation in Fbn1 C1041G/+ mice. Conclusions: Deletion of AT1aR or inhibition of Ang II production exerted similar effects in attenuating pathologies in the proximal thoracic aorta of male Fbn1 C1041G/+ mice. Inhibition of the renin-angiotensin system attenuated dysregulation of genes within the aorta related to pathology of Fbn1 C1041G/+ mice.

Insulin resistance is a feature of pregnancy and is associated with increased levels of angiotensin II (Ang II) and insulin. Therefore, pregnancy may change insulin-induced vasodilation through changes in Ang II receptors. Insulin-induced vasorelaxation was evaluated in phenylephrine-precontracted aortic rings of pregnant and non-pregnant rats, using a conventional isolated organ preparation. Experiments were performed in thoracic or abdominal aorta rings with or without endothelium in the presence and absence of NG-nitro-L-arginine methyl ester (L-NAME) (10−5 M), losartan (10−7 M), or PD123319 (10−7 M). AT1 and AT2 receptor expressions were detected by immunohistochemistry. Insulin-induced vasodilation was endothelium- and nitric oxide–dependent and decreased in the thoracic aorta but increased in the abdominal segment of pregnant rats. The insulin’s vasorelaxant effect was increased by losartan mainly on the thoracic aorta. PD123319 decreased insulin-induced vasorelaxation mainly in the pregnant rat abdominal aorta. AT1 receptor expression was decreased while AT2 receptor expression was increased by pregnancy. In conclusion, pregnancy changes insulin-induced vasorelaxation. Moreover, insulin vasodilation is tonically inhibited by AT1 receptors, while AT2 receptors appear to have an insulin-sensitizing effect. The role of pregnancy and Ang II receptors differ depending on the aorta segment. These results shed light on the role of pregnancy and Ang II receptors on the regulation of insulin-mediated vasodilation.

Aim: This study examines the effect of guideline-directed medical therapy (GDMT) on healthcare utilization in patients with heart failure with reduced ejection fraction from Optum ® Integrated File from 1 January 2007 to 30 June 2020. Materials & methods: Patients with both a beta blocker and either an ACE inhibitor (ACE-I), angiotensin receptor blocker (ARB) or angiotensin receptor neprilysin inhibitor were assigned to the GDMT cohort. All others were not on GDMT. Results: Estimated annual all cause hospitalizations and emergency department visits per 100 patients was 29% (80 vs 62 patients) and 26% higher (54 vs 43 patients; p Conclusion: In a real-world population, heart failure with reduced ejection fraction, patients not optimally managed on GDMT had higher annualized healthcare utilization when compared with patients on GDMT.

Cyclic guanosine monophosphate (cGMP), an intracellular second messenger molecule synthesized by guanylated cyclases (GCs), controls various myocardial properties, including cell growth and survival, interstitial fibrosis, endothelial permeability, cardiac contractility, and cardiovascular remodeling. These processes are mediated by the main cGMP effector protein kinase G (PKG) activation of which exerts intrinsic protective responses against the adverse effects of neurohormonal stimulation and pathological cardiac stress. Therapeutic strategies that enhance cGMP levels and PKG activation have been used for heart failure, which can be executed by reducing natriuretic peptide (NP) proteolysis, enhancing cGMP synthesis, or blocking cGMP hydrolysis. Among these, reducing NP clearance with neprilysin inhibitor combined with angiotensin receptor blocker has been shown to greatly improve the prognosis of patients with heart failure with reduced ejection fraction (HFrEF) compared to the prognosis of patients on standard therapy using angiotensin-converting enzyme inhibitors. Moreover, in a recent phase III clinical trial, soluble GC-derived cGMP generation was shown to have potential efficacy in the management of HFrEF. Despite the clinical significance of cGMP/PKG signaling activated by either soluble or particulate GCs in heart failure, the differential signaling events downstream of intracellular cGMP, which are precisely controlled not only by PKG activation but also by the changes in its targeting and compartmentalization depending on the pathophysiology of heart disease, are not yet completely understood. Hitherto, the importance of the latter PKG regulatory mechanisms in developing therapeutic strategies has not been elucidated. Further investigation of redox-based PKG modulation will aid in the successful development of clinical therapies and could also lead to the establishment of improved personalized treatments for patients with heart failure.

У діагностиці кардіоренального синдрому (КРС) знаходять широке застосування біологічні маркери, що можуть бути використані для ідентифікації патофізіологічної стадії кардіоренального синдрому, оцінки величини ризику, прогнозу та результату, а також моніторування ефективності лікування. Терапія КРС включає призначення діуретиків, вазодилататорів, інгібіторів ангіотензинперетворюючого ферменту, антагоністів рецепторів ангіотензину II, нітратів і серцевих глікозидів. Одним з ефективних методів лікування КРС є застосування методів замісної ниркової терапії.

Objectives We evaluated the efficacy and safety of dapagliflozin, a SGLT2i along with ARNI in refractory HFrEF irrespective of their diabetic status. Methods We performed a retrospective analysis of 104 symptomatic patients of HFrEF despite of optimal medical management with ARNI between January–June 2020. Despite the optimal GDMT, dapagliflozin, SGLT2i was added inpatients withrefractory heart failure. At 6-months follow-up, the primary outcome was change in left ventricular ejection fraction, and secondary outcomes included changes in NYHA functional class, vital parameters, renal function, potassium levels, and NT-pro BNP levels. Results The primary outcomeat 6-months follow-up was a mean change in left ventricular ejection fraction (LVEF) +9.00 ± 0.62 (p, Graphical abstract Image 1, Highlights • The PARADIGM-HF trial established the therapeutic value of valsartan/sacubitril, an angiotensin receptor blocker and neprilysin inhibitor. • Despite GDMT of HFrEF, many patients continue to have symptoms that are resistant to pharmaceutical and device therapy. • Current unmet needs in the treatment of refractory HFrEF can be met by focussing on the potential function of SGLTi2.

Heart failure (HF) is a common condition with an increasing prevalence. Despite a variety of evidence-based treatments for patients with HF with reduced ejection fraction, morbidity and mortality rates remain high. Furthermore, there are currently no treatments that have yet been shown to reduce complication and death rates in patients who have HF with preserved ejection fraction. Hypertension is a common comorbidity in patients with HF, contributing to disease development and prognosis. For example, hypertension is closely associated with the development of left ventricular hypertrophy, which an important precursor of HF. In particular, nighttime blood pressure (BP) appears to be an important, modifiable risk factor. Both nighttime BP and an abnormal circadian pattern of nighttime BP dipping have been shown to predict development of HF and the occurrence of cardiovascular events, independent of office BP. Key mechanisms for this association include sodium handling/salt sensitivity and increased sympathetic activation. These pathogenic mechanisms are targeted by several new treatment options, including sodium-glucose cotransporter 2 inhibitors, angiotensin receptor neprilysin inhibitors, mineralocorticoid receptor antagonists, and renal denervation. All of these could form part of antihypertensive strategies designed to control nighttime BP and contribute to the goal of achieving perfect 24-hour BP management. Nevertheless, additional research is needed to determine the effects of reducing nighttime BP and improving the circadian BP profile on the rate of HF, other cardiovascular events, and mortality.

Wakamatsu T., Iwasaki Y., Yamamoto S., et al. Type I Angiotensin II Receptor Blockade Reduces Uremia-Induced Deterioration of Bone Material Properties. Journal of Bone and Mineral Research, 36, 1, 67. https://doi.org/10.1002/jbmr.4159., Chronic kidney disease (CKD) is associated with a high incidence of fractures. However, the pathophysiology of this disease is not fully understood, and limited therapeutic interventions are available. This study aimed to determine the impact of type 1 angiotensin II receptor blockade (AT-1RB) on preventing CKD-related fragility fractures and elucidate its pharmacological mechanisms. AT-1RB use was associated with a lower risk of hospitalization due to fractures in 3276 patients undergoing maintenance hemodialysis. In nephrectomized rats, administration of olmesartan suppressed osteocyte apoptosis, skeletal pentosidine accumulation, and apatite disorientation, and partially inhibited the progression of the bone elastic mechanical properties, while the bone mass was unchanged. Olmesartan suppressed angiotensin II-dependent oxidation stress and apoptosis in primary cultured osteocytes in vitro. In conclusion, angiotensin II-dependent intraskeletal oxidation stress deteriorated the bone elastic mechanical properties by promoting osteocyte apoptosis and pentosidine accumulation. Thus, AT-1RB contributes to the underlying pathogenesis of abnormal bone quality in the setting of CKD, possibly by oxidative stress. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Hypothesis. Myocardial angiogenesis is important for maintaining cardiac contractile function in patients with cardiac hypertrophy. Evidence shows that angiotensin receptor blocker and neprilysin inhibitors (ARNIs) improve heart failure. The present study investigated the myocardial angiogenic effect of valsartan plus sacubitril in early-stage cardiac dysfunction. Materials and Methods. Male apolipoprotein E-knockout mice fed a high-fat diet were divided into control (CTL), valsartan (30 mg/kg) (VAL), sacubitril (30 mg/kg) (SAC), and valsartan plus sacubitril (30 mg/kg each) (VAL/SAC) groups after 4 weeks of prefeeding and were subsequently treated for 12 weeks. Results. The VAL/SAC group exhibited significantly higher serum brain natriuretic peptide levels; more subtle changes in left ventricular systolic diameter, fractional shortening, and ejection fraction, and significantly higher expression levels of natriuretic peptide precursor B and markers of angiogenesis, including clusters of differentiation 34, vascular endothelial growth factor A, and monocyte chemotactic protein 1, than the CTL group. Conclusions. Valsartan plus sacubitril preserved left ventricular systolic function in apolipoprotein E-knockout mice fed a high-fat diet. This result suggests that myocardial angiogenic factors induced by ARNI might provide cardioprotective effects.

Idiopathic pulmonary fibrosis (IPF) is a severe disorder leading to progressive and irreversible loss of pulmonary function. In this study we investigated the anti-fibrotic effect of vitamin D using a mouse model of IPF. Lung fibrosis was induced with bleomycin in vitamin D-sufficient and vitamin D-deficient C57BL/6 mice. We found that treatment with active vitamin D analog paricalcitol prevented mouse body weight loss and alleviated lung fibrosis, whereas vitamin D deficiency severely aggravated lung injury. At the molecular level, paricalcitol treatment suppressed the induction of fibrotic inducer TGF-β and extracellular matrix proteins α-SMA, collagen type I and fibronectin in the lung, whereas vitamin D deficiency exacerbated the induction of these proteins. Interestingly, bleomycin treatment activated the local renin–angiotensin system (RAS) in the lung, manifested by the induction of renin, angiotensinogen, angiotensin II and angiotensin receptor type 1 (AT1R). Paricalcitol treatment suppressed the induction of these RAS components, whereas vitamin D deficiency enhanced the activation of the lung RAS. We also showed that treatment of bleomycin-induced vitamin D-deficient mice with AT1R antagonist losartan relieved weight loss, substantially ameliorated lung fibrosis and markedly blocked TGF-β induction in the lung. Moreover, we demonstrated that in lung fibroblast cultures, TGF-β and angiotensin II synergistically induced TGF-β, AT1R, α-SMA, collagen type I and fibronectin, whereas 1,25-dihydroxyvitamin D markedly suppressed the induction of these fibrotic markers. Collectively, these observations strongly suggest that vitamin D mitigates lung fibrosis by blocking the activation of the lung RAS in this mouse model of IPF.

Purpose Angiotensin receptor blockers (ARBs) can ameliorate metabolic syndrome (MetS)-associated dyslipidemia, hepatic steatosis, and glucose intolerance, suggesting that angiotensin receptor (AT1) over-activation contributes to impaired lipid and glucose metabolism, which is characteristic of MetS. The aim of this study was to evaluate changes in the lipid profile and proteins of fatty acid uptake, triacylglycerol (TAG) synthesis, and β-oxidation to better understand the links between AT1 overactivation and non-alcoholic fatty liver disease (NAFLD) during MetS. Methods Four groups of 25-week-old-rats were used: (1) untreated LETO, (2) untreated OLETF, (3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 weeks) and (4) OLETF ± ARB (MINUS; 10 mg olmesartan/kg/d × 4 weeks, then removed until dissection). To investigate the dynamic shifts in metabolism, animals were dissected after an oral glucose challenge (fasting, 3 and 6 h post-glucose). Results Compared to OLETF, plasma total cholesterol and TAG remained unchanged in ARB. However, liver TAG was 55% lesser in ARB than OLETF, and remained lower throughout the challenge. Basal CD36 and ApoB were 28% and 29% lesser, respectively, in ARB than OLETF. PRDX6 abundance in ARB was 45% lesser than OLETF, and it negatively correlated with liver TAG in ARB. Conclusions Chronic blockade of AT1 protects the liver from TAG accumulation during glucose overload. This may be achieved by modulating NEFA uptake and increasing TAG export via ApoB. Our study highlights the contributions of AT1 signaling to impaired hepatic substrate metabolism and the detriments of a high-glucose load and its potential contribution to steatosis during MetS.

Background Preclinical evidence suggests a link between the renin-angiotensin system and oncogenesis. We aimed to explore the impact of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) in head and neck cancer (HNC). Methods Over 5000 patients were identified from the Surveillance, Epidemiology, and End Results-Medicare linked dataset and categorized according to ACEi and ARB and diagnoses of chronic kidney disease (CKD) or hypertension (HTN). Overall survival (OS) and cancer-specific survival (CSS) were compared using Cox multivariable regression (MVA), expressed as hazard ratios (HR) with 95% confidence intervals (95%CI). Results No significant MVA associations for OS or CSS were found for ACEi. Compared to patients with CKD/HTN taking ARB, those with CKD/HTN not taking ARB experienced worse OS (HR 1.28, 95%CI 1.09-1.51, p = 0.003) and CSS (HR 1.23, 95%CI 1.00-1.50, p = 0.050). Conclusions ARB usage is associated with improved OS and CSS among HNC patients with CKD or HTN.

Major principles for treatment of chronic heart failure with reduced left ventricular ejection fraction Aim To compare the net effect of simultaneous treatment with ARNI and SGLT2 inhibitors with the triple neurohormonal blockade in stable or decompensated patients with CHF based on Russian data.Material and methods We analyzed the risk of death per 100 patient-years in patients with HFrEF. Stable patients were followed up at the A.L. Myasnikov Institute of Cardiology (presently, A.L. Myasnikov Research Institute of Clinical Cardiology of the National Medical Research Center of Cardiology) from 2006 through 2007; data from the EPOCH-Decompensation-CHF study were used for decompensated patients (12.2 % and 36.8 %, respectively).Results When patients with stable HFrEF were successively switched from renin-angiotensin-aldosterone system (RAAS) inhibitors to ARNI (–16 %) and subsequently supplemented with SGLT2 (–13 %) the risk of death per 100 patient-years decreased from 12.2 % to 8.9 % (total risk decreased by 27 %; to save one patient the ARNI+ SGLT2 combination has to be prescribed to 30 patients). The estimated risk of death upon discharge from the hospital for the patients with decompensated CHF switched from RAAS inhibitors to ARNI (–16 %) and subsequently supplemented with SGLT2 (–13 %) was 26.9 deaths per 100 patient-years, whereas the number of patients to be treated for saving one life was only 10. Based on available data that demonstrate a greater effect of ARNI+ SGLT2 in patients immediately after CHF aggravation, the risk of death was recalculated. According to this analysis, the death rate per 1000 patient-years decreased from 36.8 to 19.9 % (relative risk decrease, 46 %), and to save one life only 6 patients had to be treated after they have achieved compensation of HFrEF.Conclusions This analysis shows the importance of early initiation of the ARNI+ SGLT2 therapy in patients with both decompensated and with stable HFrEF.

HnizdyukhRoman, Shmanko Volodymyr. Specificity of blood pressure numbers in Holter monitoring depending on gene polymorphism among residents of Ternopil region afflicted with essential arterial hypertension.Journal of Education, Health and Sport. 2021;11(7):124-134. eISSN 2391-8306. DOI http://dx.doi.org/10.12775/JEHS.2021.11.07.011 https://apcz.umk.pl/czasopisma/index.php/JEHS/article/view/JEHS.2021.11.07.011 https://zenodo.org/record/5115546 The journal has had 5 points in Ministry of Science and Higher Education parametric evaluation. § 8. 2) and § 12. 1. 2) 22.02.2019. © The Authors 2021; This article is published with open access at Licensee Open Journal Systems of Nicolaus Copernicus University in Torun, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike. (http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 02.07.2021. Revised: 15.07.2021. Accepted: 20.07.2021. Specificity of blood pressure numbers in Holter monitoring depending on gene polymorphism among residents of Ternopil region afflicted with essential arterial hypertension Roman Volodymyrovych Hnizdyukh, Volodymyr Vasylovych Shmanko I. Ya. Horbachevsky Ternopil NationalMedical University 46001, 1 Maidan Voli, Ternopil, Ukraine Corespondent e-mail: hnizdyukh_rv@i.ua Roman Volodymyrovych Hnizdyukhhttps://orcid.org/0000-0003-2833-0661 Volodymyr Vasylovych Shmanko https://orcid.org/0000-0003-1128-200X Summary The aim of thiswork isto determinespecificitiesof blood pressure (BP) numbers during the day depending on polymorphism of the A1166C-gene of angiotensin II receptor type I and T786C-promoter of the endothelial NO-synthase geneamong residents of Ternopil region afflicted with essential arterial hypertension. We have examined 86patients with arterial hypertension who were treated and examined in the therapeutic department of the Central District Hospital in Kozova, aged from 45 to 76 years.All patients were measured for body weight and height, office blood pressure; also they were checked byHolter monitoringandelectrocardiography (ECG), as well as examined forpolymorphism of endothelial NO synthase genes and angiotensin II type 1 receptor genes. Statistical processing of the obtained data was performed with the help ofthe analytics software packageincludingStatistica 8.0 (StatSoft Inc., USA)and Microsoft Office Excel-2003. The research revealedthat patients with CC genotype A1166C-gene of angiotensin II receptor of the first type had a significantly higher level of systolic blood pressure (SBP) and diastolic blood pressure (DBP)– average numbers per 24 hours, day and night – compared topatients with genotype AA(p Patients with CC of the T786C promoter of the eNOs gene had higher SBPand DBP values at all times of the day compared toindividuals with the TT genotype (p Among patientswith C-allele of both studied genes, there’s a high frequency of circadian rhythm disorders with predominance of the“non-dippers” pathological type. Key words: arterial hypertension;gene polymorphism;Holterblood pressure monitoring. ОСОБЛИВОСТІ ПОКАЗНИКІВ ДОБОВОГО МОНІТОРУВАННЯ АРТЕРІАЛЬНОГО ТИСКУ ЗАЛЕЖНО ВІД ГЕННОГО ПОЛІМОРФІЗМУ У МЕШКАНЦІВ ТЕРНОПІЛЬСЬКОЇ ОБЛАСТІ ХВОРИХ НА ЕСЕНЦІАЛЬНУ АРТЕРІАЛЬНУ ГІПЕРТЕНЗІЮ Роман Володимирович Гніздюх, Володимир Васильович Шманько Тернопільський національний медичний університет ім. І.Я. Горбачевського МОЗ України Резюме Метою нашої роботи було визначити характеристики артеріального тиску (АТ) упродовж доби залежно від поліморфізму А1166С-гена рецептора ангіотензину IIпершого типу та Т786С-промотора гена ендотеліальної NO-синтази при есенціальній артеріальній гіпертензії у мешканців Тернопільської області. Обстежено 86 пацієнтів, хворих на АГ, які знаходились на лікуванні та обстеженні у терапевтичному відділенні Козівської ЦРЛ, віком від 45 до 76 років. Усім хворим проводили вимірювання маси тіла та зросту, офісного АТ, добове моніторування АТ, електрокардіографію (ЕКГ), визначали поліморфізми генів ендотеліальної NOсинтази та генів рецепторів ангіотензину II1 типу. Статистична обробка отриманих даних проводили за допомогою пакета статистичних програм Statistica 8.0 (StatSoft Inc., США), Microsoft Office Exсel-2003. Встановлено, що хворі з СС генотипом А1166С-гена рецептора ангіотензину IIпершого типу мали достовірно вищий рівень середньодобового, середньоденного та середньонічного систолічного артеріального тиску (САТ) та діастолічного артеріального тиску (ДАТ) у порівнянні з хворими з генотипом АА (p Пацієнти носії СС генотипу Т786С-промотора гена eNOsмали вищі показники САТ і ДАТ в усі проміжки доби у порівнянні з особами з генотипом ТТ (p Для пацієнтів носіїв С-алелю обох досліджуваних генів притаманна висока частота порушень циркадного ритму з домінуванням патологічного типу non-dippers. Ключові слова: артеріальна гіпертензія, генний поліморфізм, добове моніторування артеріального тиску

Background Despite the use of optimal medical therapy, HFrEF remains a leading cause of morbidity, mortality and health care costs. The introduction of angiotensin receptor/neprilysin inhibitors (ARNIs) had a revolutionary impact on the treatment of patients with heart failure and reduced left ventricular ejection fraction (HFrEF). Methods The aim of the study was to monitor over time the perceived quality of life, the physical performance, the trend of BNP and NT-ProBNP and the NYHA functional class in patients with HFrEF during treatment with sacubitril/valsartan. We enrolled 37 patients (63 ± 10 years old, 76% men) who underwent a total of one year follow-up. All patients underwent clinical evaluation, 6MWT, blood analysis (in particular NT-pro-BNP and BNP, renal function test); Kansas City Cardiomyopathy Questionnaire (KCCQ) and the NYHA functional class assessment were also performed, at the beginning of the study and after 3, 6 and 12 months of therapy. Results We observed at each follow-up a significant improvement of KCCQ score, 6MWT, NTProBNP, BNP and of NYHA class. However, analyzing the Δ % of variation of each single parameter, the improvement was not uniform in time. We also observed that only 37% of patients tolerated the full recommended dose of sacubitril/valsartan (97/103 mg b.i.d.); of the remaining, 40% tolerated the intermediate dose (49/51 mg b.i.d.) and 23% the minimum (24/26 md b.i.d.). Conclusions Sacubitril/valsartan therapy improves significantly quality of life, physical effort resistance, BNP and NT-ProBNP and NYHA functional class in patients with HFrEF. Although not all the patients tolerated the maximum recommended dose, the beneficial effects were significant even at lower doses.

Piperazine ferulate, a derivative of ferulic acid has been widely used in clinical practice for cardiovascular and kidney diseases in China. The objective of this meta-analysis was to investigate the benefits by adding piperazine ferulate to angiotensin receptor blockers (ARBs) in diabetic nephropathy patients. PubMed, Embase, Cochrane Library, Wangfang, VIP, and CNKI database (until March 17, 2021) were comprehensively searched for randomized controlled trials investigating the effects of adding piperazine ferulate to ARBs in diabetic nephropathy patients. Data were retrieved from 14 RCTs involving 1374 patients. When compared with ARBs alone, co-administration of piperazine ferulate and ARBs significantly reduced urinary albumin excretion rate (weighted mean differences [WMD] − 20.32 μg/min; 95% confidence interval [CI] − 28.45 to − 12.19), 24-h proteinuria (WMD − 91.08 mg; 95% CI − 107.24 to − 74.91), β2-microglobulin (standard mean difference [SMD] − 2.07; 95% CI − 2.51 to − 1.63), serum level of creatinine (WMD − 8.39 μmol/L; 95% CI − 11.87 to − 4.92), fibrinogen (WMD − 0.40 g/L; 95% CI − 0.46 to − 0.33), and plasma viscosity (WMD − 0.56 mPa s; 95% CI − 0.91 to − 0.21). Subgroup analysis showed that the effects of piperazine ferulate on UAER and serum creatinine were stronger in early diabetic nephropathy. However, piperazine ferulate had no significant effects on the serum blood urea nitrogen and fasting blood glucose. Adding piperazine ferulate to ARBs may achieve additional renal protective benefits, particular in early diabetic nephropathy patients.

Objectives. To assess mean systolic and diastolic blood pressure (SBP and DBP) levels in patients ≥50 years with uncontrolled hypertension (HTN) and evaluate the correlation between BP and stroke risk. It also assessed therapeutic drug classes prescribed in these patients. Methods. A cross-sectional, observational study was conducted at 176 outpatient centers across India, including patients aged ≥50 years with elevated SBP (≥140 mmHg). The relationship between stroke risk, calculated using Stroke Riskometer™, and mean SBP, mean DBP, and other risk factors was evaluated using Pearson correlation coefficient and logistic regression analysis. Results. The study included 3791 patients (men, 60.0%; mean age: 62.1 ± 8.3 years; mean BMI: 27 kg/m2) with mean SBP 157.3 ± 12.8 mmHg and mean DBP 89.8 ± 9.7 mmHg . Five-year stroke risk in 33.9% and 10-year stroke risk in 70% patients were moderate to severe. A ~4% increase in both 5- and 10-year stroke risk with each 1 mmHg increase in mean SBP ( p < 0.0001 ) was seen. However, mean DBP did not exhibit any significant correlation with 5-year ( p = 0.242 ) or 10-year ( p = 0.8038 ) stroke risk. There was a positive correlation between mean SBP and patient age, comorbid diabetes, and smoking and alcohol habits ( p < 0.0001 ). Comorbid diabetes and smoking increased 5- and 10-year stroke risk by 2- to 5-fold. Irrespective of the risk category, most patients received antihypertensive therapy with an angiotensin receptor blocker. Conclusion. Findings corroborate an association between stroke risk and mean SBP. These real-world clinical findings indicate that efforts are required to improve primary prevention of stroke and reduce the prevalence of recurrent stroke in India.

Renal injury induced by rheumatoid arthritis is not clear and may be related to the angiotensin II. We aim to investigate the adjuvant-induced arthritis (AIA) injury in rat kidney, focusing the angiotensin II/AT1 pathway. Male Wistar rats were allocated in to three groups: Control, AIA and AIA plus losartan. The AIA was induced by injection of 100 µL of an emulsion of dissected Mycobacterium tuberculosis (50 mg/mL) on the paw. Treatment with losartan was initiated on the first day of immunization (daily subcutaneous injection, 1 mg/kg). After 60 days post immunization, we evaluated kidney function by plasma creatinine, urea and uric acid levels and creatinine depuration; kidney injury by apoptosis analysis and inflammation markers such as macrophages, transforming growth factor beta (TGF-β) and inducible nitric oxide synthase (iNOS) expression; oxidative stress by plasma thiobarbituric acid reactive substances (TBARS); renal expression of angiotensin receptors subtype 1 (AT1 ) and 2 (AT2 ) and plasma concentration of angiotensin II. AIA rats showed elevated plasma levels of creatinine, urea, uric acid, TBARS and Ang II and reduced creatinine depuration, and enhanced kidney macrophage number, TGF-β, caspase-3, iNOS and AT1 /AT2 receptors expression. The losartan reduced plasma creatinine and its clearance, reduced macrophages and the expression of TGF-β and iNOS in renal tissues, and reduced plasma TBARS. We conclude that AIA causes kidney injury by a physiopathological mechanism that involves AT1 stimulation in renal tissue, elevating the presence of macrophages, the expression of TGF-β and iNOS, as well the local oxidative stress, which contribute to renal function deterioration.

Treatment of patients with arterial hypertension with diabetes and obesity requires taking into account the individual risk of complications and the use of appropriate differentiated tactics, and therefore the appointment of complex treatment with drugs that inhibit excessive activation of the renin-angiotensin-aldosterone system, in particular angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, is the most appropriate and justified. Thus, a comparative analysis of the use of various treatment regimens in patients with arterial hypertension, concomitant type 2 diabetes mellitus and obesity was carried out using the angiotensinconverting enzyme inhibitor ramipril and the angiotensin II receptor blocker telmisartan. The inclusion of ramipril or telmisartan in standard therapy has been shown to have a positive effect on the structural and functional parameters of the left ventricle and ejection fractions. Also, at the same time, the neutral effect of these drugs on carbohydrate and improvement of some components of lipid metabolism in the examined category of patients was determined.

Background Chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from Coronavirus disease (COVID-19). Early data suggest elevated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2) expression, but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown. We aimed to determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung with disease characteristics in COPD, and the regulation of newly identified SARS-CoV-2 receptors and spike-cleaving proteases, important for SARS-CoV-2 infection. Methods We quantified gene expression using RNA sequencing of epithelial brushings and bronchial biopsies from 31 COPD and 37 control subjects. Results ACE2 gene expression (log2-fold change (FC)) was increased in COPD compared to ex-smoking (HV-ES) controls in epithelial brushings (0.25, p = 0.042) and bronchial biopsies (0.23, p = 0.050), and correlated with worse lung function (r = − 0.28, p = 0.0090). ACE2 was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p = 0.00045) and associated with use of ACE inhibitors (ACEi) (0.50, p = 0.0034), having cardiovascular disease (0.23, p = 0.048) or hypertension (0.34, p = 0.0089), and inhaled corticosteroid use in COPD subjects in bronchial biopsies (0.33, p = 0.049). Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD bronchial biopsies compared to HV-ES controls with log2FC of –0.26 (p = 0.033) and − 0.40, (p = 0.0010), respectively. However, the AGTR1:2 ratio was increased in COPD subjects compared with HV-ES controls, log2FC of 0.57 (p = 0.0051). Basigin, a newly identified potential SARS-CoV-2 receptor was also upregulated in both brushes, log2FC of 0.17 (p = 0.0040), and bronchial biopsies, (log2FC of 0.18 (p = 0.017), in COPD vs HV-ES. Transmembrane protease, serine (TMPRSS)2 was not differentially regulated between control and COPD. However, various other spike-cleaving proteases were, including TMPRSS4 and Cathepsin B, in both epithelial brushes (log2FC of 0.25 (p = 0.0012) and log2FC of 0.56 (p = 5.49E−06), respectively) and bronchial biopsies (log2FC of 0.49 (p = 0.00021) and log2FC of 0.246 (p = 0.028), respectively). Conclusion This study identifies key differences in expression of genes related to susceptibility and aetiology of COVID-19 within the COPD lung. Further studies to understand the impact on clinical course of disease are now required.

Background Although heart failure (HF) with preserved ejection fraction (HFpEF) is more common in postmenopausal women than in men, the effect of sex hormones on cardiac diastolic function remains unclear. We examined the effect of gonadectomy with or without an angiotensin receptor blocker, olmesartan (Olm), in an isoproterenol (ISO) -induced mouse model of left ventricular hypertrophy (LVH) and cardiac diastolic dysfunction. Methods ISO or ISO with Olm were administered for 28 days in sham-operated male and female, castrated (CAS), and ovariectomized (OVX) mice. The LV ejection fraction (EF) and E/A ratio were analyzed using echocardiography, and the LV and lung weight corrected by tibial length were determined as indices of LVH and lung congestion, respectively. Results On echocardiography, the systolic function did not differ between the four groups. The LV/tibial length (TL) and Lung/TL significantly increased in all groups. The LV/TL was lower in castrated-ISO vs. Male-Sham-ISO, but did not differ between Female-Sham-ISO and OVX-ISO. However, the Lung/TL of OVX-ISO was greater than that of Female-Sham-ISO. Olm prevented LV hypertrophy in all groups. The decreased E/A and increased lung weight were improved by Olm in Male-Sham and OVX-ISO, but not in the others. Conclusion These gender differences suggest that sex hormones play a pivotal role in modulating cardiac hypertrophy and diastolic dysfunction induced by chronic beta-adrenoceptor stimulation, thereby affecting the therapeutic potential of angiotensin receptor blockade.

The renin-angiotensin system (RAS) is involved in cardiovascular and hydroelectrolytic control, being associated with the development of hypertension. The restraint stress (RS) model is an aversive situation, which promotes a sustained increase in blood pressure and heart rate, and stimulation of the hypothalamic–pituitary–adrenal axis. Stress leads to an increase of angiotensin-II contents both in the circulation and the central nervous system (CNS), as well as an increased expression of AT-1 receptors in CNS structures related to stress. Stressful stimuli are associated with the modulation of autonomic nervous system, as well as baroreflex; changes in this adjustment mechanism are related to cardiovascular diseases. We hypothesized that RAS is involved in the modulation of autonomic, neuroendocrine, and functional RS-caused alterations. The intravenous (i.v) pretreatment of rats with lisinopril, an angiotensin-converting-enzyme inhibitor, reduced the RS-evoked pressor response. The doses of 0.1 and 0.3 mg/kg also reduced the RS-evoked tachycardia, while in the dose of 1 mg/kg of lisinopril potentiated the tachycardic one. Additionally, i.v. pretreatment with losartan, a selective AT-1 receptor antagonist, reduced the pressor and the tachycardic responses caused by RS. Pretreatment with lisinopril 0.3 mg/kg increased the power of the low frequency (LF) band of the systolic BP spectrum after the treatment without affecting this parameter during RS. The pretreatment with losartan 1 mg/kg increased the power of the high frequency (HF) band and reduced the LF (n.u.) and the LF/HF ratio of the pulse interval spectrum in the first hour of RS. Concerning baroreflex sensitiveness (SBR), pretreatments with losartan or lisinopril did not affect the gain of the baroreflex sequences. However, the pretreatment with losartan reduced the baroreflex effectiveness index of the total sequences in the third hour of the RS. These results indicate that Ang-II, via the AT-1 receptor, plays a facilitating influence on the cardiovascular response caused by RS; facilitates sympathetic activation and reduces parasympathetic activity related to RS; facilitates the baroreflex activation during RS and favors corticosterone release under this stress model. The impairment of Ang-II synthesis, as well as the blockade of AT-1 receptors, may constitute an important pharmacological strategy to treat cardiovascular consequences caused by stress.

Epidemiological evidence suggests that patients with hypertension infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at increased risk of acute lung injury. However, it is still not clear whether this increased risk is related to the usage of renin-angiotensin system (RAS) blockers. We collected medical records of coronavirus disease 2019 (COVID-19) patients from the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China), and evaluated the potential impact of an angiotensin II receptor blocker (ARB) on the clinical outcomes of COVID-19 patients with hypertension. A total of 30 hypertensive COVID-19 patients were enrolled, of which 17 were classified as non-ARB group and the remaining 13 as ARB group based on the antihypertensive therapies they received. Compared with the non-ARB group, patients in the ARB group had a lower proportion of severe cases and intensive care unit (ICU) admission as well as shortened length of hospital stay, and manifested favorable results in most of the laboratory testing. Viral loads in the ARB group were lower than those in the non-ARB group throughout the disease course. No significant difference in the time of seroconversion or antibody levels was observed between the two groups. The median levels of soluble angiotensin-converting enzyme 2 (sACE2) in serum and urine samples were similar in both groups, and there were no significant correlations between serum sACE2 and biomarkers of disease severity. Transcriptional analysis showed 125 differentially expressed genes which mainly were enriched in oxygen transport, bicarbonate transport, and blood coagulation. Our results suggest that ARB usage is not associated with aggravation of COVID-19. These findings support the maintenance of ARB treatment in hypertensive patients diagnosed with COVID-19.

SARS-CoV-2 uses ACE2, an inhibitor of the Renin-Angiotensin-Aldosterone System (RAAS), for cellular entry. Studies indicate that RAAS imbalance worsens the prognosis in COVID-19. We present a consecutive retrospective COVID-19 cohort with findings of frequent pulmonary thromboembolism (17%), high pulmonary artery pressure (60%) and lung MRI perfusion disturbances. We demonstrate, in swine, that infusing angiotensin II or blocking ACE2 induces increased pulmonary artery pressure, reduces blood oxygenation, increases coagulation, disturbs lung perfusion, induces diffuse alveolar damage, and acute tubular necrosis compared to control animals. We further demonstrate that this imbalanced state can be ameliorated by infusion of an angiotensin receptor blocker and low-molecular-weight heparin. In this work, we show that a pathophysiological state in swine induced by RAAS imbalance shares several features with the clinical COVID-19 presentation. Therefore, we propose that severe COVID-19 could partially be driven by a RAAS imbalance., The SARS-CoV-2 receptor ACE2 is involved in the Renin-Angiotensin-Aldosterone System (RAAS). Over-activation of RAAS in swine results in a disease state similar to that of COVID-19 in human patients, suggesting that COVID-19 pathophysiology may be driven, at least in part, by an imbalance of this hormonal system.

Background: Previous studies have shown a relationship between renin angiotensin aldosterone system (RAAS) and insulin resistance. This in turn can delay the onset of diabetes mellitus (DM). The impact of angiotensin receptor blocker (ARB) on the fasting plasma glucose (FPG) level is not clear. Objective: To compare the overtime FPG between ARB and non-ARB using. Methods: A retrospective-longitudinal cohort study, data were collected from medical records of hypertensive patients who were not diagnosed DM in 2007 and 2008, each patient was followed up 10 years. The association between antihypertensive drugs and FPG by multilevel mixed-effects linear regression was evaluated. Multistate Markov chain model was used to evaluate the probability to become pre-DM or DM stage. Results: Of 822 patients, 571 patients were excluded and 251 patients met criteria for analysis. From multilevel mixed-effects linear regression, ARB usage was associated with a nonsignificant decreased FPG when adjusted with visit (mean FPG change, -0.98; 95% CI, -2.65 to 0.69; P = .25) and with visit plus glomerular filtration rate (mean FPG change, -1.89, 95% CI, -4.88 to 1.19; P = .24). The probability of change in 10 years from normal to pre-DM stage was 0.41 and 0.38, normal to DM stage was 0.03 and 0.01, pre-DM to DM stage was 0.08 and 0.04, in non-ARB and ARB group, respectively. Conclusions: ARB tended to decrease probability to become DM. Thus, physicians should prescribe ARB in hypertensive patients to prevent new-onset DM.

Congestive heart failure (CHF) is often associated with kidney and pulmonary dysfunction. Activation of the renin‐angiotensin‐aldosterone system (RAAS) contributes to avid sodium retention, cardiac hypertrophy and oedema formation, including lung congestion. While the status of the classic components of RAAS such as renin, angiotensin converting enzyme (ACE), angiotensin II (Ang II) and angiotensin II receptor AT‐1 is well studied in CHF, the expression of angiotensin converting enzyme‐2 (ACE2), a key enzyme of angiotensin 1‐7 (Ang 1‐7) generation in the pulmonary, cardiac and renal systems has not been studied thoroughly in this clinical setting. This issue is of a special interest as Ang 1‐7 counterbalance the vasoconstrictory, pro‐inflammatory and pro‐proliferative actions of Ang II. Furthermore, CHF predisposes to COVID‐19 disease severity, while ACE2 also serves as the binding domain of SARS‐CoV‐2 in human host‐cells, and acts in concert with furin, an important enzyme in the synthesis of BNP in CHF, in permeating viral functionality along TMPRSST2. ADAM17 governs ACE2 shedding from cell membranes. Therefore, the present study was designed to investigate the expression of ACE2, furin, TMPRSS2 and ADAM17 in the lung, heart and kidneys of rats with CHF to understand the exaggerated susceptibility of clinical CHF to COVID‐19 disease. Heart failure was induced in male Sprague Dawley rats by the creation of a surgical aorto‐caval fistula. Sham‐operated rats served as controls. One week after surgery, the animals were subdivided into compensated and decompensated CHF according to urinary sodium excretion. Both groups and their controls were sacrificed, and their hearts, lungs and kidneys were harvested for assessment of tissue remodelling and ACE2, furin, TMPRSS2 and ADAM17 immunoreactivity, expression and immunohistochemical staining. ACE2 immunoreactivity and mRNA levels increased in pulmonary, cardiac and renal tissues of compensated, but not in decompensated CHF. Furin immunoreactivity was increased in both compensated and decompensated CHF in the pulmonary, cardiac tissues and renal cortex but not in the medulla. Interestingly, both the expression and abundance of pulmonary, cardiac and renal TMPRSS2 decreased in CHF in correlation with the severity of the disease. Pulmonary, cardiac and renal ADAM17 mRNA levels were also downregulated in decompensated CHF. Circulating furin levels increased in proportion to CHF severity, whereas plasma ACE2 remained unchanged. In summary, ACE2 and furin are overexpressed in the pulmonary, cardiac and renal tissues of compensated and to a lesser extent of decompensated CHF as compared with their sham controls. The increased expression of the ACE2 in heart failure may serve as a compensatory mechanism, counterbalancing the over‐activity of the deleterious isoform, ACE. Downregulated ADAM17 might enhance membranal ACE2 in COVID‐19 disease, whereas the suppression of TMPRSS2 in CHF argues against its involvement in the exaggerated susceptibility of CHF patients to SARS‐CoV2.

OBJECTIVE: Many trials confirmed the role of sacubitril–valsartan in the treatment of patients with heart failure with reduced ejection fraction (HFrEF). However, there is no sufficient data to register the effect of compulsory discontinuation of sacubitril–valsartan, either because of financial shortage or adverse effects, and shifting to the standard therapy, including angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). METHODS: The patients with HFrEF (LVEF ≤35%) were included in the study. They received treatment with sacubitril–valsartan as a replacement for an ACEI or ARB. The patients were divided into two groups: the compliant group (n=111). The non-compliant group (n=82), whose members discontinued sacubitril–valsartan after ≥5 months but

Kidney patients age faster and vascular risk factors intensify the process. Lifetime is reduced up to 16 years in patients with diabetes mellitus type 2 and kidney disease. SGLT2 inhibitors play a significant role in maintaining organ function. By inhibiting the SGLT2 transporter in the proximal tubule of the kidneys, energy and water are continuously excreted and metabolic processes that are counter-regulated are set in motion. This hypometabolic adaptation supports organ functions and induces longevity. Kidney protection extends life expectancy of patients with diabetes mellitus type 2.Also patients with heart failure benefit and a 3-stage therapy is newly being discussed. The beta blocker is combined with an SGLT2 inhibitor in the first stage. In the second stage, the angiotensin receptor/neprilysin inhibitor and then a mineralocorticoid receptor antagonist (MRA) is used. These therapies have a complementary effect.

Aims Pre‐existing cardiovascular disease in general and related risk factors have been associated with poor coronavirus disease‐2019 (COVID‐19) outcomes. However, data on outcomes of COVID‐19 among people with pre‐existing diagnosis of heart failure (HF) have not been studied in sufficient detail. We aimed to perform detailed characterization of the association of pre‐existing HF with COVID‐19 outcomes. Methods and results A retrospective cohort study based on Veterans Health Administration (VHA) data comparing 30 day mortality and hospital admission rates after COVID‐19 diagnosis among Veterans with and without pre‐existing diagnosis of HF. Cox‐regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) with adjustment for covariates. Among 31 051 veterans (97% male) with COVID‐19, 6148 had pre‐existing diagnosis of HF. The mean (SD) age of patients with HF was 70 (13) whereas the mean (SD) age of patients without HF was 57 (17). Within the HF group with available data on left ventricular ejection fraction (EF), 1844 patients (63.4%) had an EF of >45%, and 1063 patients (36.6%) had an EF of ≤45%. Patients in the HF cohort had higher 30 day mortality (5.4% vs. 1.5%) and admission (18.5% vs. 8.4%) rates after diagnosis of COVID‐19. After adjustment for age, sex, and race, HRs (95% CIs) for 30 day mortality and for 30 day hospital admissions were 1.87 (1.61–2.17) and 1.79 (1.66–1.93), respectively. After additional adjustment for medical comorbidities, HRs for 30 day mortality and for 30 day hospital admissions were 1.37 (1.15–1.64) and 1.27 (1.16–1.38), respectively. The findings were similar among HF patients with preserved vs. reduced EF, among those taking vs. not taking angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers or angiotensin receptor neprilysin inhibitors, and among those taking vs. not taking anticoagulants. Conclusions Patients with COVID‐19 and pre‐existing diagnosis of HF had a higher risk of 30 day mortality and hospital admissions compared to those without history of HF. The findings were similar by EF categories and by angiotensin‐converting enzyme inhibitors/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitors or anticoagulant use.

Objective The objective of this study was to investigate the effects of inverted photoperiods on the blood pressure and carotid arteries in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats (homologous control group). Methods and results This study used two inverted photoperiods [inverted light:dark (ILD)16 : 8 and ILD12 : 12] to create the model. A total of 27 male SHR and 27 male WKY rats were randomly divided into six groups (nine rats per group): SHR (LD12 : 12), SHR (ILD16 : 8), SHR (ILD12 : 12), WKY (LD12 : 12), WKY (ILD16 : 8) and WKY (ILD12 : 12). We recorded the trajectory of the activity rhythm of the rats and performed carotid vascular ultrasound examination, MRI (arterial spin labelling) analysis and carotid biopsy. The results showed that inverted photoperiods increased the blood pressure, carotid intima-media thickness, resistance index and blood flow velocity. In addition, inverted photoperiods led to the development of carotid arterial thrombosis, significantly reduced cerebral blood flow and increased the number of collagen fibres. Moreover, it increased the expression of angiotensin receptor and low-density lipoprotein receptor in the carotid arteries, leading to decreased expression of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase and nitric oxide synthase. Inverted photoperiods induced the formation of atherosclerotic plaque. Multiple results of SHR were worse than those of WKY rats. Conclusion Taken together, inverted photoperiods can produce a series of adverse consequences on blood pressure and carotid arteries. Hypertension can aggravate the adverse effects of inverted photoperiods.

Background: Use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) has been postulated to reduce cancer risk by inhibition of tumor progression, vascularization, and metastasis. The renin–angiotensin system is upregulated in colorectal cancers; however, the association of ACEi and ARB use with colorectal cancer risk is not well understood. Methods: The study population was 142,812 Women's Health Initiative participants free of colorectal cancer who reported on ACEi and ARB use at baseline; 2,216 incident colorectal cancers were diagnosed during 10 years of follow-up. Cox regression models estimated adjusted HRs and 95% confidence intervals for associations relative to nonuse among normotensive women, untreated hypertensive women, and hypertensive women treated with other antihypertensive medications. Results: HRs among women who used any ACEi or ARB compared with nonuse in the three referent groups ranged between 0.97 and 1.01. Findings were similar for increased ACEi/ARB duration and for medications examined as separate classes or individually. Conclusions: In this large prospective study of women, no associations of ACEi or ARB use with colorectal cancer risk were observed. Impact: Choice of drug in the large population of aging women who will be prescribed ACEi and ARB should be made without factoring in any benefit on colorectal cancer risk.

Aims Current evidence about the effect of angiotensin receptor blocker (ARB) on the outcome of heart failure with mid‐range ejection fraction (HFmrEF) is lacking. We aim to assess the association between use of ARB and 1 year all‐cause mortality after hospitalization for HFmrEF. Methods and results We analysed the data of patients with ejection fraction of 40–49% in China Patient‐centred Evaluative Assessment of Cardiac Events Prospective Heart Failure Study; 4907 patients hospitalized for heart failure from 52 Chinese hospitals were enrolled from August 2016 to May 2018. Use of ARB was determined by prescriptions at discharge. Patients who died during hospitalization or were using angiotensin‐converting enzyme inhibitors at discharge were excluded. The association between the use of ARB and outcome was assessed using stabilized inverse probability of treatment weighting‐adjusted Kaplan–Meier and Cox regression analyses. A total of 701 patients with HFmrEF were included for analysis. The mean age was 66.4 ± 12.8 years, and 267 (38.1%) were female. Of them, 244 were treated (34.8%) with ARB. During the 1 year follow‐up period, patients treated with ARB had lower all‐cause mortality compared with untreated patients (11.5% vs. 21.9%, P = 0.0005). Inverse probability of treatment weighting‐adjusted Cox regression analysis showed that use of ARB was associated with significantly reduced all‐cause mortality (adjusted hazard ratio 0.44, 95% confidence interval 0.28–0.69, P = 0.0004). Conclusions Among patients hospitalized for HFmrEF, the use of ARB was associated with lower 1 year mortality after discharge.

Objectives Individualizing a target mean arterial pressure is challenging during the initial resuscitation of patients with septic shock. The Sepsis and Mean Arterial Pressure (SEPSISPAM) trial suggested that targeting high mean arterial pressure might reduce the occurrence of acute kidney injury among those included patients with a past history of chronic hypertension. We investigated whether the class of antihypertensive medications used before the ICU stay in chronic hypertensive patients was associated with the severity of acute kidney injury occurring after inclusion, according to mean arterial pressure target. Design Post hoc analysis of the SEPSISPAM trial. Setting The primary outcome was the occurrence of severe acute kidney injury during the ICU stay defined as kidney disease improving global outcome stage 2 or higher. Secondary outcomes were mortality at day 28 and mortality at day 90. Patients All patients with chronic hypertension included in SEPSISPAM with available antihypertensive medications data in the hospitalization report were included. Measurements and main results We analyzed 297 patients. Severe acute kidney injury occurred in 184 patients, without difference according to pre-ICU exposure to antihypertensive medications. Patients with pre-ICU exposure to angiotensin II receptor blockers had significantly less severe acute kidney injury in the high mean arterial pressure target group (adjusted odd ratio 0.24 with 95% CI [0.09-0.66]; p = 0.006). No statistically significant association was found after adjustment for pre-ICU exposure to antihypertensive medications and survival. Conclusions Our results suggest that patients with septic shock and chronic hypertension treated with angiotensin II receptor blocker may benefit from a high mean arterial pressure target to reduce the risk of acute kidney injury occurrence.

Activation of AT 1 (type 1 Ang) receptors stimulates cardiomyocyte hypertrophy in vitro. Accordingly, it has been suggested that regression of cardiac hypertrophy associated with renin-Ang system blockade is due to inhibition of cellular actions of Ang II in the heart, above and beyond their effects to reduce pressure overload. We generated 2 distinct mouse lines with cell-specific deletion of AT 1A receptors, from cardiomyocytes. In the first line (C-SMKO), elimination of AT 1A receptors was achieved using a heterologous Cre recombinase transgene under control of the Sm22 promoter, which expresses in cells of smooth muscle lineage including cardiomyocytes and vascular smooth muscle cells of conduit but not resistance vessels. The second line (R-SMKO) utilized a Cre transgene knocked-in to the Sm22 locus, which drives expression in cardiac myocytes and vascular smooth muscle cells in both conduit and resistance arteries. Thus, although both groups lack AT 1 receptors in the cardiomyocytes, they are distinguished by presence (C-SMKO) or absence (R-SMKO) of peripheral vascular responses to Ang II. Similar to wild-types, chronic Ang II infusion caused hypertension and cardiac hypertrophy in C-SMKO mice, whereas both hypertension and cardiac hypertrophy were reduced in R-SMKOs. Thus, despite the absence of AT 1A receptors in cardiomyocytes, C-SMKOs develop robust cardiac hypertrophy. By contrast, R-SMKOs developed identical levels of hypertrophy in response to pressure overload–induced by transverse aortic banding. Our findings suggest that direct activation of AT 1 receptors in cardiac myocytes has minimal influence on cardiac hypertrophy induced by renin-Ang system activation or pressure overload.

Activation of central AT 1 Rs (angiotensin type 1 receptors) is required for the increased blood pressure, polydipsia, and salt intake in deoxycorticosterone acetate (DOCA)–salt hypertension. TRV120027 (TRV027) is an AT 1 R-biased agonist that selectively acts through β-arrestin. We hypothesized that intracerebroventricular administration of TRV027 would ameliorate the effects of DOCA-salt. In a neuronal cell line, TRV027 induced AT 1a R internalization through dynamin and clathrin-mediated endocytosis. We next evaluated the effect of chronic intracerebroventricular infusion of TRV027 on fluid intake. We measured the relative intake of water versus various saline solutions using a 2-bottle choice paradigm in mice subjected to DOCA with a concomitant intracerebroventricular infusion of either vehicle, TRV027, or losartan. Sham mice received intracerebroventricular vehicle without DOCA. TRV027 potentiated DOCA-induced water intake in the presence or absence of saline. TRV027 and losartan both increased the aversion for saline—an effect particularly pronounced for highly aversive saline solutions. Intracerebroventricular Ang (angiotensin) II, but not TRV027, increased water and saline intake in the absence of DOCA. In a separate cohort, blood pressure responses to acute intracerebroventricular injection of vehicle, TRV, or losartan were measured by radiotelemetry in mice with established DOCA-salt hypertension. Central administration of intracerebroventricular TRV027 or losartan each caused a significant and similar reduction of blood pressure and heart rate. We conclude that administration of TRV027 a selective β-arrestin biased agonist directly into the brain increases aversion to saline and lowers blood pressure in a model of salt-sensitive hypertension. These data suggest that selective activation of AT 1 R β-arrestin pathways may be exploitable therapeutically.

The role of antihypertensives, especially Renin–Angiotensin–Aldosterone System inhibitors, is still debatable in COVID‐19‐related severity and outcome. Therefore, we search for a more global analysis of antihypertensive medication in relation to SAS‐CoV‐2 severity using prescription data worldwide. The association between the percentage use of different types of antihypertensive medications and mortality rates due to a SARS‐CoV‐2 infection during the first 3 weeks of the pandemic was analyzed using random effects linear regression models for 30 countries worldwide. Higher percentages of prescribed angiotensin receptor blockers (ARBs) (β, 95% confidence interval [CI]; −0.02 [−0.04 to −0.0012]; p = .042) and calcium channel blockers (CCBs) (β, 95% CI; −0.023 [−0.05 to −0.0028]; p = .0304) were associated with a lower first 3‐week SARS‐CoV‐2‐related death rate, whereas a higher percentage of prescribed angiotensin‐converting enzyme inhibitors (ACEis) (β, 95% CI; 0.03 [0.0061–0.05]; p = .0103) was associated with a higher first 3‐week death rate, even when adjusted for age and metformin use. There was no association between the amount of prescribed beta‐blockers (BBs) and diuretics (Diu) and the first 3‐week death rate. When analyzing the combination of drugs that is used by at least 50% of antihypertensive users, within the different countries, countries with the lowest first 3‐week death rates had at least an angiotensin receptor blocker as one of the most often prescribed antihypertensive medications (ARBs/CCBs: [β, 95% CI; −0.02 [−0.03 to −0.004]; p = .009], ARBs/BBs: [β, 95% CI; −0.03 [−0.05 to −0.006]; p = .01]). Finally, countries prescribing high‐potency ARBs had lower first 3‐week ARBs. In conclusion, ARBs and CCB seem to have a protective effect against death from SARS‐CoV‐2 infection., Highlights Higher percentages of prescribed angiotensin receptor blockers and calcium channel blockers were associated with a lower first 3‐week SARS‐CoV‐2‐related death rate.Higher percentage of prescribed angiotensin‐converting enzyme was associated with a higher first 3‐week death rates.Countries with the lowest first 3‐week death rates had at least an angiotensin receptor blocker as one of the most often prescribed antihypertensive medications.

The renin–angiotensin system (RAS) is activated in inflammatory bowel disease (IBD), and vitamin D deficiency aggravates the development of colitis, but the relationship between the local colonic RAS and vitamin D is unclear with regard to the pathogenesis of IBD. To investigate whether vitamin D suppresses the local colonic RAS to prevent colonic mucosal inflammation in a mouse model of experimental colitis. C57BL/6 mice fed vitamin D-deficient (VDD) diet for 8 weeks were induced to colitis by 2,4,6-trinitrobenzenesulfonic acid (TNBS), with mice fed vitamin D-sufficient (VDS) diet as controls. Colitis severity was assessed by histology, and pro-inflammatory cytokines, RAS components, and signaling pathways were quantified by real-time RT-PCR and Western blotting. C57BL/6 mice fed the VDD diet for 8 weeks exhibited significantly lower serum 25(OH)D3 concentrations compared to mice fed the VDS diet. When these VDD mice were induced to colitis by TNBS, they exhibited more severe colonic inflammation and developed more severe colitis compared to the VDS counterparts. VDD diet feeding resulted in higher production of mucosal pro-inflammatory cytokines, higher activation of the myosin light chain kinase-tight junction regulatory pathway, and greater increases in mucosal permeability. VDD diet feeding also enhanced colonic RAS activation. Treatment with angiotensin II receptor blocker losartan markedly alleviated colitis in TNBS-induced VDD mice. Vitamin D deficiency promotes colonic inflammation at least in part due to over activation of the local RAS in the colon.

Objectives The authors sought to evaluate the association of heart failure hospitalization (HFH) with guideline-directed medical therapy (GDMT) prescribing patterns among patients with heart failure with reduced ejection fraction (HFrEF). Background HFH represents an important opportunity to titrate GDMT among patients with HFrEF. Methods The CHAMP-HF (Change the Management of Patients With Heart Failure) registry is a prospective registry of adults with HFrEF (ejection fraction ≤40%). Using data from the CHAMP-HF registry (N = 4,365), adjusted time-to-event models were created to study the association of HFH with GDMT prescribing patterns. Results HFH (compared with no HFH) was positively associated with initiation of angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), angiotensin receptor-neprilysin inhibitor, beta-blocker, and mineralocorticoid receptor antagonist (MRA). HFH positively associated with dose escalation of ACE inhibitor/ARB (probability ratio: 1.71, 95% confidence interval [CI]: 1.36 to 2.16) and MRA (probability ratio: 8.71, 95% CI: 4.19 to 18.10). In those on prior therapy, HFH was associated with discontinuation and de-escalation of all classes of GDMT. ACE inhibitor/ARB, angiotensin receptor-neprilysin inhibitor, beta-blocker, and MRA de-escalation/discontinuation after HFH was associated with increased risk of all-cause mortality with hazard ratios of 3.82 (95% CI: 2.42 to 6.03), 4.76 (95% CI: 2.06 to 11.03), 2.94 (95% CI: 2.04 to 4.25), and 4.81 (95% CI: 2.61 to 8.87), respectively. Conclusions HFH positively associated with changes in GDMT, including initiation, dose escalation, discontinuation, and dose de-escalation. De-escalation/discontinuation of GDMT after HFH associated with increased risk of all-cause mortality. Educational endeavors are needed to ensure GDMT is not inappropriately held in the setting of HFH. For those in whom GDMT must be held/decreased, improvement tools at discharge and post-discharge titration clinics may help ensure lifesaving GDMT regimens remain optimized.

Heart failure is an important cause of death of children. Especially, overt one within the preweaning period is fulminant and severe. However, there are no drugs with evidence for it. We recently found that angiotensin II (AngII) activates L-type Ca2+ channels through AT1 receptors (AT1R) and β-arrestin 2 in murine cardiac myocytes only in the preweaning period, indicating that AT1R/β-arrestin 2 pathway mediates positive inotropic effects before weaning. Indeed, β-arrestin-bias AT1R agonist (BBA), TRV027 caused significant long-lasting positive inotropic effects in preweaning mice without increasing serum aldosterone concentrations or inducing tachycardia, arrhythmias, increased cardiac oxygen consumption, and reactive oxygen species generation. TRV027 increased the peak amplitude of twitch Ca2+ transients not only in preweaning mouse cardiac myocytes but in human iPS cell-derived cardiac myocytes exhibiting the fetal to neonatal phenotype. Moreover, TRV027 also increased contraction of the compromised heart of the model knock-in mice mimicking human congenital dilated cardiomyopathy. Although ~80% of these mice died before weaning, TRV027 significantly increased their survival rate. TRV027 did not cause any obvious adverse effects on their preweaning wildtype littermates. Thus, we reason in this review that BBA can be important therapeutics for preweaning heart failure.

Background Myocardial infarction with non-obstructive coronary arteries (MINOCA) is common and occurs in 6–8% of all patients fulfilling the diagnostic criteria for acute myocardial infarction (AMI). This paper describes the rationale behind the trial ‘Randomized Evaluation of Beta Blocker and ACE-Inhibitor/Angiotensin Receptor Blocker Treatment (ACEI/ARB) of MINOCA patients’ (MINOCA-BAT) and the need to improve the secondary preventive treatment of MINOCA patients. Methods MINOCA-BAT is a registry-based, randomized, parallel, open-label, multicenter trial with 2:2 factorial design. The primary aim is to determine whether oral beta blockade compared with no oral beta blockade, and ACEI/ARB compared with no ACEI/ARB, reduce the composite endpoint of death of any cause, readmission because of AMI, ischemic stroke or heart failure in patients discharged after MINOCA without clinical signs of heart failure and with left ventricular ejection fraction ≥40%. A total of 3500 patients will be randomized into four groups; e.g. ACEI/ARB and beta blocker, beta blocker only, ACEI/ARB only and neither ACEI/ARB nor beta blocker, and followed for a mean of 4 years. Summary While patients with MINOCA have an increased risk of serious cardiovascular events and death, whether conventional secondary preventive therapies are beneficial has not been assessed in randomized trials. There is a limited basis for guideline recommendations in MINOCA. Furthermore, studies of routine clinical practice suggest that use of secondary prevention therapies in MINOCA varies considerably. Thus results from this trial may influence future treatment strategies and guidelines specific to MINOCA patients.