Angiotensin-converting Enzyme Research Articles

Characterizations of angiotensin-converting enzyme-2 (ACE2) peptidase activity

Angiotensin (Ang) II (1-8) is a potent vasoconstrictor known for its role in hypertension. Angiotensin-converting enzyme (ACE2) converts Ang II (1-8) to a vasodilator Ang (1-7) by removing the carboxy-terminal Phe. ACE2 more recently gained attention as the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused the coronavirus disease 2019 (COVID-19) pandemic. Given the pathophysiological importance of ACE2, the present study examined the mechanism of ACE2 catalytic activity by comparing the ability of angiotensin molecules of various lengths to compete with the artificial fluorogenic substrate. The Fluorimetric SensoLyte 390 ACE2 Activity Assay uses an Mca/Dnp fluorescence resonance energy transfer peptide as the substrate. Results showed that the natural substrate Ang II (1-8) competed with the fluorogenic substrate, reducing the fluorescence signals. Deletion of C-terminal Phe resulted in the loss of the ability to compete with the artificial substrate, as shown by the actions of Ang (1-7), Ang (2-7), and Ang (5-7). By contrast, the loss of N-terminal Asp potentiated the ability to compete with the substrate as seen by the action of Ang III (2-8). However, the loss of two amino acids (Asp-Arg) from the N-terminus reduced the ability to compete with the substrate as observed by the actions of Ang IV (3-8) and Ang (5-8). Ang I (1-10) and Ang (1-9) did not strongly compete with the substrate. Interestingly, shorter peptides Ang (1-5) and Ang (1-4) potentiated the ACE2 activity. These results suggest that Ang II and Ang III are the best natural substrates for ACE2.

Computational exploration of naturally derived peptides inhibitory mechanisms against ACE enzyme, from interactions to structural-dynamics

Naturally derived peptides have gained significant attention because of their potential to reduce blood pressure. These peptides can be derived from various sources, including snake venom, marine organisms, cow’s milk, seahorses, and plants. Investigating the underlying mechanisms of these peptides in lowering blood pressure is crucial for replacing synthetic drugs currently in use. In this regard, we conducted in silico studies, such as molecular docking, classical molecular dynamics (MD) simulations, and QM/MM simulation methods, on two naturally derived peptides (PAGPRGPA and WALKGYK) and Angiotensin II (ANGII) as the enzyme substrates for binding to sACE. The results of 500 ns MD calculations showed that the WALKGYK peptide occupies the ACE binding site, similar to the ANGII and BPPb peptides, two distinguished C-domain-specific inhibitors. Furthermore, QM/MM calculations demonstrated that no peptide bond cleavage was mediated by Zn2+ at the catalytic site of the peptides. However, during the 500 ns MD simulation, the backbone oxygens of LYS4 and GLY5 of the WALKGYK peptides were tightly coordinated to the Zn2+ ion. Free energy calculations also confirmed the higher affinity of the WALKGYK peptides for binding to sACE. In addition, structural analysis correlation showed a different pattern in PAGPRGPA compared to WALKGYK and ANGII. Despite the similarity of the peptide PAGPRGPA to typical ACE peptide inhibitors with hydrophobic ends, the electrostatic composition of the WALKGYK peptide showed a higher tendency towards ACE inhibition. Therefore, peptide residue compositions, such as WALKGYK, can be considered for designing new inhibitors with fewer side effects for sACE C-terminal inhibitors.

Discovery of a novel nanomolar angiotensin-I converting enzyme inhibitory peptide with unusual binding mechanisms derived from Chlorella pyrenoidosa

Chlorella pyrenoidosa (C. pyrenoidosa) has been cultivated in large quantities, and was proven to be antihypertensive when consumed orally. However, the antihypertensive peptides derived from C. pyrenoidosa remains scarce. In this study, trypsin was chosen to prepare the hydrolysate of C. pyrenoidosa, which was then fractionated by column chromatography. And ninety-nine peptides were identified by LC-MS/MS, after which 10 peptides were chosen by docking-based virtual screening and demonstrated the ability to inhibit ACE. Among them, LVAKA (LV-5) had the lowest IC50 (26.66 μM). LV-5, LKKAP, and PGLRP were identified as non-competitive ACE inhibitory peptides that exhibited significant stability in the face of extreme pH and high temperatures. Insilico and in-vitro simulated gastrointestinal digestion revealed that these three peptides could release ACE inhibitory peptide fragments after digestion. The sequence optimization of LV-5 led to the identification of LRAKA (LR-5), which was recognized as a novel nanomolar ACE peptide with an IC50 of 350 nM in-vitro and a potent antihypertensive effect in-vivo. Moreover, molecular dynamic simulation indicated that LR-5 interacted with an unconventional binding site in ACE. These findings underscore the potential of Chlorella as a source of antihypertensive peptides and suggest a promising future for the use of Chlorella-derived peptides in the management of hypertension.

Finerenone: A Novel Drug Discovery for the Treatment of Chronic Kidney Disease.

The most common cause of chronic kidney disease (CKD) is diabetic nephropathy (DN). Primarilymineralocorticoid receptor antagonists (MRAs) (spironolactone and eplerenone), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used for the treatment of CKD, but due to the high risk of hyperkalaemia, the combination was infrequently used. Currently after approval by FDA in 2021, finerenone was found to be effective in the treatment of CKD. Finerenone slowdowns the progression of diabetic nephropathy and lessens the cardiovascular morbidity in DN patients. The main objective of this review article is to provide a comprehensive and insightful overview of the role of finerenone by mainly focusing on its pharmacological properties, toxicity, uses, bioanalytical technique used for determination, and treatment options. Finerenone works by inhibiting the action of the mineralocorticoid receptor. Finerenone is quickly absorbed from the digestive tract after oral treatment and achieves peak plasma concentrations in 1-2 hours. Finerenone is actively metabolized through oxidation, epoxidation substitution, and direct hydroxylation. Elimination of finerenone is done through urine and feces. Determination of finerenone can be done through HPLC-MS and LSC. The present review covers the complete picture of ADME properties, bioanalytical techniques, clinical trials, toxicity, and possible avenues in this arena. Finerenone is effective compared to other mineralocorticoid receptor-like spironolactone and eplerenone, for the treatment of chronic kidney disease.

Therapeutic strategies to modulate gut microbial health: Approaches for sarcopenia management.

Sarcopenia is a progressive and generalized loss of skeletal muscle and functions associated with ageing with currently no definitive treatment. Alterations in gut microbial composition have emerged as a significant contributor to the pathophysiology of multiple diseases. Recently, its association with muscle health has pointed to its potential role in mediating sarcopenia. The current review focuses on the association of gut microbiota and mediators of muscle health, connecting the dots between the influence of gut microbiota and their metabolites on biomarkers of sarcopenia. It further delineates the mechanism by which the gut microbiota affects muscle health with progressing age, aiding the formulation of a multi-modal treatment plan involving nutritional supplements and pharmacological interventions along with lifestyle changes compiled in the review. Nutritional supplements containing proteins, vitamin D, omega-3 fatty acids, creatine, curcumin, kefir, and ursolic acid positively impact the gut microbiome. Dietary fibres foster a conducive environment for the growth of beneficial microbes such as Bifidobacterium, Faecalibacterium, Ruminococcus, and Lactobacillus. Probiotics and prebiotics act by protecting against reactive oxygen species (ROS) and inflammatory cytokines. They also increase the production of gut microbiota metabolites like short-chain fatty acids (SCFAs), which aid in improving muscle health. Foods rich in polyphenols are anti-inflammatory and have an antioxidant effect, contributing to a healthier gut. Pharmacological interventions like faecal microbiota transplantation (FMT), non-steroidal anti-inflammatory drugs (NSAIDs), ghrelin mimetics, angiotensin-converting enzyme inhibitors (ACEIs), and butyrate precursors lead to the production of anti-inflammatory fatty acids and regulate appetite, gut motility, and microbial impact on gut health. Further research is warranted to deepen our understanding of the interaction between gut microbiota and muscle health for developing therapeutic strategies for ameliorating sarcopenic muscle loss.

Polyphenol-rich Ocimum gratissimum leaf extract attenuates angiotensin-converting enzyme activity and impaired endothelial vascular function in diabetic rats

Endothelial vascular dysfunctions are prevalent among diabetic patients, significantly impacting their quality of life and prognosis. This study examined the effects of polyphenol-rich extracts from Ocimum gratissimum leaves on oxidative stress markers, serum lipid profiles, and angiotensin-converting enzyme activity in diabetic cardiac tissue. Forty Wistar rats (150–220 g) were divided into five groups: normal control, diabetic control, low-dose Ocimum gratissimum (122.46 mg/kg), medium-dose Ocimum gratissimum (244.98 mg/kg), and a positive control (standard diabetic drug). All rats except the normal control group were made diabetic via an intraperitoneal injection of 50 mg/kg streptozotocin, followed by 28 days of extract administration. Diabetes induction led to a significant (p<0.05) disruptions in lipid profiles, oxidative stress markers, and ACE activity. Treatment with Ocimum gratissimum extracts at both doses significantly (p<0.05) decreased triglyceride, low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol levels while increasing high-density lipoprotein cholesterol. Lipid peroxidation marker, malondialdehyde, was significantly (p<0.05) decreased, and antioxidant enzyme activities significantly (p<0.005) improved. ACE activity was significantly (p<0.05) reduced, approaching control levels. These results suggest that the polyphenol-rich extract of Ocimum gratissimum exerts antioxidant and cardio-protective effects, improving vascular functions in diabetic rats by improving lipid profiles, reducing oxidative stress, and suppressing ACE activity.

5-year valve academic research consortium-3 outcomes and predictors of mortality in a 10-year Asian transcatheter aortic valve implantation registry

Abstract Background Transaortic valvular implantation (TAVI) has revolutionised the management of aortic stenosis (AS). Uptake in Asia has caught up in recent years, after an initial lag due to expensive cost, limited subsidies, and scarce accessibility. Hence, longitudinal outcomes of TAVI remain largely unknown in Asian patients. Purpose This study aims to present the 5-year mortality endpoints in an Asian cohort followed up over a decade. Methods 253 patients with symptomatic severe aortic stenosis status post TAVI were retrospectively enrolled at a tertiary academic hospital from 2010-2021. The main outcomes were defined as short-term (30-day), mid-term (1-year) and long-term (5-year) all-cause mortality. Baseline demographics, procedural findings and clinical outcomes were analysed. Kaplan-Meier curves and multiple Cox regression analyses were constructed. Results The mean age was 75.2 + 10.2 years. 120 (47.4%) patients were female and 167 (66%) were Chinese. 168 patients (66.7%) received balloon-expandable valves, 80 patients (31.7%) underwent self-expandable valves, and 4 patients (1.6%) had mechanical-expandable valves. Malignancy was associated with worse short-term mortality at 30-days (HR 3.65, p = 0.054), while pulmonary disease and previous stroke were associated with worse long-term mortality at 5-years (HR 2.27, p = 0.012 and HR 2.02, p = 0.064). Worse all-cause mortality at 30-days, 1-year and 5-years were associated with high NT-Pro BNP levels (HR 1.04, p = 0.046; HR 1.05, p = 0.002 and HR 1.04, p < 0.001), the presence of peripheral arterial disease (PAD) (HR 4.32, p = 0.056; HR 4.48, p = 0.006 and HR 2.43, p = 0.023) and chronic kidney disease (CKD) (HR 6.19, p = 0.006; HR 6.77, p < 0.001 and HR 2.09, p = 0.008). Society of Thoracic Surgery (STS) score (HR 1.11, p = 0.001; HR 1.13, p < 0.001 and HR 1.12, p < 0.001) and Valve Academic Research Consortium (VARC) III endpoints of acute kidney injury (AKI) (HR 6.68, p = 0.047, HR 10.8, p < 0.001 and HR 6.99, p < 0.001), cardiogenic shock (HR 26.3, p < 0.001, HR 12.0, p < 0.001 and HR 4.29, p = 0.011) and structural complications (HR 40.3, p < 0.001, HR 18.1, p < 0.001 and HR 5.18, p = 0.008) were associated with worse all –cause mortality at time-points of 30-days, 1-year and 5-years respectively. On multivariate analyses adjusted for comorbidities and outcomes, STS score and structural complications were independent predictors of 30-day, 1-year, and 5-year all-cause mortality (HR 1.16; p = 0.003, HR 1.09, p = 0.003 and HR 1.10, p < 0.001) and (HR 62.7, p < 0.007; HR 18.9, p < 0.001 and HR 10.6, p = 0.001) respectively. Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) use was protective of survival within 1-year (HR 0.37, p = 0.022). Conclusions STS score and VARC III endpoints of structural complications were reliable predictors of all-cause mortality in Asian patients with TAVI. ACE inhibitor and ARB use was protective against mortality at 1-year.Cox regression analysesKaplan-Meier curves

Guideline-directed medical therapy and in-hospital mortality in acute coronary syndrome patients with advanced renal dysfunction

Abstract Background It is unclear whether early (initiated within 24 hours of admission) guideline-directed medical therapy [GDMT, i.e., the combined use of β-blocker, angiotensin converting enzyme inhibitor/angiotensin receptor blocker, dual antiplatelet drugs and statin] could benefit acute coronary syndrome (ACS) patients with advanced renal dysfunction [estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2]. Objectives The purpose of this study was to verify whether GDMT could improve in-hospital mortality in ACS patients with advanced renal dysfunction. Methods This study included 3,288 and 3,520 ACS patients with admission with advanced renal dysfunction from the CNEDSSP and CCC-ACS cohorts, respectively. Multivariable-adjusted analysis and propensity score matching (PSM) were employed to assess the impact of GDMT on in-hospital mortality. Results In a pooled analysis of the CNEDSSP and CCC-ACS cohorts, early GDMT was associated with significantly lower in-hospital mortality (relative ratio [RR]: 0.62, 95% CI: 0.47 to 0.81). PSM revealed an attenuation of the association of in-hospital mortality with early GDMT in ACS patients, with statistically significant associated reductions observed only in myocardial infarction (MI) patients (hazard ratio [HR]: 0.45, 95% CI: 0.27 to 0.75 in CNEDSSP cohort; HR: 0.48, 95% CI: 0.27 to 0.84 in CCC-ACS cohort). A random-effect pooled analysis for MI patients with admission advanced renal dysfunction demonstrated a 56% lower in-hospital mortality among GDMT users (RR: 0.44, 95% CI: 0.31 to 0.65). Conclusions This nationwide study highlights that early GDMT is associated with a reduced risk of in-hospital mortality in ACS patients (particularly in MI patients) with advanced renal dysfunction.

Levosimendan improves the early prognosis of patients with Non ST-segment elevation myocardial infarction and Killip class > II

Abstract Background Levosimendan is an inotropic agent known for its calcium-sensitizing myofilament effect and ATP-dependent potassium channel opening mechanism, which enhances myocardial contractility without increasing oxygen consumption. Despite its potential benefits, the impact of levosimendan on the prognosis of patients with myocardial infarction remains uncertain and requires further investigation through larger-scale studies. Purpose This study aimed to investigate the effect of levosimendan on the short-term prognosis of patients with Non-ST-segment elevation myocardial infarction (NSTEMI) and Killip> II. Methods The data for this study were derived from the Health and Medical Big Data Superplatform, comprising a retrospective cohort of patients admitted to and discharged from 72 secondary and tertiary hospitals in the City from 2010 to 2023. A total of 12472 patients with NSTEMI and Killip > II were included. Patients were divided into the levosimendan group and the non-leosimendan group based on whether levosimendan was used during hospitalization. Propensity score matching (PSM) was employed to balance covariates between the two groups. Multivariate Cox regression was used to evaluate the relationship between levosimendan and clinical outcomes. Covariates adjusted in PSM included age, sex, Killip class, early PCI, previous PCI, previous medical conditions (diabetes, hypertension, ischemic stroke, and chronic kidney disease), and medications during hospitalization (aspirin, clopidogrel, indobufen, ticagrelor, statins, cedilanid, recombinant human brain natriuretic peptide [rhBNP], milrinone, dopamine, dobutamine, and angiotensin converting enzyme inhibitor/angiotensin receptor blockers [ACEI/ARB]). The primary endpoint was major cardiovascular and cerebrovascular adverse events (MACCE), defined as the composite endpoint of cardiac death, myocardial infarction, and ischemic stroke within 3 months. Results The levosimendan group comprised 782 patients, while the non-leosimendan group included 11690 patients. After PSM, the covariates were balanced, resulting in 756 well-matched pairs. In PSM patients, the levosimendan group exhibited a significantly lower incidence of MACCE (aHR, 0.573; 95%CI, 0.466–0.704; p < 0.001) and cardiac death (aHR, 0.500; 95%CI, 0.399-0.626; p < 0.001). However, there was no significant difference in the incidence of myocardial infarction and ischemic stroke. Conclusions Levosimendan was associated with a lower incidence of MACCE within 3 months in patients with NSTEMI and Killip> II, mainly driven by lower incidence of cardiac death. However, these findings are based on observational data and require confirmation through adequately powered, randomized, controlled trials.

Epidemiology, clinical characterization, and outcomes for heart failure with improved ejection fraction

Abstract Background Contemporary guidelines propose a new classification of heart failure with improved ejection fraction (HFimpEF). The prevalence of HFimpEF is expected to increase with the implementation of guideline-directed medical therapy (GDMT); however, there are limited data on the epidemiology of and outcomes for this novel clinical entity. Purpose We describe the prevalence, GDMT use and outcomes among patients with HFimpEF within a large, integrated healthcare delivery system. Methods We identified adults ≥18 years with incident HF with reduced EF (HFrEF ≤40%) between January 2013 and December 2018 from a large, integrated healthcare system serving >4.5 million members. HFimpEF was defined as known HFrEF with a follow-up EF measurement >40% within 12 months after incident HFrEF. Among HFimpEF patients, we examined GDMT use at discharge after incident HFrEF, incident HFimpEF, and at 6- and 12-months post-HFimpEF. From 12 months post initial HFrEF diagnosis, we calculated incidence rates of subsequent worsening HF (WHF) events (i.e., HF-related hospitalization, emergency department or urgent outpatient visits adjudicated using validated natural language processing-based algorithms) and all-cause death through December 31, 2019. We compared rates between patients with HFimpEF and those with persistent HFrEF (i.e., having all LVEF measurements within 12 months of incident HFrEF ≤40%) using Cox proportional hazards models adjusted for the EF value at incident HFrEF. Results Among 12,639 patients with incident HFrEF, 4,124 (33%) experienced HFimpEF within 12 months. Among patients with HFimpEF, use of β-blockers (82%) and angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers (86%) was high, while angiotensin receptor-neprilysin inhibitor (1.2%) or mineralocorticoid receptor antagonist (28.2%) use was low. β-blockers, ACEi/ARB, and MRA use declined after incident HFimpEF (Figure, Panel A). Rates of WHF were 19.7 (95% Confidence Interval [CI]: 18.7 to 20.6) per 100 person-years among patients with HFimpEF vs. 40.0 (95% CI: 38.5 to 41.5) among patients with persistent HFrEF (hazard ratio [HR]: 0.55, 95% CI: 0.49 to 0.62; Figure, Panel B). Rates of death were 5.2 (95% CI: 4.7 to 5.7) and 8.4 (95% CI: 7.8 to 9.1) per 100 person-years among HFimpEF and persistent HFrEF, respectively (HR: 0.59, 95% CI: 0.52 to 0.67). Among patients with HFimpEF, those with an absolute EF improvement of ≥20% were less likely to experience WHF (HR: 0.82, 95% CI: 0.67 to 0.99) and death (HR: 0.85, 95% CI: 0.69 to 1.04) compared with those with <20% improvement. Conclusions One in three patients experienced improvement in EF within 12 months of initial HFrEF diagnosis. HFimpEF is associated with a reduced risk of WHF events and death, although these patients remain at significant clinical risk. Further research is necessary to assess the potential impact of sustained adherence to GDMT and therapeutic optimization on HFimpEF patient outcomes.

Circulating ACE2 and the association of endothelial progenitor cell in CAD patients

Abstract Background/Introduction Angiotensin-converting enzyme (ACE) 2 is the homologue of ACE, and the local up-regulation of ACE2 expression associates to antiatherosclerosis. ACE2 hydrolyzes the angiogensin II, which related to impair of endothelial progenitor cell (EPC) function. EPCs maintain the integrity of vascular endothelium in case of damage. Decreased number of EPCs associate thrombosis. Purpose To investigate the circulating ACE2 and the link to EPC in CAD patients. Methods Data from 650 patients with stable angina pectoris requiring invasive coronary angiography were enrolled. They were divided into two groups according to the median value of ACE2. Two interventional cardiologists diagnosed obstructive CAD by angiography review. Demographic characteristics and clinical outcomes were compared between groups. Results In all subjects (median age 67 years, male=66.9%), a higher ACE2 level indicates elder, higher prevalence of hypertension, diabetes mellitus and chronic kidney disease. Significant EPC elevation when CAD numbers increased in higher ACE2 group (SVD vs. DVD vs. MVD = 0.005 vs. 0.006 vs. 0.007, p value=0.044). In multivariate analysis, higher ACE2 is positively correlated to triple vessel disease (TVD vs. no CAD, adjusted odds ratio=1.627, 95% CI 1.026-2.579). Conclusions Our data demonstrated higher circulation ACE2 links to EPCs in CAD patients.

Role of inflammation and cholesterol efflux in myocardial infarction patients without standard modifiable risk factors

Abstract Background A substantial proportion of ST-segment elevation myocardial infarction (STEMI) patients has no standard modifiable cardiovascular risk factors (SMuRF) at admission. Knowledge on pathogenesis and risk markers of mortality in these patients remain limited. Aims We described the characteristics and prognosis of SMuRF-less patients admitted for a first STEMI in the light of recent prognostic biomarkers. Methods Baseline characteristics including interleukin (IL)-1β, hs-CRP and serum cholesterol efflux capacity were compared between patients with and without SMuRF. Determinants of 1-year all-cause mortality were assessed using univariable and multivariable Cox regression analyses. Results Among the 1604 patients included, 178 (11.1%) were SMuRF-less. SMuRF-less patients were older (66.9 ± 15.3 vs 61.9 ± 13.9, p<0.001), less often men (66.9 vs 75.9%, p<0.001) and had lower body mass index (24.2 ± 3.9 vs 26.0 ± 4.4, p<0.001) compared to patients with ≥1 SMuRFs. SMuRF-less patients presented higher rates of altered LVEF<45% and killip≥2 at admission (31.8% vs 22.8%, p=0.014 and 19 vs 12.9%, respectively, p=0.027) without differences in proportions of late STEMI presenters (symptoms-to-balloon time >360 min) did not differ between groups. SMuRF-less patients had lower rates of revascularization (82 vs 92.3%, p<0.001) and received less guidelines recommended medications (statins, β-blockers or angiotensin-converting enzyme (ACE) inhibitors) at discharge; p<0.001 for all. Compared to patients with SMuRF, SMuRF-less patients had lower serum cholesterol efflux capacity (0.79 ± 0.16 vs 0.83 ± 0.16, respectively, p<0.001), were more often in the highest tertile of IL-1β (28.7% vs 18.9%, respectively, p=0.002) with a trend towards more patients within the highest hs-CRP level tertile (24.7% vs 19.1%, respectively, p=0.077). Crude rates of mortality were more than doubled in the SMuRF-less group (18.5% vs 7.7%, respectively, p<0.001). After multivariable adjustment SMuRF-less status was associated with a higher rate of mortality at one year aHR 1.87 [1.05-2.38], p=0.029) as well as inflammation biomarkers IL-1β (HR 1.81 [1.23-2.66], p=0.003) and high tertiles of hs-CRP (HR 1.87 [1.31-2.66], p<0.001) whereas having a high serum cholesterol efflux capacity was associated with a lower mortality (HR 0.27 [0.09-0.87], p=0.0208). Conclusion In STEMI patients, SMuRF-less patients have higher levels of inflammatory biomarkers and more frequent defective serum cholesterol efflux capacity, are undertreated, and have higher rate of mortality than patients with standard modifiable cardiovascular risk factors. Optimized management of such patients is needed.

Angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers vs. calcium channel blockers for 12,478 young hypertensive patients under 40 in 10-year follow-up

Abstract Background It is uncertain whether angiotensin-converting enzyme inhibitors (ACEIs)/ angiotensin-receptor blockers (ARBs) is superior to calcium channel blockers (CCBs) in young hypertensive patients. Purpose To compare ACEIs/ARBs with CCBs in hypertensive patients <40 years for 10years. Methods We enrolled adults aged 20-39 with hypertension from 2007-2010 using the Korean national Insurance. Among 409,151 hypertensive patients, we made propensity matched analysis to compare the 2 drugs. Results 12,478 patients were enrolled, 6239 in ACEIs/ARBs and 6239 in CCBs group. Primary endpoint of a composite of myocardial infarction (MI), heart failure (HF), stroke, and total death was similar in 2 groups in young hypertensive patients in 10-year follow-up: 662 (ACEIs/ARBs) vs. 642/10000 (CCBs) with hazard ratio (HR) of 1.03 (reference, CCBs) (CI 0.90-1.18, P=0.657). In individual event of a MI, HF, stroke and total death, there was no difference in 2 groups: 99 vs 128/10000 persons (ACEIs/ARBs and CCBs respectively) with HR 0.77 (CI 0.56-1.08, P=0.13) in MI, 114 vs. 87/10000 (HR 1.32, P=0.123) in HF, 314 vs. 306 /10000 (HR 1.03, CI 0.64-1.20, P=0.795) in stroke and 184 vs. 167/10000 (HR 1.11, CI 0.85-1.44, P=0.454) in total death. Conclusions In young hypertensive patients, ACEIs/ARBs did not superior to CCBs in 10year clinical follow-up in large population.

Prevalence and prognostic relevance of non-obstructive coronary atherosclerosis in MINOCA: a meta-analysis of 35 studies

Abstract Background Myocardial infarction with non-obstructive coronary arteries (MINOCA) can result from a variety of pathological mechanisms, not always associated with atherosclerosis. It has been suggested to distinguish between patients without obstructive coronary artery disease (NObs-CAD, stenosis diameter 1-49%), and patients with smooth coronary arteries (NCA), but differences in terms of prognosis or therapeutic approaches have not been clearly elucidated. Objectives The aim of this study is to evaluate the prevalence and prognostic impact of NObs-CAD as assessed by invasive coronary angiography (ICA) in MINOCA. Methods A meta-analysis was performed including studies reporting the prevalence of NObs-CAD versus NCA in MINOCA patients. Data on prognosis stratified by the presence of NObs-CAD were collected. Random-effects models were used to estimate the prevalence of NObs-CAD. Pooled risk ratios (RR) with 95% confidence intervals (CI) for all-cause death, myocardial infarction (MI), and the composite of both outcomes of patients with NObs-CAD compared to NCA were calculated at short-term (<1 month), 1-year and long-term follow-up (more than 1 year). Results Thirty-five studies were analysed. The pooled prevalence of NObs-CAD estimated by ICA was 53% [95% CI 47-60%]. Heterogeneity was high (I2=98.0%), but none of the clinical and instrumental characteristics tested in meta-regression analyses had a significant impact on the I2, except for age (residual I2=97.2%, p=0.014) and geographical context. Specifically, studies conducted outside Europe reported a higher prevalence of NObs-CAD with lower I2 values. Thirteen studies provided prognostic data. The presence of NObs-CAD was associated with an increased risk of death or MI compared to NCA, as well as the risk of MI at 1-year follow-up (RR = 1.49 [95% CI 1.17-1.90] and RR = 1.80 [95% CI 1.26-2.59], respectively), whereas the risk of death was comparable. Similar results were observed at long-term, but not at short-term follow-up. Out of 13 studies, 4 provided information regarded the medications at discharge stratified by the presence or absence of NObs-CAD. NObs-CAD patients received more often aspirin (89% vs 69%; p<0.01), P2Y12-inhibitors (52% vs 29%; p<0.01), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (53% vs 40%; p<0.01), beta-blockers (70% vs 57%; p<0.01), and statins (86% vs 60%; p<0.01) compared to NCA. Conclusions Stratification of patients according to the degree of coronary stenosis has prognostic implications in the setting of MINOCA, since NObs-CAD patients present a higher risk of reinfarction. Further dedicated trials are needed to clarify whether these patients may benefit from a tailored approach in terms of secondary prevention strategies.Central illustration

Long-term continuation to pharmacological treatment for secondary prevention after a myocardial infarction: a register study

Abstract Background Pharmacological treatment for secondary prevention after acute myocardial infarction (MI) is crucial to prevent new events. Several studies report inconsistence and need for improvement of pharmacological treatment. Study follow-up is often less than 10 years and showing that continuation to drug treatment decreases with time. Objective To study long-term follow-up of nationally guideline recommended medical therapy (GDMT) for secondary prevention after a myocardial infarction. Method The study population consisted of individuals aged 18-84 years, who were hospitalized for a MI between January 2006 and December 2022 and were followed up to 16 years. The study subjects were identified through the National Inpatient Register and linked to the Prescribed Drug Register. Four classes of drugs were analyzed: antiplatelet/anticoagulant therapy, lowering therapy, betablockers and angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB). Time-updated survival analyses were used to investigate the relationship between continuation of preventive pharmacological treatment and mortality and recurrent MI after an acute MI. Results A total number of 139 413 individuals (mean age 69.1±10.6) were included and 33.3% were female. At baseline 51.2% had hypertension, 21.5% diabetes mellitus and 15.2% heart failure. All prescriptions of GDMT were decreased significantly after hospitalization after MI and during first years and remained plateau (figure 1). During follow-up 55487 persons died (39.8%, event rate 5.81 per 100 person years [95% CI 5.76-5.86]). Medication with antiplatelets/anticoagulantia, ACEi/ARB and statins decreased risk of all cause-mortality and myocardial infarction [HR 0.83 [95% CI 0.79-0.86], p-value <0.001, HR 0,79 [95% CI 0.77-0.83], p-value <0.001, HR 0.70 [95% CI 0.67-0.73], p-value <0.001) respectively. Conclusion Pharmacological treatment as a part of secondary prevention remained greatly underutilized both shortly and during long-term after MI. Usage of antiplatelets or antigulantia, ACEi or ARB and statins decreased the risk of all-cause mortality and recurrent myocardial infarction.

Temporal trends and regional differences of initial oral antiarrhythmic drug options in patients with new-onset atrial fibrillation: a report from the GLORIA-AF registry

Abstract Background New-onset atrial fibrillation (AF) is common and antiarrhythmic drugs (AADs) are commonly used for treating such patients. However, whether there are temporal changes and regional differences in the choice of AADs in direct acting non-vitamin K oral anticoagulants (DOACs) era is less studied. Purpose The present study aimed to analyze the temporal trends and regional differences of initial oral AAD options in patients with new-onset AF in the GLORIA-AF registry, based on a proposed modernized classification of AADs in 2018 (Circulation, 2018, PMID: 30354657). AADs involved in the present study included traditional Vaughn-Williams Class I to Class IV AAD, Class IId AAD (digoxin), and Class VII AAD, which acts on the upstream of arrhythmia including angiotensin converting enzyme inhibition, angiotensin receptor blocker, and stains. Methods Temporal changes regarding the AAD use between the two phases of GLORIA-AF and regional differences of AADs choice were investigated. Factors associated with the choice of different AADs were established by multivariate logistic regression. Results Among the 36,617 participants in the GLORIA-AF registry, 33,208 (90.7%) were prescribed with AADs: 74.0% were rate control and 10.2% were rhythm control, and among the prescribed AADs, single and dual AADs were used in 73.3% and 24.9%, respectively. Moreover, 70.5% patients received upstream target modulators (Class VII AAD). Class IIa AADs (beta-blockers) were the most commonly prescribed AAD and slightly increased from Phase II (60.58%) to Phase III (62.91%) while the use of Class IId AAD (e.g. digoxin) decreased regardless of single or combined use. AADs use varied significantly among regions but the temporal trends and regional differences were similar with that of the overall cohort. Age, gender, comorbidities, admission signs, region, and concomitant medications (e.g. anticoagulants) were associated with the choices of different AADs. Conclusions In the DOAC era, new-onset AF patients receiving AAD commonly included upstream therapy. Rate control was still the dominant strategy for patients with new-onset AF but the use of Class IId AAD significantly decreased with the increased use of Class IIa AAD. The choice of AADs demonstrated significant regional differences and concomitant anticoagulants played important roles.Temporal trends in GLORIA-AFComparisons of AADs use in GLORIA-AF

Prognostic determinants in patients with heart failure with reduced ejection fraction after a first hospitalisation for acute heart failure. COMFE registry

Abstract Introduction The clinical characteristics and determinants for prognosis of patients with a first hospitalisation for heart failure (HF) with reduced left ventricular ejection fraction (LVEF <40%) are poor described and show heterogeneous results that need major investigation. Purpose The aim of our study was to identify the clinical characteristics, prognosis and their main determinants in a prospective registry of patients with HF and reduced LVEF with a first hospital admission for acute heart failure, prognosis and their main determinants in a prospective registry in these patients. Methods We carried out a prospective registry in 2 University Hospitals of patients admitted to cardiology department due to first-time HF hospitalisation with reduced LVEF. 231 admitted consecutively between March 2021 and September 2022 were included, with a mean follow-up of 381 days. Continuous variables were represented as median (interquartile range) and categorical variables as percentage %. A multivariate logistic regression was performed in which age, sex, comorbidities, treatment, rhythm at discharge and improvement in LVEF were included; and using the Wald method, the predictors of rehospitalization and/or death were identified. Data were analysed using SPSS v. 25.0. Results The main baseline characteristics are shown in Table 1. The population had a median age of 71 years, 75% were men, with a high prevalence of arterial hypertension (HBP) (69%) and hyperlipidemia (57%). Quadruple therapy (Na-Glucose cotransporter 2 inhibitor [SGLT2i], Beta-Blocker, mineralocorticoid receptor antagonist [MRA] and angiotensin receptor-neprilysin inhibitor [ARNI], angiotensin converting enzyme inhibitor [ACEi] or Angiotensin-II receptor blocker [ARB]) was achieved in 57% at discharge. The dynamics of NTproBNP was studied from admission to completed up-titration, observing an average reduction of 37% and 32% met the criteria for improved LVEF after. The etiology is described in Figure 1a, with ischemic heart disease being the most represented (31%). Multivariate Cox regression for the combined event of readmission/death from any cause showed that treatment with SGLT2i (OR 0,48 [CI 95%: 0,23-0,98 p:0,04]) and Beta-Blocker (OR 0,35 [CI 95%: 0,14-0,87 p:0,02]) at discharge and improved LVEF (OR 0,33 [CI 95%: 0,15-0,72 p:0,006]) were protective predictors against the event; but diabetes mellitus (DM) was a predictor of a worse prognosis (OR 2,9 [CI 95%: 1,52-5,5 p:0,001]) Fig. 1b. Conclusions Patients with a first admission for HF with reduced LVEF constitute a heterogeneous clinical group. Improvement in LVEF after drug up-titration and treatment with SGLT2i and Beta-blocker are independently associated with a better prognosis. Our findings may have implications for their clinical management.Table 1Figure 1

What does routinely-collected electronic health record data tell us about the use of heart failure medication among older people in Wales? Making progress but could do better

Abstract Background European Society of Cardiology 2021 guidelines recommend 4 pillars of treatment to reduce mortality for those with heart failure (HF) and reduced ejection fraction (HFrEF): pillar 1) angiotensin converting enzyme inhibitor (ACE-I)/angiotensin receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), pillar 2) beta-blocker (BB), pillar 3) mineralocorticoid receptor antagonist (MRA), pillar 4) sodium-glucose co-transporter 2 inhibitor (SGLT2i). When there is heart failure with preserved ejection fraction (HFpEF), guidelines recommend diuretics to alleviate congestion and treatment of risk factors such as hypertension and diabetes. Prior to 2021, United Kingdom guidelines did not include SGLT2i. Purpose To examine how HF treatment is recorded in routinely-collected electronic health record (EHR) data for older people in Wales, and to explore how that has changed since 2015. Methods We conducted a retrospective, population-level, observational study using linked anonymised EHR data in Wales (2015-22). 737,230 individuals were aged 65y+ in the study period (21.5% of population in 2022). Of these, 65,010 had a code for heart failure in their primary or secondary care records. We excluded 13,990 individuals with fewer than 12 months data pre- or post-diagnosis. We looked forward, from HF diagnosis, for codes associated with specific medications. Results The final cohort comprised 51,020 individuals aged 65y and over with a diagnosis of heart failure between 2015-2022. Incidence and prevalence of heart failure increased across the study period (1.4-1.5% and 8.5-9.1% respectively). Preceding cardiovascular diagnoses included hypertension (69.5%), atrial fibrillation (36.7%), myocardial infarction (30.5%), coronary artery disease (25.7%), and valve disease (17.7%). Diabetes (41.7%), chronic kidney disease (30.9%) and cancer (26.4%) were the most common comorbidities. The subtype of HF (HFrEF or HFpEF) was only evident in 5,850. Treatments recorded most often were loop diuretics, ACE-I, and BB (Table 1). SGLT2i codes increased in 2020/2021(Figure 1). At 10-12 months post diagnosis, the proportion with simultaneous pillar combinations was; 27.4% 1 + 2, 12.5% 1, 2 + 3, and only 2% 1, 2, 3 + 4. Conclusions In Wales, there is a need to improve the coding of HF subtype in primary care records. We suggest interpreting data with the assumption that approximately half of the cohort are likely to have HFrEF. While the cohort proportion on ACE-I or beta-blockers may be appropriate, the proportion with more than 1 simultaneous pillar of treatment recorded appears low. The use of SGLT2i in codes is increasing. These results are important in evaluating health service delivery and in establishing baseline data from which to monitor improvements.

Sex-differences in prescription patterns of secondary prevention pharmacotherapy in patients with acute myocardial infarction: a 20-year perspective

Abstract Background Recent studies have demonstrated sex-related differences in secondary prevention pharmacotherapy in patients with acute myocardial infarction (AMI), although guidelines recommend the same preventive approach in both women and men. Purpose This study extends earlier work by examining temporal trends of prescribing practices of secondary prevention medications using contemporary data from a long-term period in Switzerland, with particular regard to sex inequalities. Methods For the purpose of this retrospective analysis of prospectively collected data in the Acute Myocardial Infarction in Switzerland (AMIS) Plus registry, optimal medical therapy (OMT) was defined as the combination of all five guideline-recommended medications in AMI at discharge: aspirin, P2Y12 inhibitors, lipid-lowering drugs, beta blockers, and angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Uni- and multivariable logistic regression analyses were performed. Results A total of 34'612 patients (men n=25’913, 75%) hospitalised with AMI between 2003 and 2022 were included in the analysis. The mean age was 66±13 years and women were on average 7 years older than men. Despite having more comorbidities, women benefited less frequently from OMT than men (51% vs. 60%) across all age groups (all p<0.001), with the greatest gap occurring in patients <50 years of age. Within the 20-year study period, significant increases over time were observed in the singular prescription of all OMT components, except for beta blockers (p=0.2). This translated into a marked increase in OMT prescription irrespective of age and sex (from 36% to 60%), mainly due to greater prescription of dual antiplatelet therapy (DAPT, from 71% to 91%) and lipid-lowering drugs (LLD, from 69% to 93%). The sex-related gap in OMT disfavoring women showed a uctuating trend over the years (getting reduced from 14% in 2003 to 0.7% in 2016 to widen again to 12% in 2022) whereas there was a continuous narrowing over time regarding the combination of DAPT plus LLD, from 18% to 10% at the beginning and the end of the observation, respectively (Figure 1). In multivariable analysis, age (OR 0.99, 95%CI 0.98-0.99, p<0.001) and female sex (OR 0.90, 95%CI 0.85-0.95, p<0.001) were independent predictors of deficient OMT prescription, while the performance of percutaneous coronary intervention was identified as the strongest positive predictor favoring it (OR 4.85, 95%CI 4.49-5.24, p<0.001). Conclusion Although there has been a gradual increase in the prescription of OMT over time among both women and men, concerning sex disparities disfavoring women, and particularly young women, remained. Targeted programs to reduce sex-related differences in secondary prevention care are warranted.

Sodium-glucose co-transporter-2 inhibitors : a potential cardioprotective agent?

Abstract Background Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are one of the cornerstones in the treatment of patients with heart failure (HF) , regardless the ejection fraction (EF) or the presence of diabetes mellitus (DM). Other types of medications used in the treatment of heart failure , like angiotensin converting enzyme inhibitors (ACEi) or beta-blockers (BB) have shown some degree of cardioprotection in high risk patients receiving cardiotoxic chemotherapy, but data on SGLT2i are very limited. Purpose To examine the possible differences in the development of anthracycline cardiotoxicity in diabetic patients receiving SGLT2i compared to those who don’t. Methods We retrospectively analysed the data from the oncological as well as hematological patients of our hospital. Group 1 (SGLT2) included patients with cancer who received anthracycline treatment and diabetes on treatment with SGLT2i. Group 2 (control) included patients with cancer who received anthracycline treatment and diabetes but with treatment other than SGLT2i. We recorded the basic demographic parameters, the development of cardiotoxicity (heart failure incidence, heart failure admissions, new cardiomyopathy [>10% decline in ejection fraction to <50%], and clinically significant arrhythmias) as well as the abnormal levels of troponin I (tnI) and natriuretic peptides (NTproBNP). Results Age, sex, ethnicity, cancer type, cancer stage, and other cardiac risk factors were similar between groups. The mean duration of the follow up was 2 years. In the SLT2 group were included 86 patients and in the control group 97. The rates of the cardiotoxicity events were recorded as follow : (SGLT2 vs control) Heart failure (7.4% vs 31.9%, p<0.01), heart failure admissions (3.4% vs 12.3%, p<0.05), new cardiomyopathy (6.1% vs 27.2%, p<0.05), arrhythmias (2.7% vs 24.3%, p<0.01), abnormal tnI levels (4.2% vs 14.7% , p< 0.01), abnormal NTproBNP levels (6.4% vs 30.9%, p<0.01) Conclusions SGLT2 inhibitors were associated with lower rate of cardiac events among patients with cancer and DM who were treated with anthracyclines. Further studies are needed in order to test the possible cardioprotective effects of SGLT2 inhibitors in patients at high cardiac risk treated with anthracyclines.