Angiotensin-converting Enzyme Research Articles

Blood pressure control and cardiovascular risk assessment in patients with hypertension: a pooled analysis of 6 countries in Eastern and Southern Europe (SNAPSHOT study)

Abstract Background Recent guidelines of the European Society of Cardiology (ESC) introduced stricter recommendations regarding blood pressure (BP) control, based on recommended levels following an assessment of cardiovascular (CV) risk. However, data are lacking on perception and actual BP control, and CV risk assessment. Purpose To assess BP control and CV risk assessment in patients with hypertension. Methods This is a cross-sectional multicentre study (SNAPSHOT) including pooled data from 6 countries in Europe. 9466 patients with hypertension were included from 513 participating investigators (69.6% general practitioners [GPs], 17.4% cardiologists, 6.2% endocrinologists). BP control and CV risk were assessed by investigators and compared to the re-assessment based on current ESC guidelines (SCORE1 and SCORE2&2-OP). Results 9443 patients with complete data (65.6±10.7 years, 57.0% female) were analysed from Bulgaria (35.6%), Romania (26.8%), Croatia (13.8%), Serbia (12.5%), Georgia (6.4%), and Spain (4.9%). Most patients had additional risk factors, such as overweight/obesity (81.6%), dyslipidaemia (80.8%), type 2 diabetes (32.8%) or current/former smoking (29.5%). Two or more risk factors (male gender, age ≥65 years, obesity, smoking) were more frequent in patients with very high calculated CV risk (60.9% by SCORE1, 57.7% by SCORE2&2-OP). Systolic and diastolic BPs were 139.3±17.3 mmHg and 82.3±10.9 mmHg, respectively. Almost all patients (98.5%) had their hypertension treated, 54.5% taking a single-pill combination (SPC). The most used drug classes were diuretics (59.6%), angiotensin-converting enzyme inhibitors (59.4%), and beta-blockers (57.0%). Combination therapy of 2 or 3 drug classes (SPC or not) was used in 33.2% and 34.4% of patients, respectively. According to investigators, BP was considered controlled in 75.0% of patients, whereas 48.0% of patients had BP <140/90 mmHg, and only 24.4% of patients were controlled at BP target according to guidelines (Figure 1). CV risk was estimated by investigators as low, moderate, high or very high for 10.1%, 34.9%, 32.0% and 23.0% of patients, respectively, whereas calculated CV risk was very high in most patients (59.1% by SCORE1, 86.8% by SCORE2&2-OP). CV risk estimated by investigators varied by country and by speciality, being high (29.4%, 35.0% and 32.0%) and very high (32.4%, 49.8% and 18.6%) for cardiologists, endocrinologists and GPs, respectively. Compared to calculated CV risk, CV risk estimated by investigators was frequently underestimated (54.4% by SCORE1, 67.6% by SCORE2&2-OP), varying between 30.8% in Spain and 68.2% in Bulgaria for SCORE1, and between 42.1% in Spain and 84.8% in Serbia for SCORE2&2-OP (Figure 2). Conclusion Physicians across 6 European countries tended to overestimate control of BP and underestimate CV risk in patients with hypertension. Our findings highlight the need for better assessment and management of patients according to the latest ESC guidelines.

Elegibility for Sacubitril/Valsartan in italian clinical practice: insights from the OPTIMA-HF registry

Abstract Background/Introduction Guidelines strongly recommend patients with heart failure with reduced ejection fraction (HFrEF) be treated with multiple medications proven to improve clinical outcomes, as tolerated. Among them, angiotensin receptor blocker/neprylisin inhibitor (ARNi) are the foundation of neuro-hormonal blockade in patients with HFrEF, however the degree to which gaps in this medication use and dosing persist in outpatient practice is unclear. Purpose To assess the proportion of patients with HFrEF who are eligible for ARNi based on the PARADIGM-HF trial criteria and the association between eligibility and baseline characteristics. Methods The OPTIMA-HF (Optimization of Therapy in the Italian Management of Heart Failure) registry included outpatients in Italy with chronic HFrEF receiving at least 1 oral medication for management of HF. Patients were characterized by baseline use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB)/ARNI, beta-blocker, mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter II inhibitor (SGLT2i). Patient-level factors associated with medication use were examined. Results Outpatients with HFrEF from 29 ambulatory cardiology practices and university hospitals in the OPTIMA-HF registry recruited between January 2022 and September 2023 were included. Of 1291 patients, 1018 (79%) met the PARADIGM-HF criteria and 949 of them (93%) were on ARNi. Of the enrolled patients, 342 (27%) were not on ARNi, however only 129 (38%) did not met the PARADIGM-HF inclusion criteria for ARNi prescription. Reasons for not meeting PARADIGM-HF criteria were no beta-blocker background therapy (22%), hyperkalemia (4%), hypotension (15%), chronic kidney disease (65%) and hyperkalemia (79%). In a logistic regression model not being on ARNi was associated with older age, chronic kidney disease, not being on cardiac resynchronization therapy, lower systolic blood pressure, lower BMI, and higher PAPs (Figure), representing the picture of a more fragile patient net of compliance with the PARADIGM-HF criteria. Conclusions Among outpatients with HFrEF in the OPTIMA-HF Registry, 79% met the PARADIGM-HF criteria. Strategies to improve guideline-directed use of HFrEF medications remain urgently needed, and these findings may inform targeted approaches to optimize outpatient medical therapy.

Heart failure burden among adults with congenital heart disease

Abstract Background Adult congenital heart disease (ACHD) is associated with high rates of healthcare utilization and mortality. Data on Heart failure (HF) burden among ACHD patients are limited. Purpose To study the association between HF and healthcare utilization and mortality among ACHD patients in the community. Methods The retrospective cohort study comprised 11,653≥ 18 year old ACHD patients insured by two large Israeli healthcare providers between January 2007 and December 2011. We used multivariable Cox proportional hazard and negative binomial models to study the associations of HF with mortality and healthcare utilization, respectively. Inverse treatment probability weighting accounted for drug indication. Results ACHD-HF patients (N=908; 7.8%) were older (median: 69 vs. 45 years), more likely men (53% vs. 45%), with complex congenital heart disease (14% vs. 4%), and higher comorbidity rates than ACHD patients without HF. HF was associated with higher healthcare utilization. Compared to patients without HF, ACHD-HF patients had higher adjusted relative rates (RR) of primary care (1.26, 95% confidence interval [CI]: 1.17-1.3), and cardiology clinic visits (1.9, 95% CI: 1.7-2.0), higher hospitalization rates (RR=2.0, 95% CI: 1.7-2.1), and higher risk of death (mortality hazard ratio [HR]: 1.9, 95% CI: 1.5-20.) over the study period. Among ACHD-HF patients, Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and diuretics were associated with a lower mortality risk (treated vs. untreated HR=0.56, 95% CI: 0.48-0.65; HR=0.7, 95% CI: 0.6-0.8; HR=0.84, 95% CI: 0.73-0.97; respectively). Conclusions HF presents a major burden on ACHD patients and health care systems. Drugs recommended to the general HF patient population are also associated with lower risk of hospitalization and mortality in ACHD patients. Clinical trials are needed to establish the benefit of HF pharmacotherapy in ACHD patients.Age adjusted ACHD patient survival by HF

Clinical characteristics and treatment patterns of new users of dapagliflozin for heart failure with reduced ejection fraction: an observational study programme across 12 countries (EVOLUTION HF)

Abstract Background Clinical trials have shown that dapagliflozin, a sodium–glucose cotransporter-2 inhibitor (SGLT-2i), reduces cardiovascular mortality and worsening heart failure (HF). Adoption of new therapies has historically been slow despite robust evidence. Furthermore, treatment profiles of patients in real-world settings are scarce. Purpose EVOLUTION HF is a multinational study programme that aims to describe clinical characteristics and treatment patterns among patients initiating dapagliflozin for HF with reduced ejection fraction (HFrEF) in routine clinical practice. Methods The EVOLUTION HF primary data study programme consists of prospective, observational, descriptive studies of new users of dapagliflozin for HFrEF in 12 countries (Italy, Portugal, UK and the Central and Eastern Europe and Baltic [CEEBA] region [Bulgaria, Croatia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania and Slovenia]). Patients with type 1 diabetes or prior SGLT-2i treatment were excluded. Clinical characteristics were obtained from electronic health records. A total of 2170/2555 (85%) patients were enrolled from November 2021 to November 2023; 1736 patient profiles were assessed using descriptive statistics in this interim analysis. Results In total, 256, 228, 125 and 1127 new dapagliflozin users were analysed from Italy, Portugal, the UK and the CEEBA region, respectively (Table 1). Across the 12 countries, mean patient age in the studies was 65–70 years. Patients were predominantly male (67–76%) and generally had HF with an ischaemic aetiology (35–56%) and New York Heart Association functional class II (52–85%). Mean left ventricular ejection fraction in the studies was 29–32% and estimated glomerular filtration rate was 61–77 mL/min/1.73m². Hypertension and atrial fibrillation were common comorbidities. Mean time between HF diagnosis and dapagliflozin initiation in the studies was 23–52 months. Background therapy included angiotensin receptor-neprilysin inhibitors (36–72%), angiotensin receptor blockers (4–12%) and angiotensin-converting enzyme inhibitors (9–33%). At 6 and 12 months after dapagliflozin initiation, respectively, treatment discontinuation rates across the CEEBA region were 5.22% (59/1131) and 4.66% (50/1072). Conclusions The EVOLUTION HF primary data study programme provides novel insights into clinical characteristics and treatment patterns in patients with HFrEF initiating dapagliflozin in real-world practice across a broad European population. At dapagliflozin initiation, a large proportion of patients were receiving other HF therapeutics, suggesting dapagliflozin is one of the later therapies to be initiated. Indeed, this study identified a substantial delay (23–52 months) in dapagliflozin initiation following HF diagnosis. Treatment discontinuation rates following dapagliflozin initiation were also low, reinforcing the findings of the EVOLUTION HF secondary data studies.

Association of ticagrelor vs clopidogrel with net adverse clinical events in patients with mild thrombocytopenia undergoing PCI

Abstract Backgrounds Current guidelines recommend aspirin plus ticagrelor as the preferred dual antiplatelet therapy (DAPT) for managing ST-elevation myocardial infarction (STEMI). However, there is a lack of consensus or guidelines to direct clinicians on managing patients with mild thrombocytopenia, defined as a platelet count of 100~150×109/L, undergoing percutaneous coronary intervention (PCI). Purpose This study aims to investigate the association between ticagrelor and clopidogrel with ischemic and hemorrhagic events for patients with mild thrombocytopenia undergoing PCI. Methods A retrospective cohort study of patients with mild thrombocytopenia undergoing PCI who received DAPT consisting of aspirin and a P2Y12 receptor antagonist (includinig clopidogrel or ticagrelor) was conducted using Health and Medical Big Data Super Platform from January 2010 to June 2023. All patients meeting the criteria were included in the analysis, with a follow-up of at least one year. Propensity Score Matching (PSM) was performed to equalize the effects of following characteristics: age, sex, hypertension, diabetes, dyslipidemia, stroke, atrial fibrillation, Killip class, percutaneous coronary intervention (PCI), beta-blockers, statins, calcium channel blockers (CCB), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI or ARB), angiotensin receptor-neprilysin inhibitor (ARNI), diuretic, organic nitrates, and oral anticoagulation. The primary endpoint was net adverse clinical events (NACE) at 1 year, composed of ischemic events (recurrent myocardial infarction or ischemic stroke), Bleeding Academic Research Consortium (BARC) classification ≥ 3, and cardiac death. Secondary outcomes included the components of NACE. Results A total of 3647 patients met the inclusion criteria, with 2684 receiving aspirin plus clopidogrel and 963 receiving aspirin plus ticagrelor, matched by a 1:3 ratio using the PSM method. Demographic characteristics were well balanced between the clopidogrel and ticagrelor groups. The 1-year risk of NACE did not significantly differ between ticagrelor and clopidogrel (11.1% vs. 8.4%, p=0.370). Similarly, there was no significant difference in the risk of cardiac death (7.3% vs. 4.2%, p=0.720), recurrent myocardial infarction (9.3% vs. 5.8%, p=0.550), ischemic stroke (8.8% vs. 6.7%, p=0.055), or BARC type ≥ 3 bleeding (7.9% vs. 4.5%, p=0.990). Conclusion In routine clinical practice, among patients with a platelet count of 100~150×109/L undergoing PCI, ticagrelor compared with clopidogrel was not associated with a significant difference in the risk of NACE at 1 year. Further research is warranted to assess whether ticagrelor is more effective than clopidogrel in this setting, considering potential unmeasured confounders.

ACE inhibitor and angiotensin receptor blocker use during pregnancy: data from the ESC Registry of pregnancy and cardiac disease (ROPAC)

Abstract Background and Aims Angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are not recommended during the second and third trimester due to the significant risk of congenital anomalies associated with their use. However, data are scarce, especially regarding their use in the first trimester. Our study illustrates the profile of the women who used ACE-Is or ARBs during pregnancy and to evaluate the impact on perinatal outcomes. Methods The Registry of Pregnancy and Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women with structural heart disease. Outcomes were compared between women who used ACE-Is or ARBs and those who did not. Multivariable regression analysis was performed to assess the effect of ACE-I or ARB use on the occurrence of congenital anomalies. In addition, the perinatal outcomes of patients who stopped ACE-Is and/or ARBs before pregnancy were assessed. Results ACE-I (n=35) and/or ARB (n=8) were used in 42 (0.7%) of the 5739 ROPAC pregnancies. Women who used ACE-Is or ARBs more often came from a low-or-middle-income country (57% vs 40%, p=0.021), had chronic hypertension (31% vs 6%, p<0.001), or a left ventricular ejection fraction <40% (33% vs 4%, p<0.001). No pregnancy terminations due to fetal anomaly were reported. ACE-I use during the first trimester was independently associated with an increased risk of congenital anomaly (OR 3.1; 95% CI 1.0-9.3). No adverse fetal or neonatal effects were seen when ACE-I and/or ARB were discontinued prior to pregnancy. Conclusions ACE-Is and ARBs are seldom used during pregnancy and based on our data, ACE-Is should also be avoided in the first trimester due to a higher risk of congenital anomalies. Preconception counseling is crucial to discuss the potential risks of these medications, and to evaluate the clinical condition and, if possible, the woman can be switched to an alternative medication.

Role of the cardiology pharmacist in improving quality of care for patients with acute myocardial infarction based on ESC-ACCA quality indicators

Abstract Background The European Society of Cardiology-Acute Cardiovascular Care Association (ESC-ACCA) suggested the use of quality indicators (QIs) to improve quality of care for patients with acute myocardial infarction (AMI). Among these QIs are prescribing of angiotensin-converting enzyme inhibitor (ACEi) and beta blocker (BB) if left ventricular ejection fraction (LVEF) was ≤40%, and prescribing high intensity statin and dual antiplatelet therapy (DAPT) before discharging patients from the coronary care unit (CCU). Purpose To identify the role of cardiology clinical pharmacy specialist in improving quality of care for patients with AMI based on ESC-ACCA QIs. Methods A cross-sectional study was conducted at a single CCU in Iraq between January 2021 and August 2023. Patients with AMI with or without LVEF ≤40% were included in the study. Patients' profiles were reviewed to collect data about suggestions by the cardiology clinical pharmacy specialist to initiate high intensity statin, addition of a second antiplatelet therapy to keep patients on DAPT, or addition of ACEi and/or BB if LVEF ≤40%. Results Total number of patients included was 326 of whom 119 (37%) patients had LVEF ≤40%. Drug interventions by the cardiology clinical pharmacy specialist with the initiation of statin and addition of a second antiplatelet therapy to optimize DAPT for patients with AMI and initiation of ACEi and/or BB for patients with AMI and LVEF ≤40% are shown in table 1 and figure 1. Drug interventions were based on the updated ESC guidelines and agreed by the interventional cardiologists. Conclusions Role of the cardiology clinical pharmacy specialist was important in bridging gaps in the medical therapy and improving quality of care for patients with AMI and/or LVEF ≤40% by optimizing patients medications particularly for the initiation of ACEi. ACEi was initiated in about one-quarter of the patients with AMI and LVEF ≤40% based on the suggestion of the cardiology clinical pharmacy specialist and approved by the interventional cardiologists.

Guideline-directed medical therapy implementation changes after acute coronary syndrome and their effect of prognosis: insights from Japanese real-world database using a storage system

Abstract Background The implementation of guideline-directed medical therapy (GDMT) after acute coronary syndrome (ACS) was reported to improve prognosis. However, there have been limited number of real-world studies clarifying the association between the status of GDMT implementation and clinical prognosis in ACS patients based on recent multicenter database. Purpose The purpose of this study was to survey the extent to which GDMT was performed over time in patients after percutaneous coronary intervention (PCI) for ACS, as well as to investigate the prognostic impact of GDMT. Methods This study is a retrospective, multicenter, observational study. We developed the Clinical Deep Data Accumulation System (CLIDAS), which consists of 6 university hospitals and the national cardiovascular center in Japan, directly obtains clinical data including patients background, laboratory data, echocardiogram, electrocardiogram, cardiac catheterization report, prescription, and long-term outcome from electronic medical records. 4107 patients who underwent PCI for ACS and were prescribed one or more antiplatelet drugs at baseline from April 2013 to March 2019 were analyzed, and divided into GDMT group (n = 2514) and non-GDMT group (n = 1593). GDMT was defined as all prescriptions for angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, beta-blocker, and statin at baseline. The primary outcome was the major adverse cerebrocardiovascular event (MACCE) defined as being the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Results The median follow-up duration was 2.36 years (interquartile range: 0.78-4.00 years). The study cohort consisted of 76% of men with a median age of 71 years. The incidence of MACCE was significantly lower in the GDMT group than in the non-GDMT group (8.8% vs. 13.0%, log rank P <0.001). Multivariable Cox regression analyses revealed that the GDMT group was a lower hazard ratio (HR) for MACCE after adjusting for confounding factors including the information about the first half and the second half (HR, 0.80; 95% confidence interval, 0.65-0.98; P = 0.035). The implementation rate of GDMT in the first half group (from April 2013 to March 2016) was lower than that in the second half group (from April 2016 to March 2019) (58.3% vs. 64.4%, P <0.001). Conclusion The real-world CLIDAS database revealed that GDMT was significantly associated with the reduction of MACCE in patients with ACS after PCI. In addition, an increase in the rate of GDMT implementation over time was observed.Kaplan-Meier curves for MACCE

Modern heart failure treatment is superior to conventional treatment across the left ventricular ejection spectrum: Real-life data from the Swedish Heart Failure Registry 2013-2020

Abstract Background Heart failure (HF) is a clinical syndrome characterized by high mortality and morbidity. In 2016, Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), was recommended as a new treatment option for HF in patients with HFrEF. In the 2021 European Society of Cardiology guidelines for treatment of HFrEF patients Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were introduced because they demonstrated significantly reduced HF events or cardiovascular (CV) mortality. Since ARNI and SGLT2i were introduced to treat HF, its therapeutic regimen has modernized from previous treatment with beta-blocker (BB) and angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) with mineralocorticoid receptor antagonist (MRA) as added-on in HF with reduced ejection fraction (HFrEF). Purpose This study is aimed to compare effectiveness of modern therapy including ARNI and SGLT2i with conventional heart failure treatment. Conventional HF treatment includes (BB, ACEi/ARB, with or without MRA) and modern heart failure treatment (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i) in real-world. Methods This observational study (2013-2020), using the Swedish HF Registry, involved 20,849 HF patients. Patients received either conventional (BB, ACEi/ARB, with/without MRA, n=20,140) or modern (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i, n=709) treatment at the index visit. The endpoints were all-cause and cardiovascular (CV) mortality. Results Modern HF therapy was associated with a significant 28% reduction in all-cause mortality compared to conventional HF treatment (adjusted HR [aHR]: 0.72 (95% CI 0.54 - 0.96), p=0.024), and had 33% reduced all-cause mortality (aHR: 0.67 (95% CI 0.48 - 0.94), p=0.019) within 2 years of index registration. Similarly, modern HF therapy was associated with a significant 62% reduction in CV mortality compared to conventional HF treatment (aHR: 0.38 (95% CI 0.21 - 0.68), p=0.0013). In addition, we found a 58% reduced CV mortality (aHR 0.42 (95% CI 0.22 - 0.79), p=0.0067) within 2 years of index registration. In the propensity score 1:1 matched cohort in which ARNI was included in the matching procedure, i.e., no ARNI was used in any of the two treatment groups and the effect of SGLT2i was the target assessment. The results were associated with a statistically significant risk reduction of 42% in all-cause mortality in the modern HF treatment group compared to the conventional treatment group (aHR: 0.58 (95% CI 0.36 - 0.94), p=0.028), and a 49% (aHR: 0.51 (95% CI 0.29 - 0.89), p=0.018) risk reduction within 2 years of index registration. Conclusion This study demonstrates that modern HF therapy in a real-world Swedish HF population is associated with a statistically significant risk reduction in all-cause and CV mortality, regardless of EF, sex, age, eGFR, and etiology of HF compared to conventional HF therapy.Central Illustration

Mortality rate of percutaneous coronary interventions in st-segment elevation myocardial infarction patients under the public health insurance schemes of thailand

Abstract Background ST-elevation myocardial infarction (STEMI) presents a critical public health challenge internationally, including in Thailand. Currently, standard therapeutic interventions, particularly primary percutaneous coronary interventions (pPCI), are administered to Thai citizens. However, selected healthcare systems restrict access to specific pharmaceuticals and medical devices, causing inequalities in the quality of medical care amongst different healthcare systems. Such inequalities have the potential to significantly impact the quality of life of patients, particularly in the long term. Purpose The primary objective is to compare mortality rates within one year of STEMI patients after treatment with pPCI among the public health insurance schemes of Thailand. The secondary objective is to study prognostic determinants for one-year mortality rates among patients diagnosed with STEMI who have undergone pPCI. Methodology This study is a single-centre retrospective analysis of patients with STEMI treated with pPCI. It involves patients utilising various state health insurance schemes in Thailand from 1 January 2010 to 31 December 2020. Data collection occurred through the hospital's computerised management system and the registration administration office of the Department of Provincial Administration. The data analysis employed the Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazards regression modelling method. Results The study involved 1,077 patients, categorised into three groups based on their state health insurance: Universal Health Coverage (UC) (546 patients, 50.7%), Social Security System (SS) (199 patients, 18.5%), and Civil Service Reimbursement (CS) (332 patients, 62.6%). The one-year mortality rates in these groups were 10.57%, 4.21%, and 6.47%, respectively (p=0.010). In the unadjusted model, the SS group showed a lower risk of one-year mortality rate (HR 0.38, 95% CI 0.18-0.80, p=0.011), and the CS group also demonstrated a lower risk (HR 0.59, 95% CI 0.35-0.99, p=0.047) compared to the UC group. In the adjusted model, only the CS group significantly reduced the risk of one-year mortality. Other factors that affected one-year mortality were age ≥65 years, a Killip score of 3-4, pre-discharge prescription of angiotensin-converting enzyme inhibitors, occlusion in the left anterior descending artery, and pericardial effusion. Conclusion Healthcare schemes play a significant role in influencing one-year mortality rates among STEMI patients treated with pPCI. The use of civil service reimbursement is a protective factor for the one-year mortality rate in STEMI patients. This information would be crucial for developing strategies and programs to aid healthcare policymakers at both regional and international levels in reducing morbidity and mortality.

Guideline-directed medical therapy titration for heart failure with ischaemic aetiology and its effect on cardiac remodelling and cardiovascular mortality-from a real world perspective

Abstract Background Contemporary Heart Failure (HF) pharmacological treatment has been reshaped by several landmark trials in recent years, and available evidence strongly encourages treatment up-titration to target doses. Recent literature regarding treatment sequencing demonstrated positive effects of up-titration on major outcomes regardless of HF aetiology. Purpose We investigated a contemporary Heart Failure with Reduced Ejection Fraction (HFrEF) patient cohort and ischaemic aetiology and sought to understand the effects both in terms of echocardiographic remodelling and upon mortality for cardiovascular (CV) causes of contemporary ESC guideline-directed medical therapy (GDMT) on a real-world level. Methods We retrospectively analysed data of consecutive patients with HFrEF and ischaemic genesis followed in our tertiary HF clinic between January 2019 and January 2022. Eligible patients were stratified into two groups: patients treated or not with full doses of ESC GDMT [including angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i)]. Results Overall, 203 patients (mean age 70.1±12.3 years, 165 males) were included into the analysis. Over a mean follow-up of 1223±221.2 days, 115 (56.6) patients achieved the full recommended doses of each drug. Patients with an unsuccessful up-titration had higher end-diastolic volume at transthoracic echocardiography (p for difference at first and second follow-up <0.001; figure 1, panel A), lower left ventricular ejection fraction (40.1±4.3% vs 44.3±7.8 and 38.7±4.9% vs 42.3±5.6% at the first and second follow-up, respectively) and higher CV mortality rates compared to those treated with the maximal doses (figure 1, panel B). Conclusions Up-titration of pharmacotherapy in our real-world cohort of patients with HFrEF and ischaemic aetiology demonstrated a positive effect both on pivotal echocardiographic parameters and on CV mortality. Our data suggest that timely identification and referral of patients with coronary artery disease who fail to achieve complete positive remodelling after an acute event (or during chronic disease course) for HF contemporary treatment implementation should be envisaged.Figure 1

Spectrum of heart failure in 16 sub-saharan countries: drugs strategies and 8-year trends (the february study 2016-2023)

Abstract Background Heart failure (HF) is a growing public health concern in Sub-Saharan Africa (SSA). The hospital prevalence studies estimate that in SSA, HF is responsible for 9.4% to 42.5% of all medical admission. However, little is known about the management of HF in hospitalization in SSA. Purpose To describe in hospital drugs strategies and 8-year trends in Africa. Methods We conducted a transversal and longitudinal study in cardiology departments of 37 hospitals(public and private) in 16 SSA countries. The February study is an ongoing observatory included all inpatients in February from each year since 2016. Collected data included socio-demographic and clinical characteristics, causes of admission, clinical, biological, complementary examinations, medicines, length of stay were collected by the investigating physicians. HF severity was defined according to proportion of Left Ventricular Ejection Fraction(LVEF):reduced(LVEF<40%), mildly reduced(LVEF[41-49%] or preserved(LVEF>50%). All analyses were performed with random effect on countries through scripts developed in the R software(4.0.3(2020-10-10)). Results Overall, 2351 patients(57±17.5 years; 54% men) were admitted for HF in the February study. HF representing 44.6% of all patients admitted. Proportions of patients included for HF varied across countries from 28% Democratic Republic of the Congo to 75% in Guinea. At admission, 56% of patients had reduced LVEF; 12.5% had mildly reduced and 31.5% had preserved LVEF. Proportions of drug classes varied significantly according to LVEF: diuretics were significantly less prescribed in patients with preserved LVEF(65%) compared to patients with mildly reduced(77%) or reduced(73%) LVEF (P>0.01). The same result was observed for betablockers(BB)(30%VS46% and 46%) and angiotensin-converting enzyme inhibitors(ACEI)(50%vs77% and 71%)(p<0.01). Mineralocorticoid receptor antagonists were significantly more prescribed in patients with preserved LVEF(p<0.01). The proportion of treated with BB increased significantly over the years(p<0.05) from 17% in 2016 to 62% in 2023. Proportions of drugs strategies differed significantly across countries adjusted for LVEF. Drugs strategies differed significantly according to LVEF(p<0.01). The more reduced the LVEF, the more the drugs strategy increased. In patients with preserved LVEF, the proportion of monotherapy was 20%; this decreased to 9% in patients with reduced LVEF. Combinations of three drugs increased from 35% in patients with preserved LVEF to 46% in patients with reduced LVEF. Overall, drugs strategies differed across years(p<0.05): three-drug strategies increased from 35% in 2016 to 51% in 2023 and two-drug strategies decreased from 38% in 2016 to 23% in 2023. Conclusion Up-titrated strategies were prescribed according to severity of HF and access to BB increased across years according to international guidelines. However, novel drugs classes remain unavailable in SSA.

Prognostic role of right ventricular-pulmonary artery coupling assessed by TAPSE/PASP ratio in patients with heart failure and mildly reduced ejection fraction

Abstract Background The development of right ventricular (RV)-pulmonary arterial (PA) coupling has resulted in a novel and comprehensive index for evaluating RV function in relation to the underlying RV afterload. In patients with heart failure (HF), it is acknowledged that RV-PA uncoupling are features that are associated with poor outcome. The RV-PA coupling index can be readily assessed non-invasively using the ratio of two standard echocardiographic measurements: tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP). However, few studies have defined the prognostic impact of the TAPSE/PASP ratio in patients with HF and mildly reduced EF (HFmrEF). Methods From the prospective cohort study of 1,410 hospitalized HF patients (age 68+/-15, men 62%) between August 2015 and September 2019, this study enrolled 191 HFmrEF (i.e., left ventricular ejection fraction (LVEF) 41–49%) patients whose TAPSE and PASP were measured during hospitalization and discharged alive. We studied the prognostic impact of TAPSE/PASP ratio on HFmrEF patients using by cut-off value obtained from receiver operating characteristic (ROC) analysis. The primary and secondary endpoints was defined as the all-cause death and HF re-hospitalization after discharge, respectively. Results During median follow-up of 38 [23–52] months, 48 patients (25%) died. The deceased patients had a significantly older (median 75 vs. 71 years, p<0.05), higher rate of ischemic heart disease (50% vs. 23%, p<0.05), elevated brain natriuretic peptide levels (325 vs. 159 pg/ml, p<0.05) and lower rate of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (65% vs. 80%, p<0.05) at discharge. In the ROC analysis, the cut-off value of TAPSE/PASP ratio for mortality was 0.46. Patients with TAPSE/PASP ≤0.46 had a significantly higher all-cause mortality (log-rank p<0.05) and had a tendency of higher rate of HF re-hospitalization than patients with TAPSE/PASP >0.46 (log-rank p=0.06) (Figure). Using multivariate analysis, the lower TAPSE/PASP ratio had an independent predictive value of prognosis in patients with HFmrEF (hazard ratio 2.16, 95% confidence interval; 1.08–3.92, p<0.05) (Table). Conclusion The TAPSE/PASP ratio has a significant prognostic value in patients with HFmrEF. The RV-PA uncoupling assessed by TAPSE/PASP ratio might be useful for risk assessment in patients with HFmrEF.

Comparing the anti-remodeling effect of sacubitril/valsartan and angiotensin-converting enzyme inhibition on myocardial samples of advanced heart failure patients undergoing heart transplantation

Abstract Background In decreasing heart failure (HF) hospitalization and cardiovascular death in HF patients with reduced ejection fraction, Sacubitril/Valsartan (SAC/VAL) treatment was proved to be superior to angiotensin-converting enzyme inhibition (ACEi). According to recent experimental results and clinical data based on echocardiography and circulating biomarkers, this benefit might be at least partially attributed to a greater anti-remodeling effect. However, there is a lack of direct evidence from human myocardial samples for this assumption. Purpose Therefore, we aimed to compare the anti-remodeling effect of SAC/VAL treatment to ACEi on myocardial samples of HF patients undergoing heart transplantation (HTX). Methods We studied left ventricular (LV) samples of seventy advanced HF patients who underwent HTX and received either SAC/VAL (SAC/VAL group, N=32) or ACEi treatment (ACEi group, N=38) for at least three months prior to HTX. Furthermore, all patients received beta-blockers and mineralocorticoid receptor antagonists titrated to maximally tolerated or target dose. Our groups were matched for age, sex, ejection fraction and other clinical parameters. Patients with liver or kidney failure, mechanical circulatory support, systemic inflammatory/fibrotic diseases or positive inotrope treatment were excluded. Myocardial mRNA expression of fibrotic markers and B-type natriuretic peptide (BNP) were measured with qRT-PCR and normalized to glyceraldehyde 3-phosphate dehydrogenase expression. Interstitial fibrosis area was assessed histologically. Results Preoperative plasma N-terminal pro-BNP levels were similar in the two groups (SAC/VAL: 4363±752 pg/mL vs. ACEi: 4616±1020 pg/mL; p=0.911). In contrast, the mRNA level of BNP in the myocardium was lower in patients treated with SAC/VAL (SAC/VAL: 2.2±1.05 vs. ACEi: 5.2±1.74; p=0.006). TIMP metallopeptidase inhibitor 1 (SAC/VAL: 0.07±0.01 vs. ACEi: 0.13±0.02; p=0.011), TIMP metallopeptidase inhibitor 2 (SAC/VAL: 0.06±0.01 vs. ACEi: 0.11±0.01; p<0.001), collagen type I alpha 1 chain (SAC/VAL: 0.02±0.00 vs. ACEi: 0.08±0.02; p<0.001) and collagen type III alpha 1 chain (SAC/VAL: 0.12±0.02 vs. ACEi: 0.27±0.04; p<0.001) relative gene expressions were also decreased in the LV of SAC/VAL-treated patients. Histology analysis confirmed reduced interstitial myocardial fibrosis area in the SAC/VAL group as well (SAC/VAL: 7.2±0.4% vs. ACEi: 8.6±0.5%; p=0.031). Conclusions SAC/VAL treatment decreased the myocardial expression of BNP and fibrosis-related genes to a greater extent compared with ACEi in LV samples of patients undergoing HTX. Histological analysis also verified the differences in fibrosis. Thus, the anti-remodeling effect of SAC/VAL might be superior to ACEi even in advanced HF.

Assessing the practicality of a novel heart failure therapeutic score (QUAD Score) for drug optimisation in heart failure with a reduced ejection fraction

Abstract Introduction The 4 pillars of drug treatment for heart failure with a reduced ejection fraction (HFrEF) [Angiotensin-converting enzyme inhibitors (ACEi)/Angiotensin receptor–neprilysin inhibitors (ARNi), β-blockers (BB), Mineralocorticoid receptor antagonists (MRA), and Sodium-glucose cotransporter 2 inhibitors (SGLT2i)], are recommended by international HF guidelines to improve patient outcomes. Treatment inertia remains a challenge with non-prescription or sub-optimal dosing of these therapies. We developed a pragmatic HFrEF treatment score (QUAD score) (Figure 1) to prompt initiation and/or titration of sub-optimally dosed foundational therapies. Patients are categorized as poor (<8), good (8-14), and excellent (15-24) based on the dose and number of foundational drugs prescribed. This study aims to assess the practical utility of the QUAD score and its influence on treatment optimization. Methods Unwarned prescribing HCPs were approached consecutively in person, within clinical settings. Participants were told the questions were part of a research project and they provided verbal consent. Responses were anonymous and no patients were involved; therefore, verbal consent was considered proportionate and reasonable. HCPs were given an information sheet describing the QUAD score (Figure 1). They were then presented with 3 hypothetical clinical scenarios of haemodynamically stable and uncomplicated HFrEF patients with uncalculated poor, good and excellent QUAD scores. They were asked to calculate the QUAD score and if they proposed any changes to treatment. Time was recorded using a stopwatch and proposed changes were recorded. They were then invited to answer a series of follow-on questions. Results Between September 2023 and February 2024, there were 70 respondents. 71% (50) were doctors and 29% (20) allied HCPs. 83% (58) placed patients in the correct treatment grade in at least one scenario. 62.9% (44) did so for all three scenarios (Figure 2) with numerically more HCPs compared to doctors (80% vs 56% p=0.06).The median (IQR) time in seconds required to calculate the QUAD score for clinical scenarios 1,2 and 3 was 158 (100-234), 86 (54-122) and 83 (53-119) respectively. In response to the calculated QUAD score, 94.3% (66), recommended drug treatment optimisations. On a 5-point Likert scale (1 -poor, 5- excellent), 77.1% of participants rated the QUAD score ≥3 for ease of use, and 88.6% rated ≥3 as an incentive for treatment optimization. Conclusion We demonstrated the rapid clinical usability of the QUAD Score in a cohort of unselected prescribing HCPs, with a decremental calculation time with each presented clinical scenario. HCPs were also motivated to achieve further HF drug therapy optimization based on the calculated score. We conclude that the QUAD Score as a HFrEF drug therapy score may have a role in addressing treatment inertia however, it needs validation against clinically relevant outcomes in a larger cohort of HFrEF patients.

Guideline-directed medical therapy patterns in heart failure with reduced ejection fraction: the OPTIMA-HF registry

Abstract Background/Introduction European guidelines strongly recommend an optimized pharmacological treatment in patients with heart failure with reduced ejection fraction (HFrEF) with a fast introduction of the four-pillars. Purpose Aim of the Optimization of Therapy in the Italian Management of Heart Failure [OpTIMa-HF] Registry was to collect data on HF patients to describe the current Italian population of HF patients with a specific focus on HFrEF treatment adherence and prescription rates, according to the most recent European Guidelines. Methods OPTIMA-HF is an observational, cross-sectional, multicenter, real-life study conducted in two different clinical settings: HF outpatients’ clinics of Italian University Hospitals and territorial Italian Cardiology outpatients’ services, that enrolled patients with chronic HFrEF receiving at least 1 oral medication for management of HF. Patients were characterized by baseline use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor (ARNI), beta-blocker, mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter II inhibitor (SGLT2i). Patient-level factors associated with medication use were examined. Results Overall, 1390 patients from 29 ambulatory cardiology practices and university hospitals were included. Mean age was 69.5 ± 11.9 years, 24% were female, and median EF was 33 (28-37). Among enrolled patients, 72.2% were prescribed ARNI, 17.1% ACEI/ARB, 95% beta-blocker, 75.5% MRA and 63% SGLT2i therapy (Figure 1). Despite high prescription rates for each single class, a still not sufficient number of patients was on treatment with all four pillars, in particular 40.4% considering the presence ARNI and 6.2%. When medications were prescribed, few patients were receiving target doses of ACEI/ARB (31.7%), ARNI (16%), and beta-blocker (33.3%), whereas a higher proportion were receiving target doses of MRA therapy (38%), and all were receiving target dose for SGLT2i. Among patients eligible for all classes of medication, only 1.1% were simultaneously receiving target doses of ACE/ARB/ARNI, beta-blocker, MRA and SGLT2i. Prescription rates did not significantly differ between the type of center (University Hospital vs. territorial Cardiology outpatients’ services). As regards patients not on treatment with any of the four pillars, a small but still present amount of patients had no contraindications to these drugs (Figure 1). Conclusions In this contemporary outpatient HFrEF Italian registry, significant high prescription rates of the four-pillars were observed, however therapy combination rate is still not sufficient and drugs' titration need to be implemented to receive the greatest benefits from an optimized treatment. Strategies to improve guideline-directed use of HFrEF medications remain urgently needed, and these findings may inform targeted approaches to optimize outpatient medical therapy.

S-RBD-modified and miR-486-5p-engineered exosomes derived from mesenchymal stem cells suppress ferroptosis and alleviate radiation-induced lung injury and long-term pulmonary fibrosis

BackgroundRadiation-induced lung injury (RILI) is associated with alveolar epithelial cell death and secondary fibrosis in injured lung. Mesenchymal stem cell (MSC)-derived exosomes have regenerative effect against lung injury and the potential to intervene of RILI. However, their intervention efficacy is limited because they lack lung targeting characters and do not carry sufficient specific effectors. SARS-CoV-2 spike glycoprotein (SARS-CoV-2-S-RBD) binds angiotensin-converting enzyme 2 (ACE2) receptor and mediates interaction with host cells. MiR-486-5p is a multifunctional miRNA with angiogenic and antifibrotic potential and acts as an effector in MSC-derived exosomes. Ferroptosis is a form of cell death associated with radiation injury, its roles and mechanisms in RILI remain unclear. In this study, we developed an engineered MSC-derived exosomes with SARS-CoV-2-S-RBD- and miR-486-5p- modification and investigated their intervention effects on RIPF and action mechanisms via suppression of epithelial cell ferroptosis.ResultsAdenovirus-mediated gene modification led to miR-486-5p overexpression in human umbilical cord MSC exosomes (p < 0.05), thereby constructing miR-486-5p engineered MSC exosomes (miR-486-MSC-Exo). MiR-486-MSC-Exo promoted the proliferation and migration of irradiated mouse lung epithelial (MLE-12) cells in vitro and inhibited RILI in vivo (all p < 0.05). MiR-486-MSC-Exo suppressed ferroptosis in MLE-12 cells, and an in vitro assay revealed that the expression of fibrosis-related genes is up-regulated following ferroptosis (both p < 0.05). MiR-486-MSC-Exo reversed the up-regulated expression of fibrosis-related genes induced by TGF-β1 in vitro and improved pathological fibrosis in RIPF mice in vivo (all p < 0.05). SARS-CoV-2-S-RBD-modified and miR-486-5p-engineered MSC exosomes (miR-486-RBD-MSC-Exo) were also constructed, and the distribution of DiR dye-labeled miR-486-RBD-MSC-Exo in hACE2CKI/CKI Sftpc-Cre+ mice demonstrated long-term retention in the lung (p < 0.05). MiR-486-RBD-MSC-Exo significantly improved the survival rate and pathological changes in hACE2CKI/CKI Sftpc-Cre+ RIPF mice (all p < 0.05). Furthermore, miR-486-MSC-Exo exerted anti-fibrotic effects via targeted SMAD2 inhibition and Akt phosphorylation activation (p < 0.05).ConclusionsEngineered MSC exosomes with SARS-CoV-2-S-RBD- and miR-486-5p-modification were developed. MiR-486-RBD-MSC-Exo suppressed ferroptosis and fibrosis of MLE-12 cells in vitro, and alleviated RILI and long-term RIPF in ACE2 humanized mice in vivo. MiR-486-MSC-Exo exerted anti-fibrotic effects via SMAD2 inhibition and Akt activation. This study provides a potential approach for RIPF intervention.Graphical

The Selective Endothelin Receptor Antagonist SC0062 in IgA Nephropathy: A Randomized Double-Blind Placebo-Controlled Clinical Trial.

Key Points Patients with IgA nephropathy and significant proteinuria are at high risk of progressive kidney function loss and kidney failure.We report the results of a clinical trial assessing the selective endothelin receptor antagonist SC0062 for the treatment of IgA nephropathy.SC0062 led to clinically meaningful improvements in proteinuria and did not increase risk of peripheral edema at higher doses. Background Endothelin receptor type A activation contributes to kidney injury in patients with IgA nephropathy. SC0062 is a novel selective endothelin receptor type A antagonist. We report the results of a phase 2 dose-finding trial to characterize the efficacy and safety of SC0062 in patients with IgA nephropathy. Methods We conducted a randomized, placebo-controlled, double-blind, clinical trial in adults with biopsy-proven IgA nephropathy and eGFR ≥30 ml/min per 1.73 m2 with urinary protein-creatinine ratio (UPCR) ≥0.75 g/g or proteinuria ≥1 g/24 hour despite using maximum tolerated doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were randomized 1:1:1:1 to 24-week treatment with SC0062 5, 10, and 20 mg or matching placebo once daily. The primary efficacy outcome was percent change from baseline in UPCR in 24-hour urine samples after 12 weeks of treatment. Secondary end points included changes in eGFR. Safety outcomes including treatment emerging adverse events and serious adverse events were recorded. Results Overall, 131 patients (mean age 42 years [SD, 11]; mean eGFR 72 ml/min per 1.73 m2 [SD 24] and median 24-hour UPCR 1.2 g/g [25th–75th percentile, 0.9–1.5 g/g]) were randomized to placebo (n=34) or SC0062 5 mg (n=33), 10 mg (n=32), or 20 mg (n=32). All SC0062 doses reduced UPCR versus placebo throughout treatment. At week 12, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UPCR with SC0062 5, 10, and 20 mg were−27.6% (−43.0 to −8.2), −20.5% (−37.4 to 1.0), and −38.1% (−51.4 to −21.0), respectively, and at week 24 they were−22.4% (−42.2 to 4.3), −30.9% (−48.6 to −7.0), and −51.6% (−64.2 to −34.6), respectively. No differences in eGFR were observed among treatment groups. The proportion of participants with treatment emerging adverse events or serious adverse events was balanced among treatment groups. Peripheral edema was reported by 2 (6%), 1 (3%), 1 (3%) participants in the 5, 10, and 20 mg SC0062-treated groups, respectively, compared with 5 (15%) in the placebo group. Conclusions In patients with IgA nephropathy, SC0062 reduced proteinuria and did not increase risk of peripheral edema. Clinical Trial registry name and registration number: A Study to Evaluate the Efficacy and Safety of SC0062 in the Treatment of CKD, NCT05687890.

Goat Milk Protein-Derived ACE Inhibitory Peptide SLPQ Exerts Hypertension Alleviation Effects Partially by Regulating the Inflammatory Stress of Endothelial Cells.

Hypertension has always posed a severe threat to people's health. Food-derived angiotensin-converting enzyme (ACE)-inhibitory peptides have the potential to both prevent and treat hypertension. In the current investigation, two ACE-inhibitory peptides (SLPQ and PYVRYL) from goat milk were studied for their endothelial effects using EA.hy926 cells. PYVRYL outperformed SLPQ, yet neither impacted cell survival below 200 μg/mL. Investigation of SLPQ's impact on EA.hy926 cell expression revealed 114 differentially expressed genes, with 65 downregulated and 49 upregulated. The genes were enriched in cytokine interactions, coagulation cascades, Hippo signaling, and ECM-receptor interaction. Decreased c-x-c motif chemokine ligand 2 (CXCL2), integrin subunit beta 2 (ITGB2), and fbj murine osteosarcoma viral oncogene homologue (FOS) expression and increased secreted phosphoprotein 1 (SPP1) expression may protect endothelial cells from inflammation. Our findings suggest that beyond ACE inhibition, SLPQ aids blood pressure control by influencing endothelial function, paving the way for its use as an antihypertensive food ingredient.

Case Report of Benign Diffuse Anterior Scleritis Associated with SARS-CoV-2

COVID-19 is an emerging infectious disease classified as a zoonotic illness caused by the SARS-CoV-2 strain of coronavirus. This enveloped, positive-sense, non-segmented RNA virus belongs to the order Nidovirales and the family Coronaviridae. Its primary mode of transmission is human-to-human through respiratory droplets. Ophthalmologists worldwide have reported various ocular manifestations associated with the infection. Recent studies have shown that SARS-CoV-2 binds to the cellular receptor for angiotensin-converting enzyme 2 (ACE2) and interacts with the transmembrane serine protease 2 (TMPRSS2), both of which are known to be expressed in the human cornea, retina, and conjunctival epithelium [1, 2]. The aim of this work is to present a case of a patient who developed diffuse viral scleritis related to COVID-19, detailing the diagnostic and therapeutic approaches as well as the patient's progression. We report the case of a 63-year-old man with a history of high triglycerides who developed flu-like symptoms and severe tiredness for over a week. A COVID-19 test came back positive. Ten days later, he had a painful, red right eye but no change in vision. An eye exam showed some redness in the conjunctiva, a clear cornea, and normal pressure in the eye. The fellow eye looked normal as well. He was treated with topical steroids and artificial tears, which helped initially. However, after finishing treatment, his symptoms worsened with more redness and pain, and now both eyes were affected. Further examination of the right eye showed swelling of the eyelid (preseptal cellulitis) and widespread redness in the conjunctiva. The Neosynephrine test was negative, and there was pain when moving the eye. The cornea was clear but had some superficial punctate keratitis, and the anterior chamber looked normal. The left eye also showed redness but was otherwise normal. A full lab workup (including blood tests and serologies for HSV1-2) came back normal. Considering his previous C