Angiotensin-converting Enzyme Inhibitor Treatment Research Articles

#4881 NEPHROPROTECTION IN BOYS WITH X-LINKED ALPORT SYNDROME: THE SOONER THE BETTER

Abstract Background and Aims Proteinuria (Pr) is a marker of glomerular diseases progression. The aim of study was to define the efficiency of angiotensin-converting enzyme inhibitors (ACEi) treatment in prevention of Pr development in boys with X-linked Alport's syndrome (XLAS). Method Single center observation study included boys with confirmed XLAS (n = 87). Twenty nine pts (1gr) started ACEi (enalapril 4.2±1.4 mg/m2/day) in non-proteinuric stage of disease (Pr≤100 mg/m2/day); mean age 6.2±3.9 yrs, eGFR Schwartz 118±15.2 ml/min/1.73 m2, Pr 67±23 mg/m2/day. Fifty eight pts (2gr) without preemptive ACEi treatment were observed from mean age 6.8±4.9 yrs, eGFR 119±17.3 ml/min/1.73 m2, Pr 87±43 mg/m2/day. Follow up was 6.2±3.9 yrs, mean age at the last observation was 11.7±3.9 yrs vs 14.2±4.6 yrs (p = 0.67) in 1gr and 2gr, respectively. The occurrence of Pr (Pr>100 mg/m2/day) was defined as primary end point of the study. Results The pts of 1gr had lower rate (0.48 vs 0.94, p<0.001) and higher age (10.2±3.9 vs 4.9±3.4 yrs, p = 0.3) of Pr occurrence than in 2gr. ACEi treatment reduced risk of Pr onset (OR = 0.05(95%CI 0.013-0.2)) with absolute risk reduction of Pr by 47% (RD = 0.47) and number of treated pts to prevent Pr development (NNT) 2.14. No difference was revealed between 1gr pts with and without Pr development in age of therapy start (7.1±3.3 vs 6.3±2.8 yrs), ACEi dose (2.3±0.8 vs 2.1±0.6 mg/m2/day) and COL4A5 gene mutation type (missense variants 0.72 vs 0.86). Arterial hypertension was a risk factor of Pr occurrence in 1gr (χ2 = 4,42, p = 0.04); children with Pr development was older at the last observation: 13.5±3.2 vs 9.9±3.8 yrs, p = 0.47. No side effects of treatment were observed. Conclusion The early ACEi therapy halves the risk of Pr development in boys with XLAS and may prevent the disease progression in these patients.

GASTROINTESTINAL ANGIONEUROTIC EDEMA AS A CONSEQUENCE OF ANGIOTENSIN – CONVERTING ENZYME INHIBITOR TREATMENT

Objective: To report a case of unusual severe adverse reaction to an angiotensin-converting enzyme inhibitor (ACEI). Design and method: A 33-year-old male with a history of hypertension for 10 years, asthma, and atopy was admitted to a local emergency department due to diffuse abdominal pain with vomiting and diarrhea for about 3 days. A few days earlier, the patient had blood pressure (BP) lowering treatment modified due to suboptimal BP control, with introduction of perindopril. The first ACEI dose was followed by lower abdominal pain, urge to have bowel movement, and difficulty passing stool. 24 hours later, the next dose was followed by severe, gradually increasing, diffuse abdominal pain, nausea, vomiting, and diar-rhea. With signs of peritonitis present on admission, a surgeon suspected an acute abdomen and or-dered abdominal computed tomography (CT) due to unclear etiology. CT showed diffuse infiltrates within the small intestine and its mesentery, with free abdominal fluid but no perforation. The patient was not operated and seen by an internist who suspected gastrointestinal angioneurotic edema related to ACEI. On admission to the medical unit, the patient was moderately unwell, conscious, with BP 185/110 mmHg, HR 128 bpm, SaO2 99% on room air, and no fever. Abdomen examination showed reduced bowel sounds, abdominal guarding, tenderness on palpation, especially in the mid-abdomen, and rebound tenderness. Laboratory tests showed elevated WBC (16,800/mm3) and CRP (19 mg/L). Results: Perindopril was withdrawn, the patient received antihistamines, analgesics, and intravenous fluids, with improvement of the patient's condition and reduction of pain and inflammation markers. Follow-up abdominal CT after 5 days showed resolution of small intestinal edematous lesions. The patient was discharged home in good condition, without abdominal pain, and with good BP control. The final diag-nosis was gastrointestinal angioneurotic edema associated with ACEI treatment. Conclusions: One condition may mimic another and thus unclear clinical presentations require cautious diagnostic and therapeutic decisions. In the presented case, angioneurotic edema following introduction of perin-dopril was unusually located in the gastrointestinal tract and its manifestations imitated an acute abdo-men.

Mechanism of angiotensin-converting enzyme inhibitors in the treatment of dilated cardiomyopathy based on a protein interaction network and molecular docking.

Dilated cardiomyopathy (DCM) is a severe manifestation or intermediate stage of cardiovascular disease progression with a significantly poor prognosis. Based on a protein interaction network and molecular docking, the present study determined the genes and mechanism of action of angiotensin-converting enzyme inhibitors (ACEIs) in the treatment of DCM, providing a direction for future studies on ACEI drugs for DCM. This is a retrospective study. DCM samples and healthy controls were downloaded from the GSE42955 dataset, and the targets of the potential active ingredients were obtained from PubChem. Hub genes in ACEIs were analyzed by constructing network models and a protein-protein interaction (PPI) network using the STRING database and Cytoscape software. Molecular docking was performed using Autodock vina software. Twelve DCM samples and five control samples were finally included. A total of 62 intersected genes were obtained by intersecting the differentially expressed genes with six ACEI target genes. PPI analysis identified 15 intersecting hub genes from these 62 genes. Enrichment analysis showed that the hub genes were associated with T helper type 17 (Th17) cell differentiation as well as the nuclear factor kappa-B (NF-kappa B), interleukin 17 (IL-17), mitogen-activated protein kinase (MAPK), tumor necrosis factor (TNF), phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) (PI3K-Akt), and Toll-like receptor signaling pathways. Molecular docking indicated that the compound Benazepril to produce favorable interactions with TNF proteins with a relatively higher score (-8.3). This study primarily revealed that the preventive and curative effects of ACEI treatment on DCM could be realized through multiple targets and pathways, and its mechanism of action is related to genes such as TNF, vascular endothelial growth factor A (VEGFA), interleukin 6 (IL6), C-C motif chemokine ligand 2 (CCL2), Cyclin D1 (CCND1), and AKT serine/threonine kinase 1 (AKT1), with immune- and inflammation-related signaling pathways involvement.

Renin-Angiotensin-Aldosterone System Inhibitions and Cardiovascular Outcomes in Acute Myocardial Infarction With Renal Impairment

ObjectiveTo compare the clinical outcomes of patients with acute myocardial infarction with renal impairment (AMI-RI) treated with either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in real-world clinical settings. Patients and MethodsA total of 4790 consecutive patients with AMI-RI between November 1, 2011, and December 31, 2015, were subdivided into ACEI (n=2845) and ARB (n=1945) treatment groups. The primary end points were major adverse cardiac and cerebrovascular events, including all-cause mortality, nonfatal myocardial infarction, any revascularization, cerebrovascular accident, rehospitalization, and stent thrombosis. Propensity score matching (PSM) was used to adjust for group differences. ResultsThe ARB group had a significantly higher incidence of major adverse cardiac and cerebrovascular events (at 3-year follow-up) than the ACEI group according to the unadjusted analysis (3-year hazard ratio [HR], 1.60; 95% CI, 1.43 to 1.78) and the PSM-adjusted analysis (3-year HR, 1.34; 95% CI, 1.15 to 1.56). However, any revascularization (3-year HR, 1.21; 95% CI, 0.95 to 1.54) and rehospitalization (3-year HR, 1.21; 95% CI, 0.88 to 1.67) were not significantly different between groups in the PSM-adjusted analysis. Compared with the ARB group, the ACEI group had lower rates of all-cause mortality at estimated glomerular filtration rates of at least 15 or less than 90 mL/min/1.73 m2 in the unadjusted data and at least 60 or less than 90 mL/min/1.73 m2 in the PSM-adjusted analysis. ConclusionTreatment with ACEIs seemed to be more beneficial than treatment with ARBs for patients with AMI-RI; further prospective studies are required to confirm these results.

BS-452682-4 EFFECTS OF CHRONIC ANGIOTENSIN CONVERTING ENZYME INHIBITION ON ATRIAL FUNCTION AND ARRHYTHMOGENESIS IN AGED AND FRAIL MICE

Aging is associated atrial remodeling and increased susceptibility to atrial fibrillation (AF); however, aging-dependent changes can be variable. Frailty measures health status independent of chronological age, can be quantified using a frailty index (FI) and can account for heterogeneity in aging individuals. Angiotensin converting enzyme inhibition (ACEi) can impact frailty however its effects on AF and atrial remodeling are unknown. To determine the effects of chronic ACEi on atrial structure, function, and arrhythmogenesis in aged and frail mice. Wildtype mice were treated with the ACEi enalapril (20 mg/kg/day) or placebo for 6 months starting at 75 weeks of age. Mice aged 10-15 weeks were used as young controls. Mice were used in intracardiac electrophysiology, high resolution optical mapping, patch-clamping, and histology. ACEi reduced FI in aged mice (0.24 vs 0.36; n=27-31; P<0.05) without altering blood pressure. AF susceptibility was increased in aged vs young mice (100 vs 17%; n=6; P<0.05) and reduced in ACEi vs aged mice (43 vs 100%; n=6-7; P<0.05). P wave duration was reduced in ACEi vs aged mice (27.4 vs 32.5 ms; n=7; P<0.05), showed variability within age/treatment groups, and was correlated and graded by FI (R=0.91; n=20; P<0.05). Optical mapping revealed an age dependent reduction in atrial conduction velocity (CV; 35.3 vs 40.2 cm/s; n=6-9; P<0.05) while ACEi improved CV in aged mice (37.7 vs 35.3 cm/s; n=6-9; P=0.05). CV was also correlated with FI score (R=0.72; n=24; P<0.05). Patch-clamp studies in isolated left atrial (LA) myocytes identified a reduction in action potential upstroke velocity (Vmax; 150.8 vs 165.4 V/s; n=18-32; P<0.05) that was associated with a reduction in peak sodium current (INa; -38.3 vs -52.1 pA/pF; n=7-19; P<0.05) in aged vs young mice. INa was increased in ACEi vs aged (-47.2 vs -38.3 pA/pF; n=14–19; P=0.09) and not different (P=0.62) vs young mice. Importantly, Vmax (R=0.32; n=73; P<0.05) and INa (R=0.5; n=36; P < 0.05) were graded by FI. LA fibrosis was increased in aged mice vs young (10.8 vs 3.9%; n=5-8; P<0.05), reduced in ACEi vs aged mice (8.9 vs 10.8%; n=5-8; P<0.05), and strongly correlated with FI (R=0.89; n=19; P<0.05). ACEi reduced frailty in aging mice and attenuated age-related AF and atrial remodeling. Aging was associated with substantial variability within groups. Frailty was a strong predictor of changes atrial function in aging mice including after ACEi treatment, independent of chronological age.

Effect of Discontinuation of Renin Angiotensin-System Inhibitors in Patients With Advanced Chronic Kidney Disease: A Meta-Analysis.

Renin-angiotensin system inhibitors (RAS) inhibitors include angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors decrease proteinuria, progression of chronic kidney disease (CKD), and protect against heart failure hospitalizations and cardiovascular events. There is uncertainty about the appropriate time for discontinuing ARB and ACE inhibitor treatment in patients with low estimated glomerular filtration rate (eGFR). In the present meta-analysis, we examined the effect of RAS inhibitor discontinuation on clinical outcomes in patients with advanced CKD compared to the continuation of RAS inhibitors. Two authors conducted electronic database searches in PubMed, the Cochrane Library, and Excerpta Medica Database (EMBASE) for relevant studies published from the inception of the databases to March 15th, 2023, using the following combination of keywords or key terms: "Renin-angiotensin-system," "angiotensin-converting-enzyme inhibitors", "Angiotensin receptor blockers," and "advanced chronic kidney disease."Primary outcomes assessed in this meta-analysis included cardiovascular events. Secondary outcomes assessed included all-cause mortality and end-stage kidney disease (ESKD). A total of four studies were included in this meta-analysis.The pooled analysis showed thatcardiovascular eventswere significantly higher in patients in the discontinuation group compared to the continuation group (HR: 1.38, 95% CI: 1.21-1.58), ESKD was also significantly higher in the discontinuation group (HR: 1.29, 95% CI: 1.18-1.41). No significant differences were reported between the two groups in all-cause mortality.In conclusion, our meta-analysis provides evidence that continuation of RAS inhibitors could be beneficial in patients with advanced CKD, as it is associated with less risk of cardiovascular events and ESKD.

De novo truncating variants of TRIM8 and atypical neuro-renal syndrome: a case report and literature review

BackgroundThe TRIM8 gene encodes a protein that participates in various biological processes. TRIM8 variants can lead to early termination of protein translation, which can cause a rare disease called neuro-renal syndrome. This syndrome is characterized by epilepsy, psychomotor retardation, and focal segmental glomerulosclerosis. However, we found that some patients may not present the above typical triad, and the reason may be related to their variant sites.Case presentationWe report a case of a 6-year-old boy with nephrotic-range proteinuria as the first prominent manifestation of TRIM8 variant. He had stage 3 chronic kidney disease at the time of presentation, specific facial features, and a neurogenic bladder. He had not experienced seizures previously. There were no apparent abnormalities in his growth, intelligence, or motor development. The results of whole exome sequencing showed a TRIM8 variant. Renal biopsy revealed focal segmental glomerulosclerosis and renal tubular cystic dilatation. He did not respond to hormone and angiotensin-converting enzyme inhibitor treatment; however, the symptoms of neurogenic bladder were relieved after treatment with Solifenacin.ConclusionIn this case, renal disease was the prominent manifestation; the patient had no other obvious neurological symptoms except a neurogenic bladder. Notably, the variant site is the closest to the C-terminal to date. Based on the analysis of previously reported cases, we found that as the TRIM8 variant became closer to the C-terminal, the renal lesions became more prominent, and there were fewer neurologic lesions. Our findings provide a new understanding of neuro-renal syndrome caused by TRIM8 variant. Patients may only have kidney disease as a prominent manifestation. At the same time, we found that we should also pay attention to the eye lesions of these patients. Therefore, gene analysis is helpful in identifying the etiology and guiding the prognosis of patients with hormone-resistant proteinuria. We suggest that TRIM8 should be included in gene panels designed for the genetic evaluation of hormone-resistant proteinuria.

S-06-4: IMPACT OF ANTI-HYPERTENSIVE THERAPY ON CEREBRAL FUNCTIONAL NETWORKS AND CONNECTIVITY

It is well known that hypertension is the main modifiable risk factor leading to cognitive impairment and various forms of dementia. Leveraging functional MRI it has been possible to characterize hypertensives brain functional connectivity, a main feature of cerebral activation and health measurable by resting-state functional MRI. This characterization let us analyze how pathological conditions influence the cognitive processes and the spontaneous organization of brain activity, and have shown that hypertensive patients even before showing signs of vascular dementia have alterations in cerebral connections compared to normotensive patients. Our current question is whether different classes of antihypertensives, differentiated in mechanism of action and potential to cross the blood brain barrier may have different impact on cerebral functional organization. 42 hypertensives with controlled hypertension (SBP&lt; 140mmHg e DBP&lt; 90mmHg) were subjected to resting-state functional MRI. Functional connectivity was elaborated by CONN, according to an analysis pipeline to build functional connectivity networks matrices calculating the cross-correlation of BOLD signal among different brain regions. The obtained network of connections has been analyzed by general linear model, to implement regression models that highlight the connections in the brains modulated by the specific classes of antihypertensives analyzed. The application of regression models with age, sex, BMI, alcohol, smoke, SBP and DBP levels, heart rate as covariates shown that treatment with diuretics modulate a large connectivity network among Salience Network, Default Mode Network and Language Network (Fig. A). Ace-inhibitors treatment is associated with a significant modulation of a connection between Default Mode Network and the FrontoParietal Network (Fig. B), while ARBs are associated to the modulation of connections between Cerebellar and Language Networks (Fig. C). Finally, beta-blockers are associated with connections centered in Dorsal Attention Network and projected to Language and FrontoParietal Networks (Fig. D). Globally, the most relevant functional modulation of the brain is imposed by the use of diuretics, with a possible explanation in the fact that lowering global volume of circulating blood may have a significant impact on cerebral circulation. By this analysis, we will be able to take into account the central and cognitive impact of different antihypertensive drugs on the choice of best personalized treatment of hypertension.

Salt Restriction and Angiotensin-Converting Enzyme Inhibitor Improve the Responsiveness of the Small Artery in Salt-Sensitive Hypertension.

For salt-sensitive hypertension (SSH), salt restriction and angiotensin-converting enzyme (ACE) inhibitors are essential treatments, but their effect on the function of resistance arteries is unclear. Here, we present an intravital study to detect the effect of salt restriction and ACE inhibitors on the function of the mesenteric small artery (MSA) in SSH. Dahl salt-sensitive rats were randomized into the following groups: ACE inhibitor gavage, salt restriction, ACE inhibitor combined with salt restriction, and high-salt diet. After a 12-week intervention, the mesenteric vessels maintained their perfusion in vivo, and the changes in the diameter and blood perfusion of the MSAs to norepinephrine (NE) and acetylcholine (ACh) were detected. Switching from a high-salt diet to a low-salt diet (i.e., salt restriction) attenuated the vasoconstriction of the MSAs to NE and promoted the vasodilatation to ACh, while ACE inhibitor improved the vasodilatation more obviously. Pathologically, changes in local ACE, AT1R, and eNOS expression were involved in these processes induced by a high-salt diet. Our study suggests that salt restriction and ACE inhibitor treatment improve high salt intake-induced MSA dysfunction in SSH, and salt restriction is a feasible and effective treatment. Our findings may provide a scientific basis for the treatment of hypertension.

Efficacy of human C1 esterase inhibitor concentrate for treatment of ACE-inhibitor induced angioedema

BackgroundACE inhibitor (ACEi) induced angioedema predominantly affects the upper aerodigestive tract. As ACEi induced angioedema is mediated by bradykinin, therapeutic response to antihistamines and glucocorticoids remains unsatisfactory. In bradykinin mediated hereditary angioedema, C1-esterase inhibitor (C1INH) is an effective and approved treatment since many years. Our aim was to evaluate the therapeutic effect of C1INH in ACEi induced angioedema. MethodsWe performed a double-blind, parallel-group, multicentre randomised placebo-controlled trial between December 2013 and September 2018. Eligible were adults with ACEi induced angioedema with airway obstruction. Participants were randomised 1:1 to single doses of either C1INH (20 IU/kg) or placebo (0.9% NaCl) i.v in addition to standard care (i.v. 500 mg prednisolone and 2.68 mg clemastine) i.v. Composite symptom scores were assessed at baseline and up to 48 h, at discharge and 1 week after discharge. Physician assessed time to complete oedema resolution (TCER) and time to onset of relief (TOR). Results30 patients (16 C1INH, 14 placebo) were randomised and dosed. 25 (9 C1INH, 12 placebo) completed the study. TCER was 29.63 h ± 15.56 h in the C1INH and 17.29 h ± 10.40 h in the placebo arm (p = 0.0457). TORs were 4.13 h ± 3.38 h and 2.86 h ± 1.29 h for C1INH and placebo, respectively (p = 0.4443). There were no adverse events related to study medication. ConclusionsIn the context of baseline application of steroids and antihistamines C1INH was inferior in the treatment of ACEi induced angioedema when compared to placebo with respect to time to complete resolution of symptoms.Eudra-CT Number: 2012-001670-28.

Enhancing the Anti-angiogenic Effect of Bevacizumab with ACE Inhibition on mCRC.

Angiotensin 2 has been shown to promote angiogenesis through multiple pathways. Reduction of angiotensin 2 production by angiotensin-converting enzyme inhibitors (ACEi) could enhance the antiangiogenic effect of bevacizumab and lead to improved survival. Data from metastatic colorectal cancer (mCRC) patients treated with bevacizumab in our hospital were retrospectively collected. Patients were divided into groups taking ACEi or angiotensin receptor blockers (ARB) or neither. We performed survival analysis and COX proportional hazard modelling and calculated the hazard ratio (HR). Multivariate analyses were performed to measure the impact of factors affecting survival, and subgroup analyses were performed for patients younger than 65years. We enrolled 133 patients who received bevacizumab therapy. Eighty patients were male, and 53 were female. Twenty-three patients received ACEi treatment, and 34 patients received ARB. The median age was 58years. Progression-free survival was higher in the ACEi group than in the ARB group or in the group receiving neither (7.66 vs. 5.98 vs. 5.0months; p < 0.01), corresponding to a HR of 0.44 for the ACEi group (95% CI 0.26-0.74). Overall survival was not significantly longer in the ACEi group than in the ARB group or in the group receiving neither (22.0 vs. 23.5 vs. 19.7months; p = 0.30), HR 0.66 (95% CI 0.38-1.2). In a subgroup analysis, overall survival was higher in patients younger than 65years in the ACEi group (45.0 vs. 16.2months; p = 0.02). In the final analysis, ACEi use in patients treated with bevacizumab resulted in prolonged progression-free survival, but this did not affect overall survival. Because our study is the first to look at the enhancement of the effect of bevacizumab by ACEi treatment and ACEi receiving patients are older, it would be useful to confirm our results by randomized trials.

Short-term efficacy of angiotensin receptor-neprilysin inhibitor treatment in patients with ST-segment elevation myocardial infarction with reduced ejection fraction after primary percutaneous coronary intervention: a propensity score matching study

BackgroundAcute myocardial infarction (AMI) causes a series of pathophysiological changes, including myocardial necrosis, myocardial edema, and microvascular damage. These changes eventually lead to severe cardiovascular events, such as ventricular remodeling, heart failure, and papillary dysfunction. Impaired cardiac function after ST-segment elevation myocardial infarction (STEMI) often manifests as a decrease in left ventricular ejection fraction (LVEF). Clinical trials have shown that angiotensin receptor-neprilysin inhibitor (ARNI) treatment has the potential to improve LVEF in patients with STEMI after primary percutaneous coronary intervention (PPCI).ObjectiveThe purpose of this study was to evaluate the short-term efficacy of ARNI versus angiotensin-converting enzyme inhibitor (ACEI) treatment in patients with STEMI who exhibit reduced LVEF after PPCI.MethodsA total of 169 patients with STEMI exhibiting post-PPCI LVEF below 50% who were orally treated with ARNI between December 2017 and August 2020 were selected as the experimental group. A total of 136 patients with STEMI exhibiting post-PPCI LVEF below 50% who were orally treated with an ACEI between January 2016 and August 2020 were selected as the control group. LVEF was measured using cardiac ultrasonography during hospitalization and 3 months after discharge. Linear and logistic regression analyses were performed to compare patient demographics and hospitalization variables to evaluate the risk factors for change and rate of improvement in LVEF. Propensity score matching (PSM) was used to account for confounding factors.ResultsAfter PSM, the study cohort consisted of 81 patients in the ARNI group and 123 in the ACEI group. After an average follow-up period of 3 months, no significant difference was noted in the LVEF improvement rate between the experimental and control groups (P = 0.475, 95% CI: -0.062 to 0.134). Multivariate logistic regression analysis also indicated no significant correlation between the change in LVEF and oral ARNI treatment in patients with STEMI exhibiting reduced LVEF after PPCI (P > 0.05).ConclusionThe short-term effect of ARNI treatment on the cardiac function of patients with STEMI and reduced LVEF after PPCI is not superior to that of ACEI treatment.

Role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in cryoballoon ablation outcomes for paroxysmal atrial fibrillation.

Cryoballoon ablation (CBA) is recommended for patients with paroxysmal atrial fibrillation (AF) refractory to antiarrhythmic drugs. However, only 80% of patients benefit from initial CBA. There is growing evidence that pretreatment with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) decreases the recurrence of AF postablation, particularly in nonparoxysmal AF undergoing radiofrequency ablation. The role of ACEIs and ARBs in patients with paroxysmal AF in CBA remains unknown. We decided to investigate the role of ACEIs and ARBs in preventing the recurrence of atrial arrhythmia (AA) following CBA for paroxysmal AF. To investigate the role of ACEIs and ARBs in preventing recurrence of AA following CBA for paroxysmal AF. We followed 103 patients (age 60.6 ± 9.1 years, 29% women) with paroxysmal AF undergoing CBA 1-year post procedure. Recurrence was assessed by documented AA on electrocardiogram or any form of long-term cardiac rhythm monitoring. A multivariable Cox proportional hazard model was used to assess if ACEI or ARB treatment predicted the risk of AA recurrence. After a 1-year follow-up, 19 (18.4%) participants developed recurrence of AA. Use of ACEI or ARB therapy was noted in the study population. Patients on ACEI/ARB had a greater prevalence of hypertension and coronary artery disease. On a multivariate model adjusted for baseline demographics and risk factors for AF, ACEI or ARB therapy did not prevent recurrence of AA following CBA (P = 0.72). Similarly, on Kaplan-Meier analysis pretreatment with ACEI/ARB did not predict the time to first recurrence of AA (P = 0.2173). In our study population, preablation treatment with an ACEI or ARB had no influence on the recurrence of AA following CBA for paroxysmal AF.

Robust arm and leg muscle adaptation to training despite ACE inhibition: a randomized placebo-controlled trial.

Angiotensin-converting enzyme (ACE) inhibitor treatment is widely applied, but the fact that plasma ACE activity is a potential determinant of training-induced local muscular adaptability is often neglected. Thus, we investigated the hypothesis that ACE inhibition modulates the response to systematic aerobic exercise training on leg and arm muscular adaptations. Healthy, untrained, middle-aged participants (40 ± 7 yrs) completed a randomized, double-blinded, placebo-controlled trial. Participants were randomized to placebo (PLA: CaCO3) or ACE inhibitor (ACEi: enalapril) for 8weeks and completed a supervised, high-intensity exercise training program. Muscular characteristics in the leg and arm were extensively evaluated pre and post-intervention. Forty-eight participants (nACEi = 23, nPLA = 25) completed the trial. Exercise training compliance was above 99%. After training, citrate synthase, 3-hydroxyacyl-CoA dehydrogenase and phosphofructokinase maximal activity were increased in m. vastus lateralis in both groups (all P < 0.05) without statistical differences between them (all time × treatment P > 0.05). In m. deltoideus, citrate synthase maximal activity was upregulated to a greater extent (time × treatment P < 0.05) in PLA (51 [33;69] %) than in ACEi (28 [13;43] %), but the change in 3-hydroxyacyl-CoA dehydrogenase and phosphofructokinase maximal activity was similar between groups. Finally, the training-induced changes in the platelet endothelial cell adhesion molecule-1 protein abundance, a marker of capillary density, were similar in both groups in m. vastus lateralis and m. deltoideus. Eight weeks of high-intensity whole-body exercise training improves markers of skeletal muscle mitochondrial oxidative capacity, glycolytic capacity and angiogenesis, with no overall effect of pharmacological ACE inhibition in healthy adults.

Abstract P225: Dahl Salt-sensitive And Salt-resistant Rats Exhibit Highly Disparate Blood Pressure Responses To Lifetime High Fat Diet Feeding

In an effort to understand obesity associated hypertension, we and others are using Dahl salt-sensitive (SS) rats fed a high fat diet as an experimental model. One reason for choosing this rat strain is that it is well-known that SS rats exhibit accelerated hypertension development not just in response to high salt intake but to numerous other stimuli as well, when compared to Dahl salt resistant (SR) rats. However, it is not known whether this general dichotomous sensitivity to hypertension development in SS and SR rats also extends to the impact of high fat feeding. Therefore, in the present study we tested the hypothesis that high fat feeding would cause a smaller increase in blood pressure in SR rats versus SS rats in both females and males (n=8 each). To explore possible strain differences in the mechanisms known to contribute to obesity associated hypertension, we also compared the activity of the renin angiotensin and sympathetic nervous systems in SS and SR rats. Rats were fed a high fat diet (60% kcal fat) from weaning. Blood pressure was measured by telemetry starting at 12 weeks of age. At 12 weeks, mean arterial pressures (MAP, mmHg) were 109±8 and 158±6 in male SR and SS rats, and 108±1 and 150±5 in female SR and SS rats, respectively. By 18 weeks MAP were 109±7 and 175±4 in male SR and SS rats, and 108±1 and 180±4 in female SR and SS rats, respectively. In males, plasma renin was lower, and aldosterone the same, in SS rats than SR rats. However, SS rats showed larger falls in blood pressure during week-long ACE inhibitor treatment and to acute sympathoinhibition with hexamethonium than did SR rats. In females, plasma renin and aldosterone both were higher in SS rats than SR rats. Female SS rats also showed larger falls in blood pressure to chronic ACE inhibition and acute ganglion blockade than did SR rats. These results confirm that both male and female SR rats are highly resistant to obesity associated hypertension, and that less robust activation by high fat diet of the renin angiotensin and sympathetic nervous systems may be a causative factor.

Comparison Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Patients with Unstable Angina with Preserved Left Ventricular Systolic Function.

The present study evaluated the clinical results of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) treatment in patients with unstable angina (UA) with preserved left ventricular systolic function who underwent percutaneous coronary intervention (PCI) due to uncertainty regarding the long-term prognosis using ACEI or ARB. A total of 1627 UA patients with preserved left ventricular systolic function after PCI were enrolled. After propensity score matching, there were no differences in major adverse cardiovascular and cerebrovascular events (MACCEs) (hazard ratio (HR) = .860, 95% confidence interval (CI): .465-1.590, P = .630), all-cause death (HR = .334, 95% CI: .090-1.238, P = .101), nonfatal myocardial infarction (HR = 4.929, 95% CI: .576-42.195, P = .145), stroke (HR = 1.049, 95% CI: .208-5.290, P = .954) and target vessel revascularization (TVR) (HR = 1.276, 95% CI: .537-3.031, P = .581) between the ACEI and ARB groups. In conclusion, prognoses were comparable between ACEI or ARB treatment in UA patients who had preserved left ventricular systolic function after PCI.

Abstract P3111: Can ACE Inhibitors Provide Similar Long-lasting Cardioprotection Against Chronic Anthracycline Cardiotoxicity As An Approved Drug Dexrazoxane On A Well-established Animal Model?

Background: ACE inhibitors (ACEi) have been reported cardioprotective in a secondary prevention of anthracycline (ANT) cardiotoxicity in high-risk patients. However, it remains to be determined whether they can also prevent the onset of ANT-induced cardiac damage and provide long-lasting cardioprotection in primary settings similarly as approved drug dexrazoxane (DEX). Objectives: The aim of this study was to assess whether ACEis can prevent TOP2B-mediated DNA damage induced by ANTs in the heart as a very upstream event, and thus provide long-lasting cardioprotection against chronic ANT cardiotoxicity. Methods: Chronic cardiotoxicity was induced in rabbits by daunorubicin (DAU, 3 mg/kg weekly for 10 weeks). Perindopril (PER) in two clinically relevant doses (0.05 and 0.1 mg/kg/day) was administered before and throughout the chronic DAU treatment. The cardioprotection was evaluated at the end of treatment period and after 3- and 10-week drug-free post-treatment follow-up (FU). TOP2B-depedent DNA damage signaling in the heart was determined 6 h after single dose of DAU, while TOPB interaction was studied in vitro ; the results were compared to DEX. Results: A week after completion of the chronic DAU administration, PER-co-treatment completely overcame or markedly reduced DAU-induced mortality, blood congestion and systolic dysfunction (LVFS 41.5% vs. 34.3% in the DAU group, p&lt;0.05), increase of troponin T in plasma and histopathological changes in the heart. However, most of these parameters were significantly deteriorated during 3-week drug-free FU. Further worsening of the left ventricular systolic function and cardiac morphological damage occurred in the 10-week FU which led to a heart failure-related mortality in the PER co-treated group. DEX showed very effective protection against DAU cardiotoxicity both at the end of chronic treatment and after the 10-week FU. In contrast to DEX, the PER co-treatment did not affect TOP2B activity in vitro and did not prevent DAU-induced acute p53-mediated DNA damage signaling in the heart. Conclusions: Unlike approved drug DEX, the ACEi treatment provided only temporary control of ANT cardiotoxicity development which may be associated with the lack of the effects on ANT-induced and TOP2B-mediated DNA damage response in the heart.

Angiotensin receptor-neprilysin inhibitor therapy and recurrence of atrial fibrillation after radiofrequency catheter ablation: A propensity-matched cohort study.

BackgroundCompared with conventional medicines, angiotensin receptor-neprilysin inhibitor (ARNI) could further improve the prognosis for multiple cardiovascular diseases, such as heart failure, hypertension, and myocardial infarction. However, the relationship between ARNI therapy and the recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation is currently unknown.MethodsThis study is a retrospective cohort study. Patients with consecutive persistent or paroxysmal AF undergoing first-time radiofrequency ablation were enrolled from February 2018 to October 2021. We compared the risk of AF recurrence in patients with catheter ablation who received ARNI with the risk of AF recurrence in those who received the angiotensin-converting enzyme inhibitor (ACEI). The propensity-score matched analysis was conducted to examine the effectiveness of ARNI. We used a Cox regression model to evaluate AF recurrence events.ResultsAmong 679 eligible patients, 155 patients with ARNI treatment and 155 patients with ACEI treatment were included in the analyses. At a median follow-up of 228 (196–322) days, ARNI as compared with ACEI was associated with a lower risk of AF recurrence [adjusted hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.24–0.63; p < 0.001]. In addition, no interaction was found in the subgroup analysis.ConclusionAngiotensin receptor-neprilysin inhibitor treatment was associated with a decreased risk of AF recurrence after first-time radiofrequency catheter ablation.

Risk of Mild Cognitive Impairment or Probable Dementia in New Users of Angiotensin II Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors

The cardiovascular and renal outcomes of angiotensin-II receptor blocker (ARB) and angiotensin-converting enzyme inhibitor (ACEI) treatment are well-known; however, few studies have evaluated initiation of these agents and cognitive impairment. To emulate a target trial to evaluate the cognitive outcomes of initiating an ARB- vs ACEI-based antihypertensive regimen in individuals at risk for mild cognitive impairment (MCI) and probable dementia (PD). Active comparator, new-user observational cohort study design using data from the Systolic Blood Pressure Intervention Trial (SPRINT), conducted November 2010 through July 2018. Marginal cause-specific hazard ratios (HRs) and treatment-specific cumulative incidence functions were estimated with inverse probability (IP) weighting to account for confounding. Participants were using neither an ARB nor ACEI at baseline. Data analysis was conducted from April 7, 2021, to April 26, 2022. New users of ARB vs ACEI during the first 12 months of trial follow-up. Composite of adjudicated amnestic MCI or PD. Of 9361 participants, 727 and 1313 new users of an ARB or ACEI, respectively, with well-balanced baseline characteristics between medication exposure groups after inverse probability weighting (mean [SD] age, 67 [9.5] years; 1291 ]63%] male; 240 [33%] Black; 89 [12%] Hispanic; 383 [53%] White; and 15 [2%] other race or ethnicity. In the primary analysis, during a median follow-up of 4.9 years, the inverse probability-weighted rate of amnestic MCI or PD was 4.3 vs 4.6 per 100 person-years among participants initiating ARB vs ACEI (HR, 0.93; 95% CI, 0.76-1.13). In subgroup analyses, new users of an ARB vs ACEI had a lower rate of amnestic MCI or PD among those in the standard systolic blood pressure treatment arm (HR, 0.61; 95% CI, 0.41-0.91) but not in the intensive arm (HR, 1.17; 95% CI, 0.90-1.52) (P = .007 for interaction). In this observational cohort study of US adults at high cardiovascular disease risk, there was no difference in the rate of amnestic MCI or PD among new users of an ARB compared with ACEI, although 95% CIs were wide.

Effect of angiotensin-converting enzyme inhibition on cardiovascular adaptation to exercise training.

Angiotensin‐converting enzyme (ACE) activity may be one determinant of adaptability to exercise training, but well‐controlled studies in humans without confounding conditions are lacking. Thus, the purpose of the present study was to investigate whether ACE inhibition affects cardiovascular adaptations to exercise training in healthy humans. Healthy participants of both genders (40 ± 7 years) completed a randomized, double‐blind, placebo‐controlled trial. Eight weeks of exercise training combined with placebo (PLA, n = 25) or ACE inhibitor (ACEi, n = 23) treatment was carried out. Before and after the intervention, cardiovascular characteristics were investigated. Mean arterial blood pressure was reduced (p < 0.001) by −5.5 [−8.4; −2.6] mmHg in ACEi, whereas the 0.7 [−2.0; 3.5] mmHg fluctuation in PLA was non‐significant. Maximal oxygen uptake increased (p < 0.001) irrespective of ACE inhibitor treatment by 13 [8; 17] % in ACEi and 13 [9; 17] % in PLA. In addition, skeletal muscle endurance increased (p < 0.001) to a similar extent in both groups, with magnitudes of 82 [55; 113] % in ACEi and 74 [48; 105] % in PLA. In contrast, left atrial volume decreased (p < 0.05) by −9 [−16; −2] % in ACEi, but increased (p < 0.01) by 14 [5; 23] % in PLA. Total hemoglobin mass was reduced (p < 0.01) by −3 [−6; −1] % in ACEi, while a non‐significant numeric increase of 2 [−0.4; 4] % existed in PLA. The lean mass remained constant in ACEi but increased (p < 0.001) by 3 [2; 4] % in PLA. In healthy middle‐aged adults, 8 weeks of high‐intensity exercise training increases maximal oxygen uptake and skeletal muscle endurance irrespective of ACE inhibitor treatment. However, ACE inhibitor treatment counteracts exercise training‐induced increases in lean mass and left atrial volume. ACE inhibitor treatment compromises total hemoglobin mass.