Angiotensin-converting Enzyme Inhibitor Treatment Research Articles

Mechanisms of Cachexia in Chronic Disease States

Sarcopenia and cachexia are muscle wasting syndromes associated with aging and with many chronic diseases, such as congestive heart failure (CHF), diabetes, cancer, chronic obstructive pulmonary disease and chronic kidney disease (CKD). While mechanisms are complex, these conditions are often accompanied by elevated angiotensin II (Ang II). Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme inhibitor treatment improves weight loss. It was found that Ang II infusion in rodents leads to skeletal muscle wasting. Ang II increases cytokines and circulating hormones, such as tumor necrosis factor-α, interleukin-6, serum amyloid-A and glucocorticoids, which regulate muscle protein synthesis and degradation. Ang II–induced muscle wasting is caused by alterations in insulin-like growth factor-1 signaling, enhanced muscle protein breakdown via the ubiquitin-proteasome system and decreased appetite resulting from the downregulation of hypothalamic orexigenic neuropeptides, such as Npy and orexin. Ang II also inhibits 5′ adenosine monophosphate–activated protein kinase activity and disrupts normal energy balance via the activation of 5′ adenosine monophosphate–activated protein kinase phosphatase PP2Cα. Furthermore, Ang II inhibits skeletal muscle stem (satellite) cell proliferation, leading to lowered muscle regenerative capacity. Distinct satellite cell angiotensin receptor subtypes have different effects on different stages of differentiation and are critical for the regulation of muscle regeneration. These data suggest that the renin-angiotensin system plays a critical role in mechanisms underlying cachexia in chronic disease states, and it is a promising target for the treatment of muscle atrophy in patients with diseases such as CHF and CKD.

MicroRNAs mediate the cardioprotective effect of angiotensin-converting enzyme inhibition in acute kidney injury.

Cardiovascular disease, including cardiac hypertrophy, is common in patients with kidney disease and can be partially attenuated using blockers of the renin-angiotensin system (RAS). It is unknown whether cardiac microRNAs contribute to the pathogenesis of cardiac hypertrophy or to the protective effect of RAS blockade in kidney disease. Using a subtotal nephrectomy rat model of kidney injury, we investigated changes in cardiac microRNAs that are known to have direct target genes involved in the regulation of apoptosis, fibrosis, and hypertrophy. The effect of treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril on cardiac microRNAs was also investigated. Kidney injury led to a significant increase in cardiac microRNA-212 and microRNA-132 expression. Ramipril reduced cardiac hypertrophy, attenuated the increase in microRNA-212 and microRNA-132, and significantly increased microRNA-133 and microRNA-1 expression. There was altered expression of caspase-9, B cell lymphoma-2, transforming growth factor-β, fibronectin 1, collagen type 1A1, and forkhead box protein O3, which are all known to be involved in the regulation of apoptosis, fibrosis, and hypertrophy in cardiac cells while being targets for the above microRNAs. ACE inhibitor treatment increased expression of microRNA-133 and microRNA-1. The inhibitory action of ACE inhibitor treatment on increased cardiac NADPH oxidase isoform 1 expression after subtotal nephrectomy surgery suggests that inhibition of oxidative stress is also one of mechanism of ACE inhibitor-mediated cardioprotection. These finding suggests the involvement of microRNAs in the cardioprotective action of ACE inhibition in acute renal injury, which is mediated through an inhibitory action on profibrotic and proapoptotic target genes and stimulatory action on antihypertrophic and antiapoptotic target genes.

Abstract P253: Angiotensin Converting Enzyme Inhibition vs. Angiotensin II Receptor Blockade in Marfan Mouse: Role of Bradykinin

Angiotensin receptor blockers (ARB) decrease aortic root aneurysm progression in a mouse model of Marfan syndrome, by interfering with angiotensin II (Ang II) activation of transforming growth factor beta (TGF-β) signaling. Angiotensin converting-enzyme inhibitors (ACEi) decrease the formation of Ang II, but also increase bradykinin (BK) which can activate the TGF-β pathway. We tested the hypothesis that ACEi and ARBs differ in their effect on aortic aneurysm development in Fbn1C1039G/+ mice due to different effects on BK. We compared the effect of 12-week treatment with telmisartan (3 and 24 mg/L), ramipril (30mg/L) or placebo in the presence or absence of the BK B2 receptor antagonist HOE140 (0.1 mg/Kg/day). ARB and ACEi reduced blood pressure similarly. ARB and ACEi reduced aortic root diameter (by 17.3±3% and 19.1±5%) but only ARB prevented elastin disruption (Figures 1A and 1B), decreased mast cell infiltration and P-ERK immunoreactivity in the ascending aorta. HOE-140 alone did not reduce the aortic root diameter but diminished the aortic elastin disruption. In the lung, ARB compared to ACEi treatment, prevented the development of emphysematous changes (Figure 1C), decreased mast cell infiltration (4.87±0.98% vs. 9.12±1.23%, p=0.012), and decreased MMP12 (1.02±0.08 vs. 1.52±0.13 A.U, p=0.002) and MMP9 (1.32±0.08 vs. 1.69±0.11 A.U, p=0.006) activity. HOE-140 alone prevented emphysematous changes and decreased MMP12 activity. Endogenous BK contributes to elastin disruption in the aortic root and lung by promoting activation of P-ERK and increasing MMP12 activity, respectively. Clinical studies are required to compare the efficacy of ACEi and ARB in Marfan syndrome.

Renin-Angiotensin Inhibitors Decrease Recurrence after Transurethral Resection of Bladder Tumor in Patients with Nonmuscle Invasive Bladder Cancer

Prior reports suggest that renin-angiotensin system inhibition may decrease nonmuscle invasive bladder cancer recurrence. We evaluated whether angiotensin converting enzyme inhibitor or angiotensin receptor blocker treatment at initial surgery was associated with decreased recurrence or progression in patients with nonmuscle invasive bladder cancer. Using an institutional bladder cancer database we identified 340 patients with data available on initial transurethral resection ofbladder tumor. Progression was defined as an increase to stage T2. Cox proportional hazards models were used to evaluate associations with recurrence-free and progression-free survival. Median patient age was 69.6 years. During a median followup of 3 years (IQR 1.3-6.1) 200 patients (59%) had recurrence and 14 (4.1%) had stage progression. Of those patients 143 were receiving angiotensin converting enzyme inhibitor/angiotensin receptor blockers at the time of the first transurethral resection. On univariate analysis factors associated with improved recurrence-free survival included carcinoma in situ (p = 0.040), bacillus Calmette-Guérin therapy (p = 0.003) and angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (p = 0.009). Multivariate analysis demonstrated that patients treated with bacillus Calmette-Guérin therapy (HR 0.68, 95% CI 0.47-0.87, p = 0.002) or angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (HR 0.61, 95% CI 0.45-0.84, p = 0.005) were less likely to experience tumor recurrence. The 5-year recurrence-free survival rate was 45.6% for patients treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers and 28.1% in those not treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers (p = 0.009). Subgroup analysis was performed to evaluate nonmuscle invasive bladder cancer pathology (Ta, T1 and carcinoma in situ) in 85 patients on bacillus Calmette-Guérin therapy alone and in 52 in whom it was combined with angiotensin converting enzyme inhibitor/angiotensin receptor blocker. Multivariate analysis revealed thatpatients treated with bacillus Calmette-Guérin alone (HR 2.19, 95% CI1.01-4.77, p = 0.04) showed worse recurrence-free survival compared to patients treated with bacillus Calmette-Guérin and angiotensin converting enzyme inhibitor/angiotensin receptor blocker (stage Ta HR 0.45, 95% CI 0.21-0.98, p = 0.04). Pharmacological inhibition of the renin-angiotensin system is associated with improved outcomes in patients with bladder cancer. Renin-angiotensin system inhibitor administration in nonmuscle invasive bladder cancer cases should be studied in a prospective randomized trial.

Change in prescription pattern as a potential marker for adverse drug reactions of angiotensin converting enzyme inhibitors.

Background Angiotensin converting enzyme inhibitors (ACEIs) are among the most frequently prescribed groups of medications. ACEI-induced adverse drug reactions (ADRs) are the main reason to discontinue or switch ACEI treatment. ADRs information is not available in prescription databases. Objective To identify a proxy for ACEI-induced ADRs in prescription databases. Setting The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the Netherlands and has included 14,926 subjects aged 45 years or older. Methods All ACEI starters from 2000 to 2011 were identified using prescription data within the Rotterdam Study. Participants were classified into 4 mutually exclusive groups: continuing, discontinuing, switching to angiotensin receptor blockers (ARBs), and switching to other antihypertensives. For categorization, the maximum time-interval between two prescription periods was set at 3 and 6 months. Subsequently, primary care physician files were searched and clinical events were classified as definite ADRs, probable ADRs, possible ADRs and definite non-ADRs. Finally the accuracy of different prescription patterns as indicators of ADRs was evaluated. Main outcome measure Positive predictive values (PPVs), negative predictive values (NPVs), sensitivity and specificity of the prescription patterns of the 4 groups were calculated. Results Totally, 1132 ACEI starters were included. The PPV for a definite ADR was 56.1 % for switchers to ARB, while the PPVs for switchers to other antihypertensives, and discontinuation were 39.5 and 19.5 %, respectively. After including probable ADRs and possible ADRs, PPVs for switchers to ARB increased to 68.3 and 90.5 %. A 6-month interval gave slightly higher PPVs compared to a 3-month interval (maximum 6.1 % higher). The differences in NPVs between 3 and 6-months interval groups were approximately 1.0 %. Conclusions Switching ACEIs to ARBs is the best marker for ACEI-induced ADRs in prescription databases.

Effect of angiotensin converting enzyme inhibitors on periprocedural myocardial infarction in patients with metabolic syndrome.

Metabolic syndrome (MetS) has been reported as a risk factor for cardiovascular events. The aim of the present study is to investigate the association between chronic angiotensin-converting enzyme inhibitors (ACE-I) therapy and the rate of periprocedural myocardial infarction (PMI) after elective coronary stenting among patients with MetS. The inclusion criteria were MetS and plan for elective percutaneous coronary intervention. To assess the effect of ACE-I treatment on the incidence of PMI, measurements of cardiac biomarkers (CK-MB mass and troponin I) were performed at baseline and 24 h after the procedure. A total of 459 patients fulfilling the inclusion criteria were recruited to chronic ACE-I treatment and ACE-I naive groups in a 2/1 ratio. Baseline troponin I and CK-MB levels were similar in both treatment groups, whereas they were significantly lower in ACE-I group 24 h after the procedure. Univariate analysis identified body mass index (BMI), LDL cholesterol, nitrate and ACE-I use as significant factors for the development of PMI. Multivariate regression model revealed that body mass index increased and use of nitrate and ACE-I decreased the probability of PMI independent from confounding factors (OR 1.14, 95% CI 1.05-1.23, p = 0.002 for BMI; OR 0.26, 95% CI 0.14-0.48, p = 0.01 for nitrate use, OR 0.51, 95% CI 0.27-0.93, p = 0.03 for ACE-I use). This prospective observational cohort trial demonstrated that chronic ACE-I therapy was an independent predictor for reduced PMI among patients with MetS who underwent elective coronary intervention.

Association of pretreatment with angiotensin-converting enzyme inhibitors with improvement in ablation outcome in atrial fibrillation patients with low left ventricular ejection fraction

Angiotensin-converting enzyme inhibitors (ACEIs) reduce the incidence of atrial fibrillation (AF). The purpose of this study was to assess the impact of upstream ACEI therapy on postablation AF recurrence and hospitalization in patients with low left ventricular ejection fraction (LVEF). Three hundred forty-five consecutive patients undergoing first AF ablation with low LVEF (≤45%) were classified into group 1 (ACEI+, n = 187 [54%], of whom 44 patients [23.5%] had paroxysmal AF [PAF]) or group 2 (ACEI-, n = 158 [46%]; 31 of these 158 patients [19.6%] had PAF). Additionally, 703 consecutive patients with LVEF >45% undergoing first AF ablation were included for a secondary analysis to evaluate the effect of ACEI treatment in normal ejection fraction. In group 1, ACEI therapy started ≥3 months before ablation and continued through follow-up. Baseline characteristics were similar except for hypertension, which was significantly more prevalent in ACEI+ (71% vs 51%, P < .001). At 24 ± 7 months of follow-up, 109 nonparoxysmal AF patients in group 1 (76%) and 81 (64%) in group 2 (P = .015) were recurrence free. In multivariate analysis, ACEI therapy was an independent predictor of recurrence (hazard ratio for ACEI-, 1.7, 95% confidence interval 1.1-2.7; P = .026]. However, among PAF patients, ACEI use was not associated with ablation success (80% vs 77% in ACEI+ and ACEI-, respectively; P = .82). In the normal-EF population, the success rates between ACEI+ and ACEI- cohorts were similar (71% vs 74%, P = .31). After the index procedure, 17 patients (9.1%) in the ACEI+ group and 28 (17.7%) in the ACEI- cohort (P= .02) required rehospitalization, for a 49% relative risk reduction (relative risk 0.51, 95% confidence interval 0.29-0.90). Preablation use of an ACEI is associated with improvement in ablation outcome in patients with nonparoxysmal AF with low LVEF.

PP.39.20

Objective: Angiotensin-converting enzyme inhibitors (ACEis) are beneficial in patients with heart failure and chronic kidney disease (CKD), yet their direct effects on the heart tissue remain inconclusive. It has been suggested that ACEi do not lead to continuous suppression of systemic angiotensin Ang II levels, but may exert beneficial effects by upregulating Ang 1–7, the suggested antagonist of Ang II. Here we determined the specific contributions of ACE and ACE-independent enzymes to systemic and local Ang-II and Ang 1–7 formation in heart-transplanted (HTX) patients with CKD under ACEi therapy. Design and method: In this cross-sectional, exploratory study we investigated local and systemic angiotensin formation in HTX patients. Right ventricular biopsies of allograft recipients (n = 12, with ACEi treatment and no RAS blockade) were used for assessing cardiac RAS activity by a highly sensitive mass spectrometry based assay. Ang I was spiked to biopsy homogenates, incubated in the presence or absence of selective enzyme inhibitors and the ACE and chymase mediated Ang II formation was measured. Accordingly, we assessed RAS enzyme mediated Ang 1–7 formation from Ang I as well as 1–7 formation from Ang II. Results: We demonstrated that the Ang II formation in plasma is completely ACE depended while ACEis are not efficient to inhibit cardiac Ang II formation in HTX patients. Conversely, cardiac Ang II formation was predominantly chymase-dependent. ACEi therapy significantly upregulated Ang I and Ang 1–7 plasma levels, but did not affect cardiac Ang 1–7 formation rates. The enzymes neprilysin and prolylendopeptidase significantly contributed to cardiac Ang 1–7 formation directly from Ang I and surprisingly, prolylcarboxypeptidase dominated Ang 1–7 formation from Ang II compared to a minor contribution of ACE2 in myocardial tissue of HTX patients independent of ACEi therapy. Conclusions: The local and systemic RAS is differentially regulated in HTX patients. While plasma Ang II formation is ACE-dependent, the cardiac formation of Ang II is chymase-depended. Neprilysin, prolylendopeptidase and prolylcarboxypeptidase are the major contributors of cardiac Ang 1–7 formation independent of ACE2 activity and ACEi therapy. These findings provide molecular background for ACEi therapy with considerable impact on novel RAS-interfering therapeutic approaches.

Urinary angiotensinogen level and its risk factors in patients with " subclinical" diabetic nephropathy

Objective To evaluate the level and related factors of urinary angiotensinogen in patients with subclinical diabetic nephropathy. Methods (1)A total of 80 type 2 diabetic patients without angiotensin-converting enzyme inhibitor (ACEI) or angiotensin Ⅱ receptor blocker(ARB) treatment and hypertension were divided into 3 groups according to 24-hour urinary albuminuria and estimated glomerular filtration rate(eGFR): normoalbuminuria with normal glomerular filtration rate group[urinary microalbuminuria(UMA) <30 mg/24 h, 90≤eGFR <120 ml·min-1·(1.73 m2)-1, NC group, n=28], normoalbuminuria with glomerular hyperfiltration group[UMA<30 mg/24 h, eGFR≥120 ml·min-1·(1.73 m2)-1, SDN group, n=36], microalbuminuria group[30 h≤UMA<300 mg/24 h, 90≤eGFR<120 ml·min-1·(1.73 m2)-1, EDN group, n=16]. The levels of urinary angiotensinogen among various groups were compared.(2)The levels of urine retinol binding protein(RBP), N-acetyl-β-D-glucosaminadase, α-galactosidase, and β2-microglobubin were used to evaluate the renal tubular function. Then all the patients were divided into 4 groups according to the degree of renal tubular injury; the urinary angiotensinogen was compared and the independent related factors were analyzed. (3)20 type 2 diabetic patients with microalbuminuria and ACEI or ARB treatment were also enrolled in this study. The level of urinary angiotensinogen was compared between patients with and without ACEI or ARB treatment. Results Compared with NC group, the level of urinary angiotensinogen in the SDN group was lowered[(1.47±0.11 vs 1.59±0.11)ng/ml, P<0.05], but was raised in the EDN group[(1.62±0.15)ng/ml, P<0.05]. With the aggravation of renal tubular injury, the level of urinary angiotensinogen was increased. Multiple regression analysis showed that urinary angiotensinogen was positively correlated with RBP(P<0.05)and negatively correlated with eGFR(P<0.05). Compared with the patients without ACEI or ARB treatment, the level of urinary angiotensinogen was decreased in patients with ACEI or ARB treatment [(1.43±0.16 vs 1.62±0.15)ng/ml, P<0.05]. Conclusion The level of urinary angiotensinogen in patients with subclinical diabetic nephropathy is lowered, but is then raised in patients with microalbuminuria, which may participate in the progression of renal glomerular and tubular injury in diabetic nephropathy. The renin-angiotensin system inhibitors may delay the progression of diabetic nephropathy via decreasing urinary angiotensinogen level. (Chin J Endocrinol Metab, 2015, 31: 395-399) Key words: Subclinical; Diabetic nephropathy; Urinary angiotensinogen; Renal tubular injury

Effects Of Enalapril On Interstitial PO2 And Contractile Function In The Edl Of Diabetic Rats

Angiotensin converting enzyme inhibitors (ACEi) are standard of care for Type I diabetics. ACEi play a role in preventing diseases such as heart failure, kidney disease, and diabetic neuropathy. Diabetes causes changes within skeletal muscle that alter the balance between oxygen delivery (QO2) and oxygen consumption (VO2) as reflected by changes in the interstitial PO2 (PiO2). PURPOSE: To determine if treatment with the ACEi enalapril would attenuate the effects of diabetes on PiO2 and contractile function in the rat extensor digitorum longus muscle (EDL). METHODS: Female Sprague-Dawley rats (n=33, 282 ± 3 g) were randomly assigned to control (C, 11), diabetic (D, 11), or enalapril-treated diabetic groups (E, 11). Diabetes was induced using streptozotocin (50 mg/kg) and confirmed by urine glucose (>2000 mg/dl). The E group then began a 7 wk treatment regimen of enalapril in their drinking water (15 mg/kg/d). Rats were anesthetized (sodium pentobarbital, 50 mg/kg) and the EDL was exposed and connected to a muscle tension analyzer. PiO2 (phosphorescent quenching) and contractile function were assessed at rest and during the transition to steady-state contractions (1 Hz, 6V). RESULTS: D rats weighed less than C (D, 266 ± 5 vs 305 ± 8 g) and showed atrophy of the EDL (127 ± 10 vs 177 ± 8 mg), and E rats were not different from D (285 ± 10 g and 138 ± 9 mg). Enalapril resulted in a marked reduction in mean arterial pressure (C, 116 ± 2; D, 108 ± 2; E, 91 ± 2 mmHg). Resting PiO2 was lower in D compared to C (24 ± 1 vs. 28 ± 1 mmHg). At the onset of contractions, PiO2 fell more rapidly in D than C (i.e., faster on-kinetics) as reflected by the shorter mean response time (13 ± 2 vs. 22 ± 2 s). Resting PiO2 in E (30 ± 2 mmHg) was greater than D, and on-kinetics were slower (MRT, 19 ± 2 s) and not different from C. Peak twitch tension (per muscle mass) was greater in D compared to C (1.78 ± 0.04 vs. 1.36 ± 0.04 N/g), while twitch tension in E was similar to D (1.88 ± 0.04 N/g). Fatigue was greater in both the D and E groups relative to C (C, 5 ± 1; D, 12 ± 1, E, 11 ± 1 %). CONCLUSIONS: These results confirm previous reports of a diabetes-induced imbalance between QO2 and VO2 at rest and during contractions in diabetic rats. ACEi treatment prevented these changes but did not improve contractile function or fatigue resistance. These results support the notion that ACEi treatment improves the matching of QO2 and VO2 to skeletal muscle. (Supported by Graduate Program Committee, KCOM-ATSU.)

Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis

The comparative efficacy and safety of pharmacological agents to lower blood pressure in adults with diabetes and kidney disease remains controversial. We aimed to investigate the benefits and harms of blood pressure-lowering drugs in this population of patients. We did a network meta-analysis of randomised trials from around the world comparing blood pressure-lowering agents in adults with diabetic kidney disease. Electronic databases (the Cochrane Collaboration, Medline, and Embase) were searched systematically up to January, 2014, for trials in adults with diabetes and kidney disease comparing orally administered blood pressure-lowering drugs. Primary outcomes were all-cause mortality and end-stage kidney disease. We also assessed secondary safety and cardiovascular outcomes. We did random-effects network meta-analysis to obtain estimates for primary and secondary outcomes and we presented these estimates as odds ratios or standardised mean differences with 95% CIs. We ranked the comparative effects of all drugs against placebo with surface under the cumulative ranking (SUCRA) probabilities. 157 studies comprising 43,256 participants, mostly with type 2 diabetes and chronic kidney disease, were included in the network meta-analysis. No drug regimen was more effective than placebo for reducing all-cause mortality. However, compared with placebo, end-stage renal disease was significantly less likely after dual treatment with an angiotensin-receptor blocker (ARB) and an angiotensin-converting-enzyme (ACE) inhibitor (odds ratio 0·62, 95% CI 0·43-0·90) and after ARB monotherapy (0·77, 0·65-0·92). No regimen significantly increased hyperkalaemia or acute kidney injury, although combined ACE inhibitor and ARB treatment had the lowest rank among all interventions because of borderline increases in estimated risks of these harms (odds ratio 2·69, 95% CI 0·97-7·47 for hyperkalaemia; 2·69, 0·98-7·38 for acute kidney injury). No blood pressure-lowering strategy prolonged survival in adults with diabetes and kidney disease. ACE inhibitors and ARBs, alone or in combination, were the most effective strategies against end-stage kidney disease. Any benefits of combined ACE inhibitor and ARB treatment need to be balanced against potential harms of hyperkalaemia and acute kidney injury. Canterbury Medical Research Foundation, Italian Medicines Agency.

The role of muscle sympathetic nerve activity in limiting exercise capacity in heart failure.

The role of muscle sympathetic nerve activity in limiting exercise capacity in heart failure.

Persistent Phenotypic Shift in Cardiac Fibroblasts Following Transient ACE Inhibition

Cardio‐protection afforded by ACE inhibition may be related in part to fibroblast‐specific changes. We have previously shown that transient ACE inhibitor treatment produces long‐term protection against cardiac fibrosis and inflammation in response to myocardial injury induced by L‐NAME. The present study investigates whether transient ACE inhibition produces a persistent phenotypic shift in fibroblasts that may mediate these protective effects. Adult SHR were divided into 3 groups: Control, Control+ L‐NAME (C+L), enalapril (14‐day treatment + 14‐day washout) + L‐NAME (E+L). Cardiac fibroblasts were isolated following in vivo treatment and cultured to passage 1 for measures of macrophage‐recruiting chemokine release, cellular proliferation, and collagen gene expression. In contrast to fibroblasts isolated from C+L, those from E+L rats did not show any increase in Collagen I gene expression, proliferation rate, or release of macrophage‐recruiting chemokines (MCP‐1, GM‐CSF). Our findings demonstrate that prior ACE inhibition resulted in a phenotypic change in fibroblasts to one that resisted L‐NAME‐induced activation. Understanding the mechanism by which ACE inhibition alters fibroblast response to myocardial injury may reveal a novel treatment strategy to prevent pathological cardiac remodeling and ultimate progression to heart failure. Support: Sarver Heart Center

Treatment of ACEI-related angioedema with icatibant: a case series.

No specific drugs are licensed for the treatment of ACE inhibitor (ACEI)-acquired angioedema (ACEI-AAE). Icatibant, an antagonist of the B2 receptor of bradykinin, is a potential treatment for this condition; however, its use in this setting is poorly documented. We report here clinical outcomes of 13 patients with ACEI-AAE treated with icatibant, in a real-life setting. Thirteen patients on ACEI seen in an Emergency Department (ED) with angioedema involving face, lips or the upper airways were analyzed. Angioedema due to known causes other than ACEI treatment was excluded. Initially, all patients received standard therapy (antihistamine, corticosteroids and epinephrine). Due to the lack of response and a worsening severity of symptoms, all patients received one subcutaneous injection of icatibant (30mg/mL). Following icatibant treatment, all patients experienced improvement in the symptoms. The median time from onset of clinical symptoms to injection of icatibant was 3h (IQR 2.5-5.5h). Symptom relief was reported at 30min (IQR 27.5-70min). A complete resolution of symptoms was observed at 5h (IQR 4-7h). Ten patients had previously experienced angioedema attacks. The Median time to complete resolution of the previous attacks was higher (54h; IQR 33-63h), than after icatibant (p=0.002) therapy. No patients required tracheal intubation or tracheotomy, and all patients were discharged within 24h. No adverse events were reported. Before discharge, all patients were instructed to discontinue ACEI, and to take a different antihypertensive agent. This case series supports the efficacy of icatibant in improving symptoms of ACEI-AAE.

Upregulation of SERCA2a following short-term ACE inhibition (by enalaprilat) alters contractile performance and arrhythmogenicity of healthy myocardium in rat.

Chronic angiotensin-converting enzyme inhibitor (ACEIs) treatment can suppress arrhythmogenesis. To examine whether the effect is more immediate and independent of suppression of pathological remodelling, we tested the antiarrhythmic effect of short-term ACE inhibition in healthy normotensive rats. Wistar rats were administered with enalaprilat (ENA, i.p., 5 mg/kg every 12 h) or vehicle (CON) for 2 weeks. Intraarterial blood pressure in situ was measured in A. carotis. Cellular shortening was measured in isolated, electrically paced cardiomyocytes. Standard 12-lead electrocardiography was performed, and hearts of anaesthetized open-chest rats were subjected to 6-min ischemia followed by 10-min reperfusion to examine susceptibility to ventricular arrhythmias. Expressions of calcium-regulating proteins (SERCA2a, cardiac sarco/endoplasmic reticulum Ca(2+)-ATPase; CSQ, calsequestrin; TRD, triadin; PLB, phospholamban; Thr(17)-PLB-phosphorylated PLB at threonine-17, FKBP12.6, FK506-binding protein, Cav1.2-voltage-dependent L-type calcium channel alpha 1C subunit) were measured by Western blot; mRNA levels of L-type calcium channel (Cacna1c), ryanodine receptor (Ryr2) and potassium channels Kcnh2 and Kcnq1 were measured by qRT-PCR. ENA decreased intraarterial systolic as well as diastolic blood pressure (by 20%, and by 31%, respectively, for both P < 0.05) but enhanced shortening of cardiomyocytes at basal conditions (by 34%, P < 0.05) and under beta-adrenergic stimulation (by 73%, P < 0.05). Enalaprilat shortened QTc interval duration (CON 78 ± 1 ms vs. ENA 72 ± 2 ms; P < 0.05) and significantly decreased the total duration of ventricular fibrillations (VF) and the number of VF episodes (P < 0.05). Reduction in arrhythmogenesis was associated with a pronounced upregulation of SERCA2a (CON 100 ± 20 vs. ENA 304 ± 13; P < 0.05) and complete absence of basal Ca(2+)/calmodulin-dependent phosphorylation of PLB at Thr(17). Short-term ACEI treatment can provide protection against I/R injury-induced ventricular arrhythmias in healthy myocardium, and this effect is associated with increased SERCA2a expression.

Retinal Nerve Fiber Layer Loss Is Associated with Urinary Albumin Excretion in Patients with Type 2 Diabetes

To identify the factors associated with retinal nerve fiber layer (RNFL) loss in patients with type 2 diabetes. Cross-sectional study. Ninety-six nonglaucomatous patients with type 2 diabetes without renal impairment (estimated glomerular filtration rate, ≥60 ml/minute per 1.73 m(2)). Eyes were divided into 2 groups based on the presence or absence of RNFL defects detected by red-free retinal fundus photography. All participants underwent an eye fundus examination, and the urinary albumin-to-creatinine ratio (ACR) was determined. A cardiovascular autonomic function test was performed using the following heart rate variability parameters: expiration-to-inspiration ratio, response to the Valsalva maneuver, and standing. Multiple logistic regression analyses were performed to determine potential risk factors related to the presence of RNFL defects in these patients. The association between RNFL defects and diabetic complications. Among the patients, 43 (44.8%) had localized RNFL defects (group 1), whereas the others (55.2%) did not (group 2). The RNFL defects occurred more frequently on the superior side (75.6% and 71.0% in right and left eyes, respectively) compared with the inferior side (13.8% and 0.0% in right and left eyes, respectively). Patients with RNFL defects (group 1) had significantly higher rates of diabetic retinopathy (60.5%) compared with those without RNFL defects (group 2; 32.1%; P = 0.007). The urinary ACR was significantly higher in patients with RNFL defects than in those without defects (45.3±72.1 μg/mg vs. 15.4±17.3 μg/mg creatinine, respectively; P = 0.015), whereas autonomic function test grading was similar between the groups. The urinary ACR was the only factor related to visual field defect location in both univariate (P = 0.021) and multivariate (P = 0.036) logistic regression analyses after adjusting for age; gender; presence of diabetic retinopathy; diabetes duration; smoking; statin use; and antiplatelet, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment. Urinary albumin excretion was associated with nerve fiber layer loss in patients with type 2 diabetes. Careful examination of the optic nerve head may be necessary, particularly in patients with type 2 diabetes exhibiting albuminuria.

Inhibition of ACE Retards Tau Hyperphosphorylation and Signs of Neuronal Degeneration in Aged Rats Subjected to Chronic Mild Stress.

With increasing life expectancy, Alzheimer's disease (AD) and other types of age-associated dementia are on the rise worldwide. Treatment approaches for dementia are insufficient and novel therapies are not readily available. In this context repurposing of established drugs appears attractive. A well-established class of cardiovascular drugs, which targets the angiotensin II system, is such a candidate, which currently undergoes a paradigm shift with regard to the potential benefit for treatment of neurodegenerative symptoms. In search for additional evidence, we subjected aged rats to chronic unpredictable mild stress, which is known to enhance the development of AD-related neuropathological features. We report here that four weeks of chronic mild stress induced a strong upregulation of the hippocampal angiotensin-converting enzyme (Ace) at gene expression and protein level. Concomitantly, tau protein hyperphosphorylation developed. Signs of neurodegeneration were detected by the significant downregulation of neuronal structure proteins such as microtubule-associated protein 2 (Map2) and synuclein-gamma (Sncg). Ace was involved in neurodegenerative symptoms because treatment with the brain-penetrating ACE inhibitor, captopril, retarded tau hyperphosphorylation and signs of neurodegeneration. Moreover, ACE inhibitor treatment could counteract glutamate neurotoxicity by preventing the downregulation of glutamate decarboxylase 2 (Gad2). Taken together, ACE inhibition targets neurodegeneration triggered by environmental stress.

A meta-analysis of the effects of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers on insulin sensitivity in hypertensive patients without diabetes

AimsThis study sought to compare the effects of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) on insulin sensitivity (IS) in hypertensive patients without diabetes. MethodsStudies on the observation of IS in hypertensive patients without diabetes who received ACEI and ARB prior to December 2013 was collected using computer-based retrieval of the PUBMED, EMBASE, and COCHRANE databases. The primary indicators included IS, fasting plasma glucose (FPG), and fasting plasma insulin (FPI). The secondary indicators included systolic blood pressure (SBP) and diastolic blood pressure (DBP). A meta-analysis was performed using the STATA and Review Manager 5.2 software. The effects of these two drugs on IS in hypertensive patients without diabetes were analyzed using the fixed effect model and the random effect model. ResultsA total of 203 cases of patients involved in 4 clinical studies were included. As compared to ARB, ACEI treatment resulted in more effective improvement of IS in hypertensive patients without diabetes (SMD: 0.45, 95% CI 0.17–0.73), although these two drugs did not show significant differences with regards to FPG (WMD: 0.00, 95% CI −0.19–0.20), FPI (WMD: −0.34, 95% CI −1.31–0.63), SBP (WMD: 2.85, 95% CI −1.55–7.24), and DBP (WMD: 0.81, 95% CI −1.12–2.75). ConclusionIn patients showing no significant difference in blood pressure control, the comparison between ACEI and ARB showed that the former type of drug more effectively relieved IS in hypertensive patients without diabetes.

Abstract 15597: Acute Venous Congestion Causes Angiotensin II formation via Angiotensin-Converting Enzyme Activation in Compensated Ambulatory Patients with Systolic Heart Failure

Background: Plasma levels of angiotensin II (AII) are increased in congestive states such as heart failure (HF). The current study examined i) whether venous congestion (VC) itself promotes AII formation, and ii) the contributions of angiotensin-converting enzyme (ACE) vs. other enzymes such as chymases to AII generation in patients with systolic HF. Methods: 42 ambulatory patients with NYHA functional class II or III, an LVEF &lt;40%, no evidence of VC on physical exam and on stable medical therapy were studied. To experimentally model VC, venous arm pressure was increased to 30 mmHg above baseline by inflating a pressure cuff around the dominant arm. Blood was sampled from test and control arm (lacking an inflated cuff) before and after 90 minutes of VC. Radioimmunoassay was used for plasma AII measurements.The effect of ACE inhibitor (ACEI) based therapy (N=29) vs. non-ACEI (N=13) was compared. Results: The age of the study cohort was 53±12 years, 29% were female, 31% had an ischemic etiology and the LVEF was 22±8%. Baseline AII levels were 3-times lower in the ACEI vs. non-ACEI group (24±10 vs. 76±40 pg/mL, P&lt;0.001). Plasma AII was significantly higher in the congested over control arm only in non-ACEI group after 90 minutes of VC (figure). No adverse event was observed during the test. Conclusions: Our study provides the first direct evidence that VC is sufficient to cause AII formation in compensated ambulatory HF patients on non-ACEI based therapy. ACEI treatment completely abolished this increase suggesting activation of ACE, rather than other enzymes such as chymases, to be the cause of volume-dependent AII formation in response to peripheral VC.

Incidence, trends, and predictors of ischemic stroke 1 year after an acute myocardial infarction.

Ischemic stroke after acute myocardial infarction is an important complication. It is unknown whether the risk has changed because the treatment of acute myocardial infarction has improved during the past decade. There is also conflicting data about predictors of stroke risk. To obtain the 1-year incidence of stroke after acute myocardial infarction, the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions database for the years 1998 to 2008 was merged with the Swedish National Patient Register (NPR). The time trend was studied by dividing the entire time period into 5 separate periods. Independent predictors were identified using a multivariable Cox proportional hazards regression model. Between 1998 and 2008, 7185 of 173 233 patients with acute myocardial infarction had an ischemic stroke within 1 year (4.1%). There was a 20% relative risk reduction during the study period (1998-2000 versus 2007-2008) relative risk 0.80 (95% confidence interval, 0.75-0.86; P<0.001. Independent predictors of stroke were age, female sex, ST-segment-elevation myocardial infarction, previous stroke, previous diabetes mellitus, heart failure at admission, angiotensin-converting enzyme inhibitor treatment and atrial fibrillation. Reperfusion treatment with fibrinolysis and percutaneous coronary intervention and treatment with aspirin, P2Y12-inhibitors, and statins predicted a reduced risk of stroke. The risk of ischemic stroke within a year after myocardial infarction is substantial but has clearly been reduced during the studied time period. The major predictive factors found to correlate well with previous investigations. Reperfusion treatment, thrombocyte aggregation inhibition, and lipid lowering are the main contributors to the observed risk reduction.