Diuretic use and outcomes in patients with heart failure with reduced ejection fraction: Insights from the VICTORIA trial.

AIMS: In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF. METHODS AND RESULTS: We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1-39, 41-80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post-randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1-39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41-80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all pinteraction > 0.5). Post-randomization diuretic dose changes for vericiguat and placebo showed similar rates of up-titration (19.6 and 20.2/100 person-years), down-titration (16.8 and 18.1/100 person-years), and stopping diuretics (22.9 and 24.2/100 person-years). CONCLUSIONS: Loop diuretic TDD at randomization was independently associated with worse outcomes in this high-risk population. The efficacy of vericiguat was consistent across the range of diuretic doses.

Recurrent heart failure hospitalizations increase the risk of mortality in heart failure patients with atrial fibrillation and type 2 diabetes mellitus in the United Kingdom: a retrospective analysis of Clinical Practice Research Datalink database.

BACKGROUND: Heart failure (HF) is a global illness and is a leading cause of hospitalizations. Recurrent HF hospitalization (HFH) is associated with increased risk of cardiovascular (CV) and all-cause mortality, thereby burdening the health system. Type 2 diabetes mellitus (T2DM) and atrial fibrillation (AF) are two important comorbidities in patients living with HF. This study aims to assess the association between recurrent HFHs with CV and all-cause mortality in patients living with HF and having AF and/or T2DM. METHODS: This study was conducted using primary care data from the Clinical Practice Research Datalink database with linkage to hospital data and mortality data. Adults living with HF and with at least 1 HFH were identified from January 2010 to December 2014. Patients were grouped based on the number of recurrent HFHs. During follow-up, all-cause mortality or CV mortality for the HF population with AF and T2DM was recorded. RESULTS: Overall, 32.9% of 2344 T2DM patients and 28.2% of 4585 AF patients had at least 1 recurrent HFH. The patients were relatively elderly and were predominantly male. The mean number of all-cause hospitalizations in HF patients having T2DM and AF, with ≥ 1 recurrent HFH were significantly higher than patients without recurrent HFH. The annualized mortality rates in CV mortality as the primary cause and for all-cause mortality and increased with recurrent HFHs, in T2DM and AF patients. The risk of CV mortality as primary cause and all cause morality were 5.39 and 3.19 times higher in T2DM patients with 3 recurrent HFHs versus no recurrent HFH. Similarly, the risk of CV mortality as primary cause and all cause morality was 5.98 and 4.3 times higher in AF patients with 3 recurrent HFHs versus those with no recurrent HFH. CONCLUSIONS: Recurrent HFHs are strongly associated with CV mortality and all-cause mortality in HF patients with TD2M or AF. The hospitalization rate highlights the need for treatment and disease management, which will improve the course of the disease and help patients stay out of hospital.

Hospitalization Rates in Patients with Heart Failure and Reduced Ejection Fraction Initiating Sacubitril/Valsartan or Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers: A Retrospective Cohort Study.

INTRODUCTION: The angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan (SAC/VAL) has shown benefit in patients with symptomatic heart failure (HF), including those naïve to renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, and is considered the preferred RAASi for chronic HF. Real-world data on ARNI, specifically in RAASi-naïve patients, are limited. This study compared real-world outcomes of ARNI (SAC/VAL) vs. angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy in RAASi-naïve patients with HF and reduced ejection fraction (HFrEF). METHODS: This retrospective cohort study included de-identified data on RAASi-naïve patients with HFrEF (left ventricular ejection fraction ≤ 40%) who had newly initiated SAC/VAL or ACEi/ARB between July 1, 2015, and March 31, 2019, from the Optum® Electronic Health Records database in the US. New SAC/VAL users were propensity score matched 1:2 with new ACEi/ARB users by pre-selected characteristics. One-year post-index rates of all-cause, HF, and cardiovascular hospitalizations and the composite of HF hospitalization or emergency room (ER) visits were measured using negative binomial regression. Time to first all-cause hospitalization, HF hospitalization, and composite of HF hospitalization or ER visits was measured using a subdistribution hazards model. RESULTS: The matched sample included 3059 new SAC/VAL and 6118 new ACEi/ARB users. Rates of all-cause hospitalization and composite of HF hospitalization or ER visits were significantly lower with SAC/VAL compared with ACEi/ARB (incidence rate ratio [95% confidence interval]: 0.87 [0.81-0.93] and 0.87 [0.81-0.94], respectively), whereas rates of HF hospitalizations and cardiovascular hospitalizations were similar (1.00 [0.91-1.11] and 0.94 [0.87-1.02], respectively). Time-to-event analyses also showed a similar trend. CONCLUSIONS: In real-world clinical practice, RAASi-naïve patients with HFrEF initiating SAC/VAL were less likely to be hospitalized than those initiating ACEi/ARB, suggesting a potential for a reduced clinical and economic burden in these patients.

Burden and Quality of Life Among Female and Male Patients with Heart Failure in Europe: A Real-World Cross-Sectional Study.

PURPOSE: To characterize symptoms, clinical burden, and health-related quality of life (HRQoL) among women and men with heart failure (HF) with a left ventricular ejection fraction (LVEF) of ≤60% in Europe. PATIENTS AND METHODS: A real-world cross-sectional study was conducted in France, Germany, Italy, Spain, and United Kingdom from June to November 2019. Patient record forms were completed by 257 cardiologists and 158 general practitioners for consecutive patients with HF. The same patients were invited to complete a questionnaire comprising patient-reported outcomes: the Minnesota Living with Heart Failure Questionnaire (MLHFQ), five-level five-dimension EuroQol questionnaire (EQ-5D-5L), Visual Analogue Scale (VAS), and Work Productivity and Activity Impairment questionnaire. RESULTS: The mean age of 804 patients (men, n=517; women, n=287) was 68.6 years (men, 67.8 years; women, 70.2 years; p=0.0022). The mean LVEF was 44.7% (men, 43.6%; women, 46.8%; p<0.0001). Patients reported dyspnoea when active (overall, 55.7%; men, 56.0%; women, 55.3%), fatigue/weakness/faintness (34.5%; men, 32.9%; women, 37.2%), and oedema (20.3%; men, 18.7%; women, 23.1%) as the most troublesome HF symptoms. Overall, 54.1% of patients reported low mood/depression (men, 50.8%; women, 60.1%). The overall MLHFQ mean score was higher (ie, poorer HRQoL) among women vs men (37.9 vs 34.6; p=0.0481). MLHFQ was consistently higher (ie, poorer HRQoL) for women vs men across the physical (18.6 vs 16.6; p=0.0041) and emotional (9.4 vs 7.9; p=0.0021) scoring domains. Mean EQ-5D utility (0.69 vs 0.75; p=0.0046) and VAS scores (55.4 vs 61.3; p<0.0001) were lower among women compared with men. Overall, 23.4% of patients were hospitalized owing to HF in the previous year (men, 22.7%; women, 24.6%). Patients reported 43.2% activity impairment due to HF (men, 41.6%; women, 46.4%; p=0.01). CONCLUSION: HF causes a substantial burden on patients, with a greater burden among women vs men. This gender-related difference is consistent with other HF studies, warranting further research to understand the underlying reasons.

Caregivers of Patients with Heart Failure: Burden and the Determinants of Health-Related Quality of Life.

PURPOSE: To assess the burden among caregivers of patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≤60%. The burden by New York Heart Association (NYHA) functional class was also characterized. PATIENTS AND METHODS: A cross-sectional study was conducted in France, Germany, Italy, Spain, and UK from June to November 2019. Patient record forms were completed by 257 cardiologists and 158 general practitioners for consecutive HF patients. Caregivers who accompanied the patient to their consultation completed a caregiver self-completion survey voluntarily, which included the Family Caregiver Quality of Life Questionnaire (FAMQOL) and 5-level 5-dimension EuroQol questionnaire (EQ-5D-5L). RESULTS: We analyzed 361 caregivers of patients with HF (NYHA class I, n=41; II, n=212; III IV, n=108). Mean age of caregivers was 58.8 years (NYHA I/II/III-IV: 59.1/60.8/54.6 years; p=0.0029), with majority being females (73.1%). Caregivers spent on average 19.8 hours/week caring for a HF patient, which increased with increase in NYHA class (I/II/III-IV: 11.8/18.1/25.9 hours/week; p=0.0094). Caregivers (24.1%) reported providing emotional support/encouragement to patients as the most troublesome/inconvenient caregiving activity (no significant difference across NYHA class). Nearly one-third of caregivers experienced stress (NYHA I/II/III-IV: 17.1%/28.8%/40.7%; p=0.0111) and anxiety (26.8%/24.1%/39.8%; p=0.0127) due to caregiving burden. The overall FAMQOL mean score decreased significantly (poorer QoL) with increase in NYHA class (I/II/III-IV: 58.1/56.3/52.2; p=0.0069). A trend of decreasing scores with increasing NYHA class was observed across physical, emotional, and social domains (each p≤0.012). CONCLUSION: Caregivers of HF patients with LVEF ≤60% experienced a significant burden, which was higher among caregivers of patients with more severe and symptomatic disease.

Recurrent heart failure hospitalizations increase the risk of cardiovascular and all-cause mortality in patients with heart failure in Sweden: a real-world study.

AIMS: Heart failure (HF) is a leading cause of hospitalization and is associated with high morbidity and mortality. We examined the impact of recurrent HF hospitalizations (HFHs) on cardiovascular (CV) mortality among patients with HF in Sweden. METHODS AND RESULTS: Adults with incident HF were identified from linked national health registers and electronic medical records from 01 January 2005 to 31 December 2013 for Uppsala and until 31 December 2014 for Västerbotten. CV mortality and all-cause mortality were evaluated. A time-dependent Cox regression model was used to estimate relative CV mortality rates for recurrent HFHs. Assessment was also done for ejection fraction-based HF phenotypes and for comorbid atrial fibrillation, diabetes, or chronic renal impairment. Overall, 3878 patients with HF having an index hospitalization were included, providing 9691.9 patient-years of follow-up. Patients were relatively old (median age: 80 years) and were more frequently male (55.5%). Compared with patients without recurrent HFHs, the adjusted hazard ratio (HR [95% confidence interval; CI]) for CV mortality and all-cause mortality were statistically significant for patients with one, two, three, and four or more recurrent HFHs. The risk of CV mortality and all-cause mortality increased approximately six-fold in patients with four or more recurrent HFHs vs. those without any HFHs (HR [95% CI]: 6.26 [5.24-7.48] and 5.59 [4.70-6.64], respectively). Similar patterns were observed across the HF phenotypes and patients with comorbidities. CONCLUSIONS: There is a strong association between recurrent HFHs and CV and all-cause mortality, with the risk increasing progressively with each recurrent HFH.

Real-world effectiveness and safety of sacubitril/valsartan in heart failure: A systematic review.

BACKGROUND: PARADIGM-HF demonstrated superiority of sacubitril/valsartan (sac/val) over enalapril in patients with heart failure with reduced ejection fraction (HFrEF). However, patients in clinical practice may differ in their characteristics and overall risk compared with patients in clinical trials, and additional outcomes can be observed in real world (RW). Hence, a systematic review was conducted to identify and describe RW data on sac/val. METHODS: RW studies evaluating the effects of sac/val in adult patients with HFrEF with a sample size ≥100 were identified via MEDLINE® and Embase® from 2015 to January 2020. Citations were screened, critically appraised and relevant data were extracted. RESULTS: A total of 68 unique studies were identified. Nearly half of the studies were conducted in Europe (n = 34), followed by the US (n = 15) and Asia (n = 11). Median follow-up period varied from 1 to 19 months. Mean age ranged between 48.7 and 79.0 years; patients were mostly male and in New York Heart Association (NYHA) functional class II/III, and mean left ventricular ejection fraction varied between 23%and 38%. Of studies performing comparisons, most reported superior efficacy of sac/val in reducing the risk of HF hospitalisations, all-cause hospitalisations, and all-cause mortality as compared to standard-of-care. Many studies reported significant improvements in NYHA functional class and reduction in biomarker levels post sac/val. Hypotension and hyperkalaemia were the most frequently reported adverse events. CONCLUSIONS: This comprehensive overview of currently available RW evidence on sac/val complements the evidence from randomised controlled trials, substantiating its effectiveness in heterogeneous real-world HF populations.

Recurrent hospitalizations are associated with increased mortality across the ejection fraction range in heart failure.

AIMS: The proportion of patients hospitalized for heart failure (HF) with preserved left ventricular ejection fraction (LVEF) is rising, but no approved treatment exists, in part owing to incomplete characterization of this particular HF phenotype. In order to better define the characteristics of HF phenotypes in Finland, a large cohort with 12 years' follow-up time was analysed. METHODS AND RESULTS: Patients diagnosed between 2005 and 2017 at the Hospital District of Southwest Finland were stratified according to LVEF measure and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. For this retrospective registry study, previously diagnosed HF patients were defined as follows: patients with reduced ejection fraction (HFrEF; LVEF ≤ 40%; n = 4042), mid-range ejection fraction (HFmrEF; LVEF > 40-50% and NT-proBNP ≥ 125 pg/mL; n = 1468), and preserved ejection fraction (HFpEF; LVEF > 50% and NT-proBNP ≥ 125 pg/mL; n = 3122) and followed up for 15 022, 4962, and 10 097 patient-years, respectively. Cardiovascular (CV) hospitalization and mortality, influence of pre-selected covariates on hospitalization and mortality, and the proportion of HFpEF and HFmrEF patients with a drop in LVEF to HFrEF phenotype were analysed. All data were extracted from the electronic patient register. HFrEF patients were rehospitalized slightly earlier than HFpEF/HFmrEF patients, but the second, third, and fourth rehospitalization rates did not differ between the subgroups. Female gender and better kidney function were associated with reduced rehospitalizations in HFmrEF and HFrEF, with a non-significant trend in HFpEF. Each additional hospitalization was associated with a two-fold increased risk of death and 2.2- to 2.3-fold increased risk of CV death. All-cause mortality was higher in patients with HFpEF. Although CV mortality was less frequent in HFpEF patients, it was associated with increased NT-proBNP concentrations at index in all patient groups. During the 10 years following the index date, 26% of HFmrEF patients and 10% of HFpEF patients progressed to an HFrEF phenotype. CONCLUSIONS: These findings suggest that disease progression, in terms of increased frequency of hospitalizations, and the relationship between increased number of hospitalizations and mortality are similar by LVEF phenotypes. These data highlight the importance of effective treatments that can reduce hospitalizations and suggest a role for monitoring NT-proBNP levels in the management of HFpEF patients in particular.

Recurrent heart failure hospitalizations are associated with increased cardiovascular mortality in patients with heart failure in Clinical Practice Research Datalink.

AIMS: Heart failure (HF) is a leading cause of hospitalization and is associated with high morbidity and mortality post-diagnosis. Here, we examined the impact of recurrent HF hospitalization (HFH) on cardiovascular (CV) and all-cause mortality among HF patients. METHODS AND RESULTS: Adult HF patients identified in the Clinical Practice Research Datalink with a first (index) hospitalization due to HF recorded in the Hospital Episode Statistics data set from January 2010 to December 2014 were included. Patients were followed up until death or end of study (December 2017). CV mortality as primary and as any reported cause and all-cause mortality were evaluated. An extended Cox regression model was used for reporting adjusted relative CV mortality rates for time-dependent recurrent HFHs. Overall, 8603 HF patients with an index hospitalization were included, providing 15 964 patient-years of follow-up. Patients were relatively old (median age: 80 years) and were mostly male (54.6%), with main co-morbidities being hypertension and atrial fibrillation. Recurrent HFHs occurred one, two, three, and more than four times in 1561 (18.2%), 518 (6.02%), 206 (2.4%), and 153 (1.8%) patients, respectively. The median time to mortality was 215 (38-664) days for 50.8% of patients who died for any cause during the study period and 139 (27-531) days for 31.3% who died with CV reasons as primary cause. Compared with those of patients without recurrent HFHs, the adjusted hazard ratios (95% CI) for CV mortality as primary cause were 2.65 (2.35-2.99), 3.69 (3.06-4.43), 5.82 (4.48-7.58), and 5.95 (4.40-8.05) for those with one, two, three, and more than four recurrent HFHs. CONCLUSIONS: There is a strong association between recurrent HFH and CV mortality, with the risk increasing progressively with each recurrent HFH.

A Database Cohort Study to Assess the Risk of Angioedema Among Patients with Heart Failure Initiating Angiotensin-Converting Enzyme Inhibitors in the USA.

INTRODUCTION: Real-world evidence on the risk of angioedema associated with angiotensin-converting enzyme inhibitors (ACEIs) in patients with heart failure (HF) is scarce. OBJECTIVE: This non-interventional study aimed to estimate the incidence of and risk factors for angioedema in patients with HF initiating an ACEI in real-world practice. METHODS: This was a retrospective cohort study using claims data from the PharMetrics Plus database, supplemented with consumer health data, from 1 January 2007 to 31 March 2015. Patients with HF initiating an ACEI were followed up for a maximum of 1 year, until the first occurrence of angioedema or until cohort exit. Angioedema incidence rates were estimated and stratified by potential risk factors such as race, age, sex, and time from initiation of ACEI therapy. For each risk factor, the unadjusted and adjusted hazard ratio (HR) was calculated; exploratory analyses were carried out to account for all potential confounders. RESULTS: We identified 21,639 patients with HF initiating an ACEI (mean age 58 years; 35.6% women; mean follow-up 205 days). The 1-year incidence of angioedema per 1000 patient-years was 3.3 [95% confidence interval (CI) 2.4-4.5]. The incidence was higher in Black [6.2 (95% CI 3.1-12.5)] than in non-black [2.9 (95% CI 2.1-4.1)] patients, higher in women [5.2 (95% CI 3.4-7.9)] than in men [2.3 (95% CI 1.5-3.6)], and greatest in the first 30 days of ACEI therapy. CONCLUSIONS: The risk of angioedema in patients with HF initiating an ACEI observed in this study is in line with published estimates for the general patient population treated with ACEIs.

Negative effects of rofecoxib treatment on cardiac function after ischemia-reperfusion injury in APOE3Leiden mice are prevented by combined treatment with thromboxane prostanoid-receptor antagonist S18886 (terutroban).

OBJECTIVE: Selective cyclooxygenase-2 inhibition by rofecoxib was associated with increased risk of cardiovascular events. We hypothesized that concomitant treatment with thromboxane prostanoid receptor antagonist S18886 might ameliorate possible negative effects. We evaluated the effects of S18886, rofecoxib, and the interaction of both compounds in a combined treatment on myocardial infarct (MI) size and cardiac function after experimental ischemia/reperfusion injury in hyperlipidemic APOE*3Leiden transgenic mice. DESIGN: Prospective, randomized, control trial. SETTING: Research laboratory. SUBJECTS: Hyperlipidemic APOE*3Leiden transgenic mice. INTERVENTIONS: After four weeks of feeding an atherogenic diet, MI was induced by a 30-min ligation of the left anterior descending coronary artery, followed by reperfusion. Oral compound treatment was initiated 90 mins before MI, and continued daily by gavage for seven days. Four treatment groups (n = 12, each) were studied: solvent (Control), S18886, rofecoxib, and S18886 plus rofecoxib. MEASUREMENTS AND MAIN RESULTS: One week after MI, the mice were anesthetized and cardiac function was quantified by left ventricular (LV) pressure-volume relationships obtained by miniature pressure-conductance catheters. The ischemic area was measured by morphometry and expressed as percentage of LV area. No significant differences in infarct size were found between groups. Compared with control, treatment with S18886 did not affect heart function whereas the rofecoxib group had significantly lower cardiac output (4.5 +/- 0.8 vs. 3.2 +/- 1.1 mL/min, p < 0.01), lower ejection fraction (40 +/- 8 vs. 27 +/- 11%, p < 0.005), and increased end-systolic volume (18.6 +/- 5.7 vs. 28.6 +/- 9.0 muL, p < 0.05). The group with combined (S18886+rofecoxib) treatment was not different from control. Statistical analysis showed significant interactive effects between S18886 and rofecoxib indicating that negative effects of rofecoxib on cardiac function were prevented by S18886 treatment. CONCLUSIONS: Rofecoxib treatment reduced global and systolic LV function after ischemia-reperfusion injury in APOE*3Leiden mice. These negative effects are prevented by combined treatment with thromboxane prostanoid-receptor antagonist S18886 (terutroban).

Thromboxane A2/prostaglandin H2 receptor activation mediates angiotensin II-induced postischemic neovascularization.

OBJECTIVE: We analyzed the involvement of thromboxane (TX) A2/prostaglandin (PG) H2 (TP) receptor in ischemia-induced neovascularization in mice. METHODS AND RESULTS: Unilateral hindlimb ischemia was induced by right femoral artery ligature in male C57BL/6J mice (n=7 per group). Animals were then treated with or without TP receptor antagonist (S18886, 5 or 10 mg/kg per day; ramatroban, 10 mg/kg per day) or aspirin (30 mg/kg per day) in drinking water for 21 days. Hindlimb ischemia raised plasma level of TXB2, the stable metabolite of TXA2, by 4.7-fold. This increase was blocked by aspirin treatment whereas S18886 (5 or 10 mg/kg per day) had no effect. However, neither S 18886 nor aspirin affected postischemic neovascularization. We next assessed the putative involvement of TXA2 signaling in angiotensin II (Ang II) proangiogenic pathway. Ang II (0.3 mg/kg per day) enhanced TXB2 plasma levels by 2.6-fold over that of control (P<0.01). Ang II-induced TXB2 upregulation was reduced by cotreatment with Ang II type I receptor antagonist (candesartan, 20 mg/kg per day). Angiographic score, capillary number, and foot perfusion were improved by 1.7-, 1.7-, and 1.4-fold, respectively, in Ang II-treated mice compared with controls (P<0.05). Ang II proangiogenic effect was associated with a 1.6-fold increase in VEGF-A protein content (P<0.05) and a 1.4-fold increase in the number of Mac-3-positive cells (ie, macrophages) in ischemic areas (P<0.05). Interestingly, treatments with TP receptor antagonists or aspirin hampered the proangiogenic effects of Ang II. CONCLUSIONS: Endogenous activation of TXA2 receptor by eicosanoids did not modulate spontaneous neovascularization in the setting of ischemia. Conversely, TXA2 signaling is involved in Ang II-induced AT1-dependent vessel growth.

The thromboxane receptor antagonist S18886 attenuates renal oxidant stress and proteinuria in diabetic apolipoprotein E-deficient mice.

Arachidonic acid metabolites, some of which may activate thromboxane A(2) receptors (TPr) and contribute to the development of diabetes complications, including nephropathy, are elevated in diabetes. This study determined the effect of blocking TPr with S18886 or inhibiting cyclooxygenase with aspirin on oxidative stress and the early stages of nephropathy in streptozotocin-induced diabetic apolipoprotein E(-/-) mice. Diabetic mice were treated with S18886 (5 mg . kg(-1) . day(-1)) or aspirin (30 mg . kg(-1) . day(-1)) for 6 weeks. Neither S18886 nor aspirin affected hyperglycemia or hypercholesterolemia. There was intense immunohistochemical staining for nitrotyrosine in diabetic mouse kidney. In addition, a decrease in manganese superoxide dismutase (MnSOD) activity was associated with an increase in MnSOD tyrosine-34 nitration. Tyrosine nitration was significantly reduced by S18886 but not by aspirin. Staining for the NADPH oxidase subunit p47(phox), inducible nitric oxide synthase, and 12-lipoxygenase was increased in diabetic mouse kidney, as were urine levels of 12-hydroxyeicosatetraenoic acid and 8-iso-prostaglandin F(2alpha). S18886 attenuated all of these markers of oxidant stress and inflammation. Furthermore, S18886 significantly attenuated microalbuminuria in diabetic mice and ameliorated histological evidence of diabetic nephropathy, including transforming growth factor-beta and extracellular matrix expression. Thus, in contrast to inhibiting cyclooxygenase, blockade of TPr may have therapeutic potential in diabetic nephropathy, in part by attenuating oxidative stress.

The thromboxane A2 receptor antagonist S18886 prevents enhanced atherogenesis caused by diabetes mellitus.

BACKGROUND: S18886 is an orally active thromboxane A2 (TXA2) receptor (TP) antagonist in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. We previously showed that S18886 inhibits atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice by a mechanism independent of platelet-derived TXA2. Atherosclerosis is accelerated by diabetes and is associated with increased TXA(2) and other eicosanoids that stimulate TP. The purpose of this study was to determine whether S18886 lessens the enhanced atherogenesis in diabetic apoE(-/-) mice. METHODS AND RESULTS: Diabetes mellitus was induced in apoE(-/-) mice with streptozotocin and was treated or not with S18886 (5 mg.kg(-1).d(-1)). After 6 weeks, aortic lesion area was increased >4-fold by diabetes in apoE(-/-) mice, associated with similar increases in serum glucose and cholesterol. S18886 largely prevented the diabetes-related increase in lesion area without affecting the hyperglycemia or hypercholesterolemia. S18886 prevented deterioration of endothelial function and endothelial nitric oxide synthase expression, as well as increases in intimal markers of inflammation associated with diabetes. In human aortic endothelial cells in culture, S18886 also prevented the induction of vascular cell adhesion molecule-1 and prevented the decrease in endothelial nitric oxide synthase expression caused by high glucose. CONCLUSIONS: The TP antagonist inhibits inflammation and accelerated atherogenesis caused by diabetes, most likely by counteracting effects on endothelial function and adhesion molecule expression of eicosanoids stimulated by the diabetic milieu.

Atherosclerosis regression and TP receptor inhibition: effect of S18886 on plaque size and composition--a magnetic resonance imaging study.

AIMS: Endothelial dysfunction, platelet hyperactivity, and inflammation play a crucial role in atherogenesis. A growing body of evidence suggests that inhibition of the thromboxane A2 (TxA2 or TP) receptor may improve endothelial function and reduce the inflammatory component of atherosclerosis in addition to its demonstrated antiplatelet activity. Consequently, we sought to assess the effect of a novel TP receptor antagonist S18886, on atherosclerotic lesion progression and composition by serial non-invasive magnetic resonance imaging (MRI). METHODS AND RESULTS: S18886 was compared with control in an experimental model of established aortic atherosclerosis in New Zealand White rabbits (n=10). The animals underwent MRI of the abdominal aorta at the time of randomization and at the end of treatment. Subsequently, animals were euthanized and specimens were stained for histopathology and immunohistochemistry with anti-alpha-actin antibodies for vascular smooth muscle cells (VSMC), anti-RAM-11 for macrophages, anti-caspase-3 for apoptotic cells, anti-MMP-1 for metalloproteinases, and anti-endothelin-1 (ET-1) as a marker of endothelial dysfunction. MRI analysis revealed a significant reduction in total vessel area (TVA) and vessel wall area (VWA) in the S18886 group (P<0.05). Immunostaining analysis showed a significant decrease in RAM-11, caspase-3, MMP-1, ET-1 and an increase in alpha-actin in the treated group (P<0.05 vs. control). CONCLUSION: Inhibition of the TP receptor by S18886 causes a regression of advanced atherosclerotic plaques. In addition, the reduction in the markers for macrophages, apoptotic cells, metalloproteinases, and endothelin-1 and the increase in VSMC, suggests that S18886 may not only halt the progression of atherosclerosis, but also transform lesions towards a more stable phenotype. The possibility of combining antithrombotic and antiatherosclerotic activity by means of the administration of TP inhibitors deserves further investigation in a clinical setting.