Clinical efficacy of angiotensin receptor-neprilysin inhibitor in de novo heart failure with reduced ejection fraction.

BACKGROUND/AIMS: We aimed to analyze the efficacy of angiotensin receptor-neprilysin inhibitor (ARNI) by the disease course of heart failure (HF). METHODS: We evaluated 227 patients with HF in a multi-center retrospective cohort that included those with left ventricular ejection fraction (LVEF) ≤ 40% undergoing ARNI treatment. The patients were divided into patients with newly diagnosed HF with ARNI treatment initiated within 6 months of diagnosis (de novo HF group) and those who were diagnosed or admitted for HF exacerbation for more than 6 months prior to initiation of ARNI treatment (prior HF group). The primary outcome was a composite of cardiovascular death and worsening HF, including hospitalization or an emergency visit for HF aggravation within 12 months. RESULTS: No significant differences in baseline characteristics were reported between the de novo and prior HF groups. The prior HF group was significantly associated with a higher primary outcome (23.9 vs. 9.4%) than the de novo HF group (adjusted hazard ratio 2.52, 95% confidence interval 1.06-5.96, p = 0.036), although on a higher initial dose. The de novo HF group showed better LVEF improvement after 1 year (12.0% vs 7.4%, p = 0.010). Further, the discontinuation rate of diuretics after 1 year was numerically higher in the de novo group than the prior HF group (34.4 vs 18.5%, p = 0.064). CONCLUSION: The de novo HF group had a lower risk of the primary composite outcome than the prior HF group in patients with reduced ejection fraction who were treated with ARNI.

Association of the magnitude of the difference in blood pressure between office and ambulatory measurements with blood pressure variability in untreated individuals.

OBJECTIVES: We evaluated the association between cardiovascular risk factors and the magnitude of the difference in systolic blood pressure (SBP) between office and ambulatory measurements (masked effect) in untreated individuals without apparent hypertension-mediated organ damage (HMOD). METHODS: The inclusion criteria were 1) age ≥ 20 years, 2) blood pressure ≥ 140/90 mmHg at the outpatient clinic, and 3) not receiving antihypertensive medications. The difference between office and ambulatory SBP was calculated by subtracting the ambulatory daytime SBP from the office SBP. The association between the masked effect and SBP variability was analyzed in individuals without HMOD (no electrocardiographic left ventricular hypertrophy, spot urine albumin-to-creatinine ratio < 30 mg/g, and estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2, n = 296). RESULTS: Among the cardiovascular risk factors, ambulatory BP variability was significantly correlated with the SBP difference. The standard deviation (SD) and coefficient of variation (cv) of 24-h SBP exhibited a significant negative linear association with the SBP difference in univariate and multivariate analyses adjusted for age, sex, presence of diabetes, and 24-h ambulatory SBP. A significant association was observed in patients with ambulatory daytime hypertension. In the multivariate analysis, individuals with a negative SBP difference > -5 mmHg exhibited a higher SD and cv of 24-h SBP than those with a negative SBP difference ≤ -5 mmHg or a positive SBP difference. CONCLUSIONS: The results of our study suggest that the magnitude of the negative difference in office and ambulatory SBP may be a potential risk factor, even in individuals without apparent HMOD. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov ( NCT03855605 ).

Clinical outcomes of gastrointestinal bleeding management during anticoagulation therapy.

BACKGROUND: Acute gastrointestinal (GI) bleeding is not an uncommon complication of oral anticoagulation (OAC) therapy that requires medication cessation. However, drug cessation may cause fatal stroke or systemic embolization in patients at high thromboembolic risk. Here we sought to find an appropriate anticoagulation cessation strategy in cases of GI bleeding during OAC therapy. METHODS: This single-center retrospective cohort analysis was performed between 2010 and 2018. Patients were enrolled if the following three consecutive conditions were met: 1) electrocardiography electrocardiography-proven atrial fibrillation; 2) OAC therapy; and 3) GI bleeding. We divided the drug cessation strategy into the continuation and discontinuation groups. During 1-year follow-up, the rates of major thromboembolic and rebleeding events were calculated. RESULTS: One hundred and forty-six patients (continuation [n = 54] vs. discontinuation [n = 92] group) were enrolled. Patients in the discontinuation group were more likely to be older (69.8 ± 9.0 yrs vs. 74.9 ± 8.9 yrs, p = 0.001), while patients in the continuation group were more likely to have undergone cardiac valve surgery (51.9% vs. 20.7%, p<0.001). The presence of a mechanical mitral valve was a determinant of continuation strategy (38.9% vs. 7.5%, p<0.001). However, the mean CHA2DS2-VASc (3.4±1.3 vs. 4.1±1.6, p = 0.010) and Glasgow-Blatchford (8.0±2.4 vs. 8.9±2.5, p = 0.037) scores were higher in the discontinuation group. Two major embolic strokes occurred in each group (3.7% vs. 2.2%, p = 0.585). Four of 54 (7.4%) and five of 92 (5.4%) patients had rebleeding events during follow-up (p = 0.632). One embolic event in the continuation group and one rebleeding event in the discontinuation group were fatal. The Glasgow-Blatchford score was a predictor of 1-year rebleeding events (odds ratio [OR], 1.36; 95% confidence interval [CI], 0.68-2.20; p = 0.028). The high CHA2DS2-VASc score showed a strong trend (OR, 1.71; 95% CI, 0.92-3.20; p = 0.089) in 1-year thromboembolic events. CONCLUSION: No single risk factor or drug cessation strategy was attributed to adverse clinical events after GI bleeding. The risk of future thrombotic or rebleeding events should be individualized and controlled for based on a pre-existing stratification system.

Comparison of inflammatory markers between diabetic and nondiabetic ST segment elevation myocardial infarction.

BACKGROUND: Inflammation plays a significant role in acute coronary syndrome (ACS) and type 2 diabetes mellitus (DM). There may be similar inflammatory changes in non-DM patients with ST elevation myocardial infarction (STEMI) and DM patients with stable angina (SA), and DM patients with STEMI may have more severe changes than the former two groups. The objectives of this study were to investigate whether the level of inflammation was similar in patients with non-DM STEMI and DM SA, and to evaluate whether the changes in the level of inflammation were more severe in patients with DM STEMI compared to the other two groups. METHODS AND RESULTS: A variety of inflammatory markers including: highly sensitive C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), IL-18, vascular cell adhesion molecule-1 (VCAM-1), and matrix metallopeptidase-9 (MMP-9) as well as insulin resistance were compared among the three groups: DM STEMI (90 patients), DM SA (91 patients), and non-DM STEMI (76 patients). Inflammatory marker levels were not significantly different between the DM SA and non-DM STEMI groups. However, hsCRP and IL-6 were increased in the DM STEMI compared to the DM SA patients (p=0.005 and p=0.004, respectively). In addition, hsCRP, ESR, and IL-18 were increased in the DM STEMI compared to the non-DM STEMI patients (p=0.017, p=0.020, and p=0.033, respectively). Furthermore, the fasting insulin and the homeostasis model assessment were significantly increased in the DM STEMI compared to the DM SA patients (p=0.04 and p=0.004, respectively). CONCLUSIONS: DM SA and non-DM STEMI may have similar inflammatory changes. DM STEMI may be a more severe inflammatory condition compared to patients with DM SA or non-DM STEMI.

Correlation between circulating angiogenic cell mobilizations and recovery of coronary flow reserve in patients with acute myocardial infarction.

BACKGROUND: The correlations between circulating angiogenic cell mobilizations and improvement of microvascular integrity were investigated in patients (n=110) with acute myocardial infarction (AMI) during an 8-month follow up. METHODS AND RESULTS: Coronary flow reserve (CFR) was measured at baseline and at 8 months by using an intracoronary Doppler wire. Serial changes in the absolute numbers of circulating angiogenic cells such as CD34+, CXCR4+, CD117+, CD133+ and C-met+ were measured at baseline, day 1, day 5 and at 8 months. The absolute numbers of circulating angiogenic cells at day 1 were significantly higher than those at baseline. A positive correlation was found between the numbers of circulating angiogenic cells of CD34+, CXCR4+, CD117+ and CD133+ cells at day 1 and the CFR changes from baseline. The cut-off value of CFR changes at 8 months by a receiver operating characteristic curve between a circulating CD34+ cell at day 1 and changes of CFR at 8 months was 0. Late-loss showed the positive correlation with the absolute number of C-met+ cells and the negative correlation with the absolute number of CXCR4+ cells after AMI. The negative correlation was found between changes in high-sensitive C-reactive protein and soluble intercellular adhesion molecule-1 and changes in CFR at 8 months. CONCLUSIONS: The recovery of microvascular integrity after acute ischemic injury was expedited by the increases in circulating angiogenic cell mobilization together with the greater decreases in inflammatory cytokines. The improvement in CFR could be predicted by the measurement of circulating angiogenic cells after AMI.

Cellular and molecular changes associated with inhibitory effect of pioglitazone on neointimal growth in patients with type 2 diabetes after zotarolimus-eluting stent implantation.

OBJECTIVE: To investigate the mechanistic basis underlying antirestenosis and the antiatherogenic effect of pioglitazone in patients with type 2 diabetes mellitus who were undergoing zotarolimus-eluting stent implantation. METHODS AND RESULTS: Recent studies highlight the beneficial effect of pioglitazone in attenuating neointimal growth after stent implantation. Patients with coronary artery diseases were randomly assigned to pioglitazone (n=47) or placebo (n=47) after stent implantation. Pioglitazone significantly reduced neointimal hyperplasia within the stented lesion and attenuated total plaque burden in the in-segment regions of the stent, as assessed by intravascular ultrasonography at the 8-month follow-up. These changes were preceded by reduced circulating natural killer (NK) cells, diminished interleukin 6 and monocyte chemoattractant protein-1 levels, and downregulation of chemokine receptor 2 at 2 days after stent implantation; and an elevated interleukin 10 level at 10 days after implantation. Furthermore, the proliferation and migration of vascular smooth muscle cells were inhibited in the presence of pioglitazone-treated patient serum, demonstrating that the antiproliferative effects of pioglitazone occurred concurrently with its antiinflammatory action. CONCLUSIONS: Our data present early cellular and immunologic changes by pioglitazone that might have been associated with antirestenotic and antiatherogenic effects in diabetic patients. Inhibiting proinflammatory responses while promoting antiinflammatory circuits, together with an antiproliferative action, may, in part, account for the antirestenotic effect of pioglitazone by altering vascular remodeling processes in the early phase.