The Associations of Diuretics and Laxatives Use with Cardiovascular Mortality. An Individual Patient-Data Meta-analysis of Two Large Cohort Studies Abstract Purpose To investigate the associations of diuretics overall, non-potassium-sparing diuretics in specific, and laxative use with cardiovascular mortality (CVM) in subjects with antihypertensive treatment. Methods Analyses included 4253 participants, aged 50 to 75 years, from the German ESTHER cohort and 105,359 participants, aged 50 to 69 years, from the UK Biobank. Cox proportional hazard regression models were applied in both studies, and then results were pooled using random-effects model meta-analyses. Results During 14 and 7 years of follow-up, 476 and 1616 CVM cases were observed in the ESTHER study and the UK Biobank, respectively. Compared to non-users, a 1.6-fold (hazard ratio [95% confidence interval] 1.57 [1.29; 1.90]), a 1.4-fold (1.39 [1.26; 1.53]), and no statistically significantly increased (1.13 [0.94; 1.36]) CVM were observed in users of diuretics overall, non-potassium-sparing diuretics in specific, and laxatives, respectively. Concurrent use of non-potassium-sparing diuretics and laxatives was associated with a 2-fold increased CVM (2.05 [1.55; 2.71]) when compared to users of neither diuretics nor laxatives. However, a test for interaction slightly missed statistical significance (p = 0.075). Conclusions These consistent results from two large cohort studies imply that more research is needed on the safety of diuretics in routine care. Although not statistically significant in this study, a drug-drug interaction of non-potassium-sparing diuretics and laxatives appears plausible. Physicians and pharmacists are advised to clarify additional laxative use in users of non-potassium-sparing diuretics and inform about the risk of concurrent use. Moreover, closer potassium monitoring intervals (e.g., every 3 months) might be indicated in concurrent users to prevent fatal cardiovascular events.

After the AUGUSTUS Trial, Should Apixaban Be the Only Direct Oral Anticoagulant to Be Used in Triple Therapy in Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention?

Effects of PDE-5 Inhibition on the Cardiopulmonary System After 2 or 4 Weeks of Chronic Hypoxia Abstract Purpose In pulmonary hypertension (PH), hypoxia represents both an outcome and a cause of exacerbation. We addressed the question whether hypoxia adaptation might affect the mechanisms underlying PH alleviation through phosphodiesterase-5 (PDE5) inhibition. Methods Eight-week-old male Sprague-Dawley rats were divided into two groups depending on treatment (placebo or sildenafil, a drug inhibiting PDE5) and were exposed to hypoxia (10% O2) for 0 (t0, n = 9/10), 2 (t2, n = 5/5) or 4 (t4, n = 5/5) weeks. The rats were treated (0.3 mL i.p.) with either saline or sildenafil (1.4 mg/Kg per day). Results Two-week hypoxia changed the body weight (− 31% vs. − 27%, respectively, P = NS), blood hemoglobin (+ 25% vs. + 27%, P = NS) and nitrates+nitrites (+ 175% vs. + 261%, P = 0.007), right ventricle fibrosis (+ 814% vs. + 317%, P < 0.0001), right ventricle hypertrophy (+ 84% vs. + 49%, P = 0.007) and systolic pressure (+ 108% vs. + 41%, P = 0.001), pulmonary vessel density (+ 61% vs. + 46%, P = NS), and the frequency of small (< 50 µm wall thickness) vessels (+ 35% vs. + 13%, P = 0.0001). Most of these changes were maintained for 4-week hypoxia, except blood hemoglobin and right ventricle hypertrophy that continued increasing (+ 52% vs. + 42%, P = NS; and + 104% vs. + 83%, P = 0.04). To further assess these observations, small vessel frequency was found to be linearly related with the right ventricle-developed pressure independent of hypoxia duration. Conclusions Thus, although hypoxia adaptation is not yet accomplished after 4 weeks, PH alleviation by PDE5 inhibition might nevertheless provide an efficient strategy for the management of this disease.

Oral Anticoagulation for Atrial Fibrillation Thromboembolism Prophylaxis in the Chronic Kidney Disease Population: the State of the Art in 2019 Abstract Atrial fibrillation (AF) is the most common cardiac rhythm disturbance and is associated with increased risk of thromboembolism. Oral anticoagulants are effective at reducing rates of thromboembolism in patients with AF in the general population. Patients with AF and concurrent chronic kidney disease (CKD) have higher risk of thromboembolism and bleeding compared with patients with normal renal function. Among moderate CKD and end-stage renal disease (ESRD) patients on chronic dialysis, the use of oral anticoagulants is controversial. Use of warfarin, while beneficial in non-CKD patients, raises a number of concerns such as increased bleeding risk, labile anticoagulant effect, and calciphylaxis, especially in the ESRD population. The newer direct oral anticoagulant (DOAC) agents have demonstrated comparable efficacy and improved safety profiles compared with coumadin but are not as well studied in the CKD population. This review highlights the efficacy and safety of coumadin and the DOACs for thromboembolism prophylaxis in non-valvular AF patients with CKD.

Effect of Tofogliflozin on Systolic and Diastolic Cardiac Function in Type 2 Diabetic Patients Abstract Purpose Recent studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors have a favorable effect on cardiovascular events in diabetic patients. However, the underlying mechanism associated with a favorable outcome has not been clearly identified. The purpose of this study was to investigate the effect of tofogliflozin, SGLT2 inhibitor, on systolic and diastolic cardiac function in patients with type 2 diabetes mellitus (T2DM). Methods We enrolled 26 consecutive T2DM out-patients on glucose-lowering drugs who initiated tofogliflozin and underwent echocardiography before and ≥ 6 months after tofogliflozin administration. During this period, we also enrolled 162 T2DM out-patients taking other glucose-lowering drugs as a control group. Propensity score analysis was performed to match the patient characteristics. As a result, 42 patients (tofogliflozin group 21 patients and control group 21 patients) were finally used for analysis. Left ventricular systolic function was assessed by measuring 2D-echocardiographic left ventricular ejection fraction (LVEF) and diastolic cardiac function by pulsed wave Doppler-derived early diastolic velocity (E/e′). Results There were no significant differences in patient characteristics and echocardiographic parameters at baseline. The change in LVEF from baseline to follow-up was 5.0 ± 6.9% in the tofogliflozin group and − 0.6 ± 5.5% in the control group; difference significant, p = 0.006. The change in E/e′ was − 1.7 ± 3.4 in the tofogliflozin group and 0.7 ± 4.1 in the control group; difference significant, p = 0.024. Conclusions In addition to conventional oral glucose-lowering drugs, additional tofogliflozin administration had a favorable effect on left ventricular systolic and diastolic function in patients with T2DM.

Long-Term Efficacy and Safety of Immunomodulatory Therapy for Atherosclerosis Abstract Background and Aims The long-term effect of immune tolerance has not been explored so far in atherosclerosis. In the present study, we assessed the effect of mucosal tolerance to a multi antigenic construct expressing three peptides from ApoB, HSP60, and outer membrane protein from Chlamydia pneumonia (AHC) for 30 weeks at every 6-week interval to understand the kinetics of immune modulation in disease progression. The safety profile of the molecule was also evaluated in mice. Methods Apobtm2SgyLdlrtm1Her/J mice (5–6 weeks) were orally dosed with multi antigenic construct (AHC) molecule on alternate days, followed by high-fat diet feeding to initiate atherosclerosis. Results Treated animals showed an efficient reduction in plaque growth and lipid accumulation at 6 weeks (49%, p < 0.01) and 12 weeks (42.3%, p < 0.01) which decreased to 29% (p = 0.0001) at 18 weeks and at later time points. Macrophage accumulation was significantly lower at all time points (53% at 12 weeks to 27% at 30 weeks). Regulatory T cells increased in the spleen following treatment until 12 weeks (week 0 (2.57 ± 0.18 vs. 6.36 ± 0.03, p = 0.02), week 6 (4.52 ± 0.2 vs. 8.87 ± 0.32, p = 0.02), and week 12 (8.74 ± 0.37 vs. 15.4 ± 0.27, p = 0.02)) but showed a decline later. A similar trend was observed with tolerogenic dendritic cells. We observed an increase in antibody levels to low-density lipoprotein and oxidized LDL at later stages. AHC molecule was found to be safe in acute and repeated dose toxicity studies. Conclusions Our results suggest that immune tolerance to AHC protein by oral administration is able to provide efficient atheroprotection up to 18 weeks and moderately at later stages. Apart from immune regulatory cells, protective antibodies may also have a role in controlling atherosclerosis.

Pirfenidone in Heart Failure with Preserved Ejection Fraction—Rationale and Design of the PIROUETTE Trial Abstract Background The PIROUETTE (PIRfenidOne in patients with heart failUre and preserved lEfT venTricular Ejection fraction) trial is designed to evaluate the efficacy and safety of the anti-fibrotic pirfenidone in patients with chronic heart failure and preserved ejection fraction (HFpEF) and myocardial fibrosis. HFpEF is a diverse syndrome associated with substantial morbidity and mortality. Myocardial fibrosis is a key pathophysiological mechanism of HFpEF and myocardial fibrotic burden is strongly and independently associated with adverse outcome. Pirfenidone is an oral anti-fibrotic agent, without haemodynamic effect, that leads to regression of myocardial fibrosis in preclinical models. It has proven clinical effectiveness in pulmonary fibrosis. Methods The PIROUETTE trial is a randomised, double-blind, placebo-controlled phase II trial evaluating the efficacy and safety of 52 weeks of treatment with pirfenidone in patients with chronic HFpEF (symptoms and signs of heart failure, left ventricular ejection fraction ≥ 45%, elevated natriuretic peptides [BNP ≥ 100 pg/ml or NT-proBNP ≥ 300 pg/ml; or BNP ≥ 300 pg/ml or NT-proBNP ≥ 900 pg/ml if in atrial fibrillation]) and myocardial fibrosis (extracellular matrix (ECM) volume ≥ 27% measured using cardiovascular magnetic resonance). The primary outcome measure is change in myocardial ECM volume. A sub-study will investigate the relationship between myocardial fibrosis and myocardial energetics, and the impact of pirfenidone, using 31phosphorus magnetic resonance spectroscopy. Discussion PIROUETTE will determine whether pirfenidone is superior to placebo in relation to regression of myocardial fibrosis and improvement in myocardial energetics in patients with HFpEF and myocardial fibrosis (NCT02932566). Clinical Trial Registration clinicaltrials.gov (NCT02932566) https://clinicaltrials.gov/ct2/show/NCT02932566

Attainment of Guideline-Directed Medical Treatment in Stable Ischemic Heart Disease Patients With and Without Chronic Kidney Disease Abstract Background Stable ischemic heart disease (SIHD) is prevalent in patients with chronic kidney disease (CKD); however, whether guideline-directed medical therapy (GDMT) is adequately implemented in patients with SIHD and CKD is unknown. Hypothesis Use of GDMT and achievement of treatment targets would be higher in SIHD patients without CKD than in patients with CKD. Methods This was a retrospective study of 563 consecutive patients with SIHD (mean age 67.8 years, 84% Caucasians, 40% females). CKD was defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73m2 using the four-variable MDRD Study equation. We examined the likelihood of achieving GDMT targets (prescription of high-intensity statins, antiplatelet agents, renin-angiotensin-aldosterone system inhibitors (RAASi), and low-density lipoprotein cholesterol levels < 70 mg/dL, blood pressure < 140/90 mmHg, and hemoglobin A1C < 7% if diabetes) in patients with (n = 166) and without CKD (n = 397). Results Compared with the non-CKD group, CKD patients were significantly older (72 vs 66 years; p < 0.001), more commonly female (49 vs 36%; p = 0.002), had a higher prevalence of diabetes (46 vs 34%; p = 0.004), and left ventricular systolic ejection fraction (LVEF) < 40% (23 vs. 10%, p < 0.001). All GDMT goals were achieved in 26% and 24% of patients with and without CKD, respectively (p = 0.712). There were no between-group differences in achieving individual GDMT goals with the exception of RAASi (CKD vs non-CKD: adjusted risk ratio 0.73, 95% CI 0.62–0.87; p < 0.001). Conclusions Attainment of GDMT goals in SIHD patients with CKD was similar to patients without CKD, with the exception of lower rates of RAASi use in the CKD group.

Obesity-Related Genetic Determinants of Heart Failure Prognosis Abstract Purpose Recent advances in genomics offer a smart option for predicting future risk of disease and prognosis. The objective of this study was to examine the prognostic value in heart failure (HF) patients, of a series of single nucleotide polymorphisms (SNPs). Methods A selection of 192 SNPs found to be related with obesity, body mass index, circulating lipids or cardiovascular diseases were genotyped in 191 patients with HF. Anthropometrical and clinical variables were collected for each patient, and death and readmission by HF were registered as the primary endpoint. Results A total of 53 events were registered during a follow-up period of 438 (263–1077) days (median (IQR)). Eight SNPs strongly related to obesity and HF prognosis were selected as possible prognostic variables. From these, rs10189761 and rs737337 variants were independently associated with HF prognosis (HR 2.295 (1.287–4.089, 95% CI); p = 0.005), whereas rs10423928, rs1800437, rs737337 and rs9351814 were related with bad prognosis only in obese patients (HR 2.142 (1.438–3.192, 95% CI); p = 0.00018). Combined scores of the genomic variants were highly predictive of poor prognosis. Conclusions SNPs rs10189761 and rs737337 were identified, for the first time, as independent predictors of major clinical outcomes in patients with HF. The data suggests an additive predictive value of these SNPs for a HF prognosis. In particular for obese patients, SNPs rs10423928, rs1800437, rs737337 and rs9351814 were related with a bad prognosis. Combined scores weighting the risk of each genomic variant could effect interesting new tools to stratify the prognostic risk of HF patients.