Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, their effects on cardiac structure and function in HFrEF are uncertain. Methods: We designed a multicenter randomized, double-blind, placebo-controlled trial to investigate the cardiac effects of empagliflozin in patients in NYHA functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomized 1:1 to empagliflozin 10 milligrams once daily or placebo, stratified by age (<65 and ≥65 years) and glycemic status (diabetes or prediabetes). The co-primary outcomes were change from baseline to 36 weeks in LV end-systolic volume indexed to body surface area (LVESVi) and LV global longitudinal strain (LV GLS) measured using cardiovascular magnetic resonance (CMR). Secondary efficacy outcomes included other CMR measures (LVEDVi, LVEF), diuretic intensification, symptoms (Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS)), 6-minute walk distance (6MWD), B-lines on lung ultrasound and biomarkers (including NT-proBNP). Results: From April 2018 to August 2019, 105 patients were randomized: 77 (73.3%) male, mean age 68.7 [SD 11.1] years, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LVEF 32.5% [9.8%], and 81 (77.1%) NYHA II and 24 (22.9%) NYHA III. Patients received standard treatment for HFrEF. Compared with placebo, empagliflozin reduced LVESVi by 6.0 (-10.8 to -1.2) ml/m 2 (p=0.015). There was no difference in LV GLS. Empagliflozin reduced LVEDVi by 8.2 (-13.7 to -2.6) ml/m 2 (p=0.0042) and reduced NT-proBNP by 28 (2 to 47) %, p=0.038. There were no between-group differences in other CMR measures, KCCQ-TSS, 6MWD or B-lines. Conclusions: The SGLT2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes. Favorable reverse LV remodeling may be a mechanism by which SGLT2 inhibitors reduce HF hospitalization and mortality in HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique Identifier: NCT03485092.

Background: Microalbuminuria is an early sign of kidney disease in diabetes and indicates cardiovascular risk. We tested if a prespecified urinary proteomic risk classifier (CKD273) was associated with development of microalbuminuria and if progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone. Methods: Prospective multicentre study in people with type 2 diabetes, normal urinary albumin excretion and preserved renal function in 15 European specialist centres. High-risk individuals determined by CKD273 were randomised 1:1 (interactive web response system) in a double-blind randomised controlled trial comparing spironolactone 25 mg o.d. to placebo. Primary endpoint was development of confirmed microalbuminuria in all individuals with available data. Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone and association between CKD273 and impaired renal function defined as a glomerular filtration rate < 60 ml/min per 1•73 m 2. This study is registered with ClinicalTrials.gov: NCT02040441 and is completed. Findings: From March 25, 2014 to September 30, 2018 we followed 1775 participants, 12% (n=216) had high-risk urinary proteomic pattern of which 209 were included in the trial and assigned spironolactone (n=102) or placebo (n=107). Median follow-up time was 2•51 years (IQR 2•0-3•0). Progression to microalbuminuria was seen in 28•2% of high-risk and 8•9% of low-risk people (P< 0•001) (hazard ratio (HR), 2•48; 95% confidence interval [CI], 1•80 to 3•42 P<0•001, independent of baseline clinical characteristics). A 30% decline in eGFR from baseline was seen in 42 (19•4 %) high-risk participants compared to 62 (3•9 %) low-risk participants, HR 5•15; 95 % CI (3•41 to 7•76; p<0.0001). Development of microalbuminuria was seen in 35 (33%) randomised to placebo and 26 (25%) randomised to spironolactone treatment (HR 0•81, 95% CI, 0•49 to 1•34, P=0•41). Harms: hyperkalaemia was seen in 13 versus 4, and gynaecomastia in 3 versus 0 subjects on spironolactone and placebo, respectively. Interpretation: In people with type 2 diabetes and normoalbuminuria, the urinary proteomic classifier CKD273 was associated with a 2•5 times increased risk for progression to microalbuminuria over a median of 2•5 years, independent of clinical characteristics. Spironolactone did not prevent progression to microalbuminuria in high-risk subjects.

Our results demonstrate that acute exposure to tobacco smoking as well as electronic cigarettes influences vascular and respiratory function. Where tobacco smoking significantly increased microparticle formation, indicative of possible endothelial injury, electronic cigarettes use induced vasoreactivity and decreased peak expiratory flow. These findings suggest that both electronic cigarettes and tobacco smoking negatively impact vascular function.

Background: Patients with left ventricular systolic dysfunction (LVSD) following myocardial infarction (MI) are at high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system (RAS) inhibition may result in greater attenuation of adverse LV remodeling due to increased levels of substrates for neprilysin with vasodilatory, anti-hypertrophic, anti-fibrotic and sympatholytic effects. Methods: We performed a prospective, multi-center, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103mg twice daily with valsartan 160mg twice daily in patients ≥3 months following MI with a LV ejection fraction (LVEF) ≤40% who were taking a RAS inhibitor (equivalent dose of ramipril ≥2.5mg twice daily), and a beta-blocker unless contraindicated or intolerant. Patients in New York Heart Association functional classification ≥II or with signs and symptoms of HF were excluded. The primary outcome was change from baseline to 52-weeks in LV end-systolic volume index (LVESVI) measured using cardiac magnetic resonance imaging (MRI). Secondary outcomes included other MRI measurements of LV remodeling, change in N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-TnI), and a patient global assessment of change questionnaire. Results: From July 2018 to June 2019, 93 patients were randomized: mean age 60.7±10.4 years, median time from MI 3.6 years (IQR 1.2-7.2), mean LVEF 36.8%±7.1, median NT-proBNP 230pg/mL (124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LVESVI; adjusted between-group difference -1.9mL/m 2 (95%CI -4.9, 1.0); p=0.19. There were no significant between-group differences in NT-proBNP, hs-TnI, LV end-diastolic volume index, left atrial volume index, LVEF, LV mass index, or patient global assessment of change. Conclusions: In patients with asymptomatic LVSD following MI, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique identifier: NCT03552575