Fractional flow reserve vs. angiography in guiding management to optimize outcomes in non-ST-segment elevation myocardial infarction: the British Heart Foundation FAMOUS-NSTEMI randomized trial

Aim: We assessed the management and outcomes of non-ST segment elevation myocardial infarction (NSTEMI) patients randomly assigned to fractional flow reserve (FFR)-guided management or angiography-guided standard care. Methods and results: We conducted a prospective, multicentre, parallel group, 1 : 1 randomized, controlled trial in 350 NSTEMI patients with ≥ coronary stenosis ≥30% of the lumen diameter assessed visually (threshold for FFR measurement) (NCT01764334). Enrolment took place in six UK hospitals from October 2011 to May 2013. Fractional flow reserve was disclosed to the operator in the FFR-guided group (n = 176). Fractional flow reserve was measured but not disclosed in the angiography-guided group (n = 174). Fractional flow reserve ≤0.80 was an indication for revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). The median (IQR) time from the index episode of myocardial ischaemia to angiography was 3 (2, 5) days. For the primary outcome, the proportion of patients treated initially by medical therapy was higher in the FFR-guided group than in the angiography-guided group [40 (22.7%) vs. 23 (13.2%), difference 95% (95% CI: 1.4%, 17.7%), P = 0.022]. Fractional flow reserve disclosure resulted in a change in treatment between medical therapy, PCI or CABG in 38 (21.6%) patients. At 12 months, revascularization remained lower in the FFR-guided group [79.0 vs. 86.8%, difference 7.8% (−0.2%, 15.8%), P = 0.054]. There were no statistically significant differences in health outcomes and quality of life between the groups. Conclusion: In NSTEMI patients, angiography-guided management was associated with higher rates of coronary revascularization compared with FFR-guided management. A larger trial is necessary to assess health outcomes and cost-effectiveness

Neoformation of pedogenic carbonates by irrigation and fertilization and their contribution to carbon sequestration in soil

© 2015 Elsevier B.V. The impact of land use change and farming management on soil organic carbon (SOC) and soil inorganic carbon (SIC), particularly pedogenic carbonates (PC), was assessed in a semi-humid region of China. The SOC and SIC content and stocks were measured, and δ13C values were used to calculate the percentage of PC and lithogenic carbonates (LC) in the total SIC. Over the 39-year period, organic fertilizers at high and low rates (OFH and OFL), mineral fertilizers (MF), and a control site without fertilizers (CK) showed an increase of PC compared to a natural fallow plot (F). The main pathway of SIC accumulation was the neoformation of pedo-atmogenic carbonates contributing to C sequestration of at least 0.38, 0.27, 0.23, and 0.12MgCha-1yr-1 for the OFH, OFL, MF, and CK treatments, respectively. The LC stock remained similar in all treatments except for the CK, where LC was significantly lower than all of the other treatments which suggested dissolution. An increase in OC stocks in response to organic fertilization was not limited to the surface soil, but it continued down the soil profile to a depth of 160cm. The maximum potential for neoformation of PC depends on Ca2+ and Mg2+ availability; in this study these cations were provided by irrigation water. However, organic and mineral fertilizers modify this potential. Without organic and mineral fertilization, the PC formed at the expense of dissolution and re-precipitation of LC, even when substantial quantities of Ca2+ and Mg2+ were present in the soil. Our experimental results indicate that the neoformation of PC should be considered during estimation of soil carbon stocks and sequestration for the development of optimal fertilization, irrigation and land use practices.13

Heart rate variability in patients with atrial fibrillation and hypertension

© 2020 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation Background: Atrial fibrillation (AF) and hypertension are independently associated with impaired autonomic function determined using heart rate variability (HRV). As these conditions frequently co-exist, we sought to determine whether AF would worsen HRV in hypertensive patients. Design: We studied HRV in AF (and hypertension) (n = 61) and hypertension control group (n = 33). The AF (and hypertension) group was subdivided into permanent AF (n = 30) and paroxysmal AF (n = 31) and re-studied. Time-domain, frequency-domain and nonlinear measures of HRV were determined. Permanent AF group (n = 30) was followed up after 8 weeks following optimisation of their heart rate and blood pressure (BP). Results: Time-domain and nonlinear indices of HRV were higher in AF (and hypertension) group compared to hypertensive controls (P ≤.01). Time-domain and nonlinear indices of HRV were higher in permanent AF group compared to paroxysmal AF (P ≤.001). Permanent AF was an independent predictor of HRV on multivariable analysis (P =.006). Optimisation of heart rate and BP had no significant impact on HRV in permanent AF. Conclusions: AF, independent of hypertension, is characterised with marked HRV and is possibly related to vagal tone. HRV is higher in permanent AF compared to paroxysmal AF suggesting evident autonomic influence in the pathophysiology of permanent AF. Modulation of autonomic influence on cardiovascular system should be explored in future studies

Management of colorectal cancer presenting with synchronous liver metastases

Up to a fifth of patients with colorectal cancer (CRC) present with synchronous hepatic metastases. In patients with CRC who present without intestinal obstruction or perforation and in whom comprehensive whole-body imaging confirms the absence of extrahepatic disease, evidence indicates a state of equipoise between several different management pathways, none of which has demonstrated superiority. Neoadjuvant systemic chemotherapy is advocated by current guidelines, but must be integrated with surgical management in order to remove the primary tumour and liver metastatic burden. Surgery for CRC with synchronous liver metastases can take a number of forms: the 'classic' approach, involving initial colorectal resection, interval chemotherapy and liver resection as the final step; simultaneous removal of the liver and bowel tumours with neoadjuvant or adjuvant chemotherapy; or a 'liver-first' approach (before or after systemic chemotherapy) with removal of the colorectal tumour as the final procedure. In patients with rectal primary tumours, the liver-first approach can potentially avoid rectal surgery in patients with a complete response to chemoradiotherapy. We overview the importance of precise nomenclature, the influence of clinical presentation on treatment options, and the need for accurate, up-to-date surgical terminology, staging tests and contemporary management options in CRC and synchronous hepatic metastatic disease, with an emphasis on multidisciplinary care

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Cuff inflation time significantly affects blood flow recorded with venous occlusion plethysmography

© 2019, The Author(s). Purpose: We tested whether the values of limb blood flow calculated with strain-gauge venous occlusion plethysmography (VOP) differ when venous occlusion is achieved by automated, or manual inflation, so providing rapid and slower inflation, respectively. Method: In 9 subjects (20–30 years), we calculated forearm blood flows (FBF) values at rest and following isometric handgrip at 70% maximum voluntary contraction (MVC) when rapid, or slower inflation was used. Result: Rapid and slower cuff inflation took 0.23 ± 0.01 (mean ± SEM) and 0.92 ± 0.02 s, respectively, reflecting the range reported in published studies. At rest, FBF calculated from the 1st cardiac cycle after rapid and slower inflation gave similar values: 10.5 ± 1.4 vs. 9.6 ± 1.3 ml dl − 1  min − 1 , respectively (P > 0.05). However, immediately post-contraction, FBF was ~ 40% lower with slower inflation: 54.6 ± 5.1 vs. 33.8 ± 4.2 ml dl − 1  min − 1 (P < 0.01). The latter value was similar to that calculated over the 3rd cardiac cycle following rapid inflation: 2nd cardiac cycle: 40.5 ± 4.5; 3rd cycle: 32.6 ± 4.5 ml dl − 1  min − 1 . Regression analyses of FBFs recorded at intervals post-contraction showed those calculated over the 1st, 2nd, or 3rd cardiac cycles with rapid inflation correlated well with those from the 1st cardiac cycle with manual inflation (r = 0.79, 0.82, 0.79; P < 0.01). However, only the slope for the 3rd cycle with rapid inflation vs. slower inflation was close to unity (2.07, 1.34, and 0.94, respectively). Conclusion: These findings confirm that the 1st cardiac cycle following venous occlusion should be used when calculating FBF using VOP and, but importantly, indicate that cuff inflation should be almost instantaneous; just ≥ 0.9 s leads to substantial underestimation, especially at high flows

Forearm vasodilator responses to environmental stress and reactive hyperaemia are impaired in young South Asian men

© 2018, The Author(s). Purpose: Prevalence of cardiovascular disease (CVD) is greater in South Asians (SAs) than White Europeans (WEs). Endothelial dysfunction and blunted forearm vasodilatation to environmental stressors have been implicated in CVD. We investigated whether these features are present in young SA men. Methods: In 15 SA and 16 WE men (19–23 years), we compared changes in forearm blood flow, arterial blood pressure (ABP), forearm vascular conductance (FVC), heart rate, and electrodermal resistance (EDR; sweating) following release of arterial occlusion (reactive hyperaemia endothelium-dependent) and 5 single sounds at 5–10 min intervals (stressors). Results: All were normotensive. Peak reactive hyperaemia was smaller in SAs than WEs (FVC increase: 0.36 ± 0.038 vs 0.44 ± 0.038 units; P < 0.05). Furthermore, in WEs, mean FVC increased at 5, 15, and 20 s of each sound (vasodilatation), but increased at 5 s only in SAs, decreasing by 20 s (vasoconstriction). This reflected a smaller proportion of SAs showing forearm vasodilatation at 15 s (5/15 SAs vs 11/16 WEs: P < 0.01), the remainder showing vasoconstriction. Concomitantly, WEs showed greater bradycardia and EDR changes. Intra-class correlation analyses showed that all responses were highly reproducible over five sounds in both WEs and SAs. Moreover, sound-evoked changes in ABP and FVC were negatively correlated in each ethnicity (P < 0.01). However, WEs showed preponderance of forearm vasodilatation and depressor responses; SAs showed preponderance of vasoconstriction and pressor responses. Conclusions: Endothelium-dependent vasodilatation is blunted in young SA men. This could explain their impaired forearm vasodilatation and greater pressor responses to repeated environmental stressors, so predisposing SAs to hypertension and CVD

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)