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Congestion is one of the main predictors of poor outcome in patients with heart failure (HF). Assessing and monitoring congestion is essential for optimizing HF therapy. Among the various available methods, serial measurements of estimated plasma volume (ePVS) using routine blood count and/or body weight (e.g., the Strauss, Duarte, Hakim formulas) may be useful in HF management. Further prospective study is warranted to determine whether ePVS can help optimize decongestion therapy (loop diuretics, mineralocorticoid receptor antagonists, SGLT2i) in various HF settings. This narrative review summarizes the recent evidence supporting the association of ePVS with clinical congestion and outcome(s) and discusses future directions for monitoring ePVS in HF. Graphic abstract

ObjectiveWe sought to evaluate prognostic markers of clinical outcome in asymptomatic patients with moderate to severe aortic stenosis (AS).DesignProspective follow-up of asymptomatic patients with moderate to severe AS. The patients underwent clinical and Doppler echocardiographic evaluation.SettingDepartment of Cardiology.Patients163 patients with moderate to severe AS (aortic valve area ≤0.6 cm2/m2).Main outcome measuresRisk stratification. Predefined endpoints for assessing the outcome were the occurrence during follow-up of symptoms, aortic valve replacement or death.ResultsDuring follow-up (mean, 20 (19) months), 11 patients developed symptoms but were not operated on, 57 required aortic valve replacement and six patients died. In multivariable Cox regression analysis, four parameters that were associated with the outcome were identified: peak aortic jet velocity, left ventricular systolic (LV) longitudinal deformation, valvulo-arterial impedance and indexed left atrial area. Using receiver−operator characteristic curve analysis, a peak aortic jet velocity ≥4.4 m/s, a LV longitudinal myocardial deformation ≤15.9%, a valvular-arterial impedance ≥4.9 mm Hg/ml per m2 and an indexed left atrial area ≥12.2 cm2/m2 were identified as the best cut-off values to be associated with events.ConclusionsIn asymptomatic patients with moderate to severe AS, measurements that integrate the ventricular, vascular and valvular components of the disease improve risk stratification.

ObjectiveThe primary objective was to assess the characteristics and prognosis of pyogenic spondylodiscitis (PS) in patients with infective endocarditis (IE). The secondary objectives were to assess the factors associated with occurrence of PS.MethodsProspective case–control bi-centre study of 1755 patients with definite IE with (n=150) or without (n=1605) PS. Clinical, microbiological and prognostic variables were recorded.ResultsPatients with PS were older (mean age 69.7±18 vs 66.2±14; p=0.004) and had more arterial hypertension (48% vs 34.5%; p<0.001) and autoimmune disease (5% vs 2%; p=0.03) than patients without PS. The lumbar vertebrae were the most frequently involved (84 patients, 66%), especially L4–L5. Neurological symptoms were observed in 59% of patients. Enterococci and Streptococcus gallolyticus were more frequent (24% vs 12% and 24% vs 11%; p<0001, respectively) in the PS group. The diagnosis of PS was based on contrast-enhanced MRI in 92 patients, bone CT in 88 patients and 18F-FDG PET/CT in 56 patients. In-hospital (16% vs 13.5%, p=0.38) and 1-year (21% vs 22%, p=0.82) mortalities did not differ between patients with or without PS.ConclusionsPS is a frequent complication of IE (8.5% of IE), is observed in older hypertensive patients with enterococcal or S. gallolyticus IE, and has a similar prognosis than other forms of IE. Since PS is associated with specific management, multimodality imaging including MRI, CT and PET/CT should be used for early diagnosis of this complication of endocarditis.

Aims Sodium zirconium cyclosilicate (SZC, formerly ZS‐9) is a selective K+ binder to treat adults with hyperkalaemia. HARMONIZE‐Global examined the efficacy and safety of SZC among outpatients with hyperkalaemia from diverse geographic and ethnic origins. Methods and results This phase 3, randomized, double‐blind, placebo‐controlled study recruited outpatients with serum K+ ≥5.1 mmol/L (measured by point‐of‐care i‐STAT device) at 45 sites in Japan, Russia, South Korea, and Taiwan. Following open‐label treatment with thrice‐daily SZC 10 g during a 48 h correction phase (CP), patients achieving normokalaemia (K+ 3.5–5.0 mmol/L) were randomized 2:2:1 to once‐daily SZC 5 g, SZC 10 g, or placebo during a 28 day maintenance phase (MP). The primary endpoint was mean central‐laboratory K+ level during days 8–29 of the MP. Of 267 patients in the CP, 248 (92.9%) entered the MP. During the CP, mean central‐laboratory K+ was reduced by 1.28 mmol/L at 48 h vs. baseline (P < 0.001). During the MP (days 8–29), SZC 5 and 10 g once‐daily significantly lowered mean central‐laboratory K+ by 9.6% and 17.7%, respectively, vs. placebo (P < 0.001 for both). More patients had normokalaemia (central‐laboratory K+ 3.5–5.0 mmol/L at day 29) with SZC 5 (58.6%) and 10 g (77.3%) vs. placebo (24.0%), with the greatest number of normokalaemic days in the 10‐g group. The most common adverse events with SZC were mild or moderate constipation and oedema. Conclusions Normokalaemia achieved during the CP was maintained over 28 days with SZC treatment among outpatients with hyperkalaemia.

Pharmacological inhibition of VEGF-A has proven to be effective in inhibiting angiogenesis and vascular leak associated with cancers and various eye diseases. However, little information is currently available on the binding kinetics and relative biological activity of various VEGF inhibitors. Therefore, we have evaluated the binding kinetics of two anti-VEGF antibodies, ranibizumab and bevacizumab, and VEGF Trap (also known as aflibercept), a novel type of soluble decoy receptor, with substantially higher affinity than conventional soluble VEGF receptors. VEGF Trap bound to all isoforms of human VEGF-A tested with subpicomolar affinity. Ranibizumab and bevacizumab also bound human VEGF-A, but with markedly lower affinity. The association rate for VEGF Trap binding to VEGF-A was orders of magnitude faster than that measured for bevacizumab and ranibizumab. Similarly, in cell-based bioassays, VEGF Trap inhibited the activation of VEGFR1 and VEGFR2, as well as VEGF-A induced calcium mobilization and migration in human endothelial cells more potently than ranibizumab or bevacizumab. Only VEGF Trap bound human PlGF and VEGF-B, and inhibited VEGFR1 activation and HUVEC migration induced by PlGF. These data differentiate VEGF Trap from ranibizumab and bevacizumab in terms of its markedly higher affinity for VEGF-A, as well as its ability to bind VEGF-B and PlGF.

In international trials, glucagon-like protein-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2Is) were effective in improving cardiovascular (CV) outcomes. We assessed the effect of GLP-1RAs and SGLT2Is treatment effect on CV endpoints by geographical region in multiple international trials using random effects weighted least squares meta-regressions. The estimated effects of both SGLT2Is and GLP-1RAs on major adverse CV events (MACE) in North America (SGLT2Is n = 12,399, HR 0.90, 95% CI 0.81-1.01; GLP-1RAs n = 12,515, HR 0.95, 95% CI 0.83- 1.09) and in Europe (SGLT2Is n = 19,435, HR 0.93, 95% CI 0.85-1.02; GLP-1RAs n = 22,812, HR 0.88, 95% CI 0.79-0.99) were numerically lower but not statistically different to the rest of the world (ROW) (SGLT2Is n = 15,127, HR 0.83, 95% CI 0.75-0.92, p-value for interaction 0.26; GLP-1RAs n = 17,494, HR 0.82, 95% CI 0.73-0.92, p-value for interaction 0.28). Effects of SGLT2Is on heart failure readmission or CV death varied significantly by region (P = 0.0094). The effect of SGLT2Is was significantly smaller in Europe (n = 18,653, HR 0.86, 95% CI 0.78-0.95) than in the ROW (n = 12,463, HR 0.68, 95% CI 0.61-0.76, P = 0.0024). The smaller effect in North America (n = 9776, HR 0.76, 95% CI 0.66-0.87) did not differ significantly from that in the ROW (P = 0.2370). The effects of SGLT2Is on HF events are larger in the ROW. Further analyses and studies are needed to better elucidate the differential effects of SGLTIs and GLP-1RAs by geographical regions.

Most studies examining potential associations between psychological factors and cardiovascular outcomes have focused on depression or anxiety. The effect of perceived stress on incident coronary heart disease (CHD) has yet to be reviewed systematically. We conducted a systematic review and meta-analysis of the association between perceived stress and incident CHD. Ovid, MEDLINE, and PsycINFO were searched as data sources. Prospective observational cohort studies were selected that measured self-reported perceived stress and assessed incident CHD at ≥6 months. We extracted study characteristics and estimates of the risk of incident CHD associated with high perceived stress versus low perceived stress. We identified 23 potentially relevant articles, of which 6 met our criteria (n = 118,696). Included studies measured perceived stress with validated measurements and nonvalidated simple self-report surveys. Incident CHD was defined as new diagnosis of, hospitalization for, or mortality secondary to CHD. Meta-analysis yielded an aggregate risk ratio of 1.27 (95% confidence interval 1.12 to 1.45) for the magnitude of the relation between high perceived stress and incident CHD. In conclusion, this meta-analysis suggests that high perceived stress is associated with a moderately increased risk of incident CHD.

Inflammation contributes to all phases of the atherothrombotic process, and patients with elevated inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have increased vascular risk. Yet, it remains unknown whether direct inhibition of inflammation will reduce cardiovascular event rates. The CANTOS will evaluate whether interleukin-1β (IL-1β) inhibition as compared with placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable patients with coronary artery disease who remain at high vascular risk due to persistent elevations of hsCRP (>2 mg/L) despite contemporary secondary prevention strategies. Canakinumab is a human monoclonal antibody that selectively neutralizes IL-1β, a proinflammatory cytokine that plays multiple roles in the atherothrombotic process and that undergoes activation by the nucleotide-binding leucine-rich repeat-containing pyrin receptor 3 inflammasome, a process promoted by cholesterol crystals. Canakinumab significantly reduces systemic C-reactive protein and other inflammatory biomarker levels, is generally well tolerated, and is currently indicated for the treatment of inherited IL-1β driven inflammatory diseases such as the Muckle-Wells syndrome. In a multinational collaborative effort using an event-driven intention-to-treat protocol, CANTOS will randomly allocate 17,200 stable postmyocardial infarction patients with persistent elevation of hsCRP to either placebo or to canakinumab at doses of 50, 150, or 300 mg every 3 months, administered subcutaneously. All participants will be followed up over an estimated period of up to 4 years for the trial primary end point (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death) as well as for other vascular events, total mortality, adverse events, and specific clinical end points associated with inflammation including new onset diabetes, venous thrombosis, and atrial fibrillation. If positive, CANTOS would confirm the inflammatory hypothesis of atherothrombosis and provide a novel cytokine-based therapy for the secondary prevention of cardiovascular disease and new-onset diabetes.

In patients with cryptogenic stroke and patent foramen ovale with atrial septal aneurysm or large interatrial shunt, closure of the PFO and administration of antiplatelet medications resulted in a lower rate of recurrent stroke than antiplatelet therapy alone.

BackgroundThe diagnosis of cardiac amyloidosis (CA) is challenging owing to vague symptomatology and non-specific echocardiographic findings.ObjectiveTo describe regional patterns in longitudinal strain (LS) using two-dimensional speckle-tracking echocardiography in CA and to test the hypothesis that regional differences would help differentiate CA from other causes of increased left ventricular (LV) wall thickness.Methods and results55 consecutive patients with CA were compared with 30 control patients with LV hypertrophy (n=15 with hypertrophic cardiomyopathy, n=15 with aortic stenosis). A relative apical LS of 1.0, defined using the equation (average apical LS/(average basal LS + mid-LS)), was sensitive (93%) and specific (82%) in differentiating CA from controls (area under the curve 0.94). In a logistic regression multivariate analysis, relative apical LS was the only parameter predictive of CA (p=0.004).ConclusionsCA is characterised by regional variations in LS from base to apex. A relative ‘apical sparing’ pattern of LS is an easily recognisable, accurate and reproducible method of differentiating CA from other causes of LV hypertrophy.