Heart failure related cardiogenic shock: An ISHLT consensus conference content summary.

In recent years, there have been significant advancements in the understanding, risk-stratification, and treatment of cardiogenic shock (CS). Despite improved pharmacologic and device-based therapies for CS, short-term mortality remains as high as 50%. Most recent efforts in research have focused on CS related to acute myocardial infarction, even though heart failure related CS (HF-CS) accounts for >50% of CS cases. There is a paucity of high-quality evidence to support standardized clinical practices in approach to HF-CS. In addition, there is an unmet need to identify disease-specific diagnostic and risk-stratification strategies upon admission, which might ultimately guide the choice of therapies, and thereby improve outcomes and optimize resource allocation. The heterogeneity in defining CS, patient phenotypes, treatment goals and therapies has resulted in difficulty comparing published reports and standardized treatment algorithms. An International Society for Heart and Lung Transplantation (ISHLT) consensus conference was organized to better define, diagnose, and manage HF-CS. There were 54 participants (advanced heart failure and interventional cardiologists, cardiothoracic surgeons, critical care cardiologists, intensivists, pharmacists, and allied health professionals), with vast clinical and published experience in CS, representing 42 centers worldwide. State-of-the-art HF-CS presentations occurred with subsequent breakout sessions planned in an attempt to reach consensus on various issues, including but not limited to models of CS care delivery, patient presentations in HF-CS, and strategies in HF-CS management. This consensus report summarizes the contemporary literature review on HF-CS presented in the first half of the conference (part 1), while the accompanying document (part 2) covers the breakout sessions where the previously agreed upon clinical issues were discussed with an aim to get to a consensus.

Do virtual renal clinics improve access to kidney care? A preliminary impact evaluation of a virtual clinic in East London.

BACKGROUND: Early identification of people with CKD in primary care, particularly those with risk factors such as diabetes and hypertension, enables proactive management and referral to specialist services for progressive disease. The 2019 NHS Long Term Plan endorses the development of digitally-enabled services to replace the 'unsustainable' growth of the traditional out-patient model of care.Shared views of the complete health data available in the primary care electronic health record (EHR) can bridge the divide between primary and secondary care, and offers a practical solution to widen timely access to specialist advice. METHODS: We describe an innovative community kidney service based in the renal department at Barts Health NHS Trust and four local clinical commissioning groups (CCGs) in east London. An impact evaluation of the changes in service delivery used quantitative data from the virtual CKD clinic and from the primary care electronic health records (EHR) of 166 participating practices. Survey and interview data from health professionals were used to explore changes to working practices. RESULTS: Prior to the start of the service the general nephrology referral rate was 0.8/1000 GP registered population, this rose to 2.5/1000 registered patients by the second year of the service. The majority (> 80%) did not require a traditional outpatient appointment, but could be managed with written advice for the referring clinician. The wait for specialist advice fell from 64 to 6 days. General practitioners (GPs) had positive views of the service, valuing the rapid response to clinical questions and improved access for patients unable to travel to clinic. They also reported improved confidence in managing CKD, and high levels of patient satisfaction. Nephrologists valued seeing the entire primary care record but reported concerns about the volume of referrals and changes to working practices. CONCLUSIONS: 'Virtual' specialist services using shared access to the complete primary care EHR are feasible and can expand capacity to deliver timely advice. To use both specialist and generalist expertise efficiently these services require support from community interventions which engage primary care clinicians in a data driven programme of service improvement.

The effect of left ventricular assist device therapy in patients with heart failure and mixed pulmonary hypertension.

BACKGROUND: Diastolic pressure gradient (DPG) of ≥7 mmHg has been proposed to distinguish mixed pulmonary hypertension from isolated post-capillary pulmonary hypertension in heart failure (HF). We evaluated the changes in pulmonary hemodynamics with left ventricular assist devices (LVADs) in patients with DPG of ≥7 or <7 mmHg, and effects on peak oxygen uptake (VO2) in patients with advanced HF. METHODS: Pre- and post-LVAD implant pulmonary hemodynamics (including right atrial (RA) pressures, DPG, pulmonary vascular resistance (PVR), pulmonary capacitance (PCap) and cardiac output), echocardiography, cardiopulmonary exercise test were measured in 38 consecutive patients. RESULTS: Ten of 38 patients had baseline DPG ≥7 mmHg. There were no significant difference in baseline characteristics, peak VO2 and ventilation slope, but PVR were higher, and PCap lower in patients with DPG ≥7 mmHg. Pulmonary artery pressures improved in all patients, but PVR and DPG remained higher and PCap lower in patients with baseline DPG ≥7 mmHg after a median follow-up of 181 (IQR 153-193) days. Peak VO2 increased and ventilation slope reduced post-LVAD, and these improvements were comparable between groups. Only RA pressure reduction and exercise increase in heart rate were significant predictors of peak VO2 increase on multivariate analysis. CONCLUSIONS: Baseline DPG of ≥7 mmHg compared to DPG <7 mmHg have persistently lower PCap and higher PVR post-LVAD, but the increase in peak VO2 was comparable despite these residual pulmonary vascular abnormalities. The improvement in peak VO2 was related to reduction in right atrial pressure and exercise increase in heart rate.

Mechanism of neutrophil dysfunction: neutrophil serine proteases cleave and inactivate the C5a receptor.

Neutrophil dysfunction, resulting in inefficient bacterial clearance, is a feature of several serious medical conditions, including cystic fibrosis (CF) and sepsis. Poorly controlled neutrophil serine protease (NSP) activity and complement activation have been implicated in this phenomenon. The capacity for excess NSP secretion and complement activation to influence the expression and function of the important neutrophil-activating receptor C5aR was investigated. Purified NSPs cathepsin G (CG), neutrophil elastase (NE), and proteinase 3 cleaved C5aR to a 26- to 27-kDa membrane-bound fragment, thereby inactivating its C5a-induced signaling ability. In a supernatant transfer assay, NSPs released from neutrophils in response to C5a induced the cleavage of the C5aR on unstimulated cells. Stimulation of myeolomonocytic U937 cells and purified neutrophils with C5a resulted in downregulation of the C5aR on these cells, which, in the case of U937 cells, was largely caused by NSP-mediated cleavage of C5aR, but in the case of neutrophils, intracellular degradation was likely the main mediator in addition to a small role for NSPs. CG and NE in bronchoalveolar lavage fluid from CF patients both contributed to C5aR cleavage. We propose two converging models for C5a- and NSP-mediated neutrophil dysfunction whereby C5aR cleavage is induced by NSPs, secreted in response to: 1) excess C5a generation or other stimuli; or 2) necrosis. The consequent impairment of C5aR activity contributes to suboptimal local neutrophil priming and bacterial clearance. NSP inhibitors with specificity for both CG and NE may aid the treatment of pathologies associated with neutrophil dysfunction including sepsis and CF.

Predictive value of atrial high-rate episodes for arterial stiffness and endothelial dysfunction in dual-chamber pacemaker patients.

BACKGROUND: Various pacing studies have demonstrated an association between right ventricular pacing (RVp) and atrial fibrillation (AF), even after preserving atrioventricular (AV) synchrony. We aimed to assess the interaction between arterial stiffness, endothelial function and atrial high-rate episodes (AHRE) in patients with dual-chamber pacemakers. METHODS: We studied 101 patients with dual-chamber pacemakers incorporated with sophisticated AF detection and therapy algorithms. Macrovascular endothelial dysfunction (ED) was measured by the relative change in aortic augmentation index (AIx), using carotid artery applanation tonometry in response to inhaled salbutamol and sublingual glyceryl trinitrate. Microvascular ED was measured by cutaneous laser Doppler flowmetry (LDF) in response to acetylcholine (Ach, endothelium dependent) and sodium nitroprusside (SNP, endothelium independent). Arterial stiffness was measured using carotid-femoral pulse wave velocity (PWVcf). 'Reservoir pressure' (Pr, MATLAB) describes the aortic 'cushioning' properties. RESULTS: Mean age of the cohort was 72.1 ± 10.8 years; men (n = 69) 68.3%. Of 101 dual-chamber pacemaker patients, 23.8% (n = 24) had AHRE detected on the baseline pacemaker interrogation. PP, PWVcf and Pr were significantly higher in patients with AHRE compared with those without AHRE. The change in AIx with salbutamol (∆% AIx Sal) and acetylcholine-induced changes in LDF (Δ%LDF Ach) were lower in patients with AHRE compared with those without AHRE. In patients with AHRE, significant correlations were observed between%Vp and Δ%LDF Ach (P = 0.03) as well as between PP and Δ%LDF Ach (P = 0.05). On multivariate analysis, PP, Pr, PWVcf and ∆% AIx Sal remained as independent predictors of AHRE. CONCLUSION: In patients with dual-chamber pacemakers, both higher arterial stiffness and greater endothelial dysfunction independently predicted AHRE, irrespective of the degree (or mode) of pacing. Arterial stiffness and endothelial dysfunction may potentially contribute to the perpetuation of atrial arrhythmias beyond the adverse effects of ventricular pacing alone.

Prognostic role of plasma von Willebrand factor and soluble E-selectin levels for future cardiovascular events in a 'real-world' community cohort of patients with atrial fibrillation.

BACKGROUND: Endothelial damage/dysfunction may contribute to a prothrombotic state in patients with atrial fibrillation (AF) and the increased risk of thromboembolism and cardiovascular events. Raised plasma von Willebrand factor (vWf), an established marker of endothelial damage/dysfunction, has been associated with stroke and vascular events, at least in a clinical trial population. Soluble E-selectin (sE-sel) is another biomarker of endothelial activation/dysfunction, with more limited data on prognostic outcomes in AF. OBJECTIVE: To assess the relationship between the levels of vWf, sE-sel and clinical adverse outcomes (including stroke, MI and all-cause mortality) in a 'real-world' community cohort of patients with AF. METHODS: We studied 423 patients (mean age 72·7 ± 8·4 years, 55·6% male) with nonvalvular AF, with a median follow-up of 19 (9-31) months. Plasma vWf and sE-sel levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: There were 94 clinical adverse events (22·2%) observed during a median follow-up of 19 months. Patients with clinical events had significantly higher vWf (P < 0·001) and sE-sel levels at baseline (P < 0·001) compared with those who were event free. Kaplan-Meir analyses demonstrated that more clinical adverse events occurred in the upper tertile of vWf [upper vs. lowest tertile, RR 3·8, 95% CI (2·63-5·57), P < 0·001; upper vs. middle tertile, RR 10·5, 95% CI (5·33-20·60), P < 0·001]. Similarly, the highest tertile of sE-sel was associated with more adverse events [upper vs. lowest tertile, RR 3·7, 95% CI (2·51-5·31), P < 0·001; upper vs. middle tertile, RR 6·5, 95% CI (3·56-11·91), P < 0·001]. CONCLUSION: High plasma vWf and soluble E-selectin levels are associated with an increased risk of clinical adverse events (acute myocardial infarction, ischaemic stroke and all-cause mortality) in 'real-world' patients with AF. These soluble biomarkers may potentially aid clinical risk stratification in this common arrhythmia.

Circulating levels of adiponectin, leptin, and tumour necrosis factor alpha in hypertension.

BACKGROUND: Abnormal adipocyte function is implicated in the coalition of multiple cardiovascular risk factors, where aberrant circulating levels of the adipose-derived hormones adiponectin, leptin, and tumour necrosis factor (TNF) alpha may provide the putative link between hypertension and increased cardiovascular risk. The pragmatic utility of these 'adipocytokines' in the clinical setting of hypertension is unclear, and we hypothesized a relationship of circulating adipocytokines to hypertension, and associated cardiovascular morbidity. METHOD: Using a cross-sectional approach, we measured plasma adipocytokines in 278 'high-risk' treated hypertensive participants of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) study (mean (SD) age 62.9 (7.7) years), who were compared to 54 newly diagnosed untreated hypertensives (61.3 (10.9) years) and 55 healthy controls (48.3 (12.3) years). RESULTS: Levels of all three adipocytokines were lower amongst treated hypertensives compared to newly diagnosed hypertensives and healthy controls (P<0.001 for leptin and adiponectin), and varied with gender, co-morbidities (e.g. diabetes, cardiovascular disease (CVD), left ventricular hypertrophy) and by treatments (e.g. statins and beta-blockade). Levels of adiponectin (P<0.001) and leptin (P=0.02) rose in an ordinal fashion with increasing hypertension severity (grade). Levels of leptin were associated with diastolic blood pressure in a positive fashion (P<0.001). CONCLUSIONS: While hypertension affects adipocytokine levels, the clinical interpretation of circulating levels in hypertension is confounded by a range of factors. The positive relation between leptin and adiponectin with hypertension severity may reflect an underlying adaptive response that is attenuated during pharmacological hypertension management.

Widening access to cardiovascular healthcare: community screening among ethnic minorities in inner-city Britain - the Healthy Hearts Project.

BACKGROUND: The burden of cardiovascular disease (CVD) in Britain is concentrated in inner-city areas such as Sandwell, which is home to a diverse multi-ethnic population. Current guidance for CVD risk screening is not established, nor are there specific details for ethnic minorities. Given the disparity in equitable healthcare for these groups, we developed a 'tailored' and systematic approach to CVD risk screening within communities of the Sandwell locality. The key anticipated outcomes were the numbers of participants from various ethnic backgrounds attending the health screening events and the prevalence of known and undiagnosed CVD risk within ethnic groups. METHODS: Data was collected during 10 health screening events (September 2005 and July 2006), which included an assessment of raised blood pressure, overweight, hyperlipidaemia, impaired fasting glucose, smoking habit and the 10 year CVD risk score. Specific features of our approach included (i) community involvement, (ii) a clinician who could deliver immediate attention to adverse findings, and (iii) the use of an interpreter. RESULTS: A total of 824 people from the Sandwell were included in this study (47% men, mean age 47.7 years) from community groups such as the Gujarati Indian, Punjabi Indian, European Caucasian, Yemeni, Pakistani and Bangladeshi. A total of 470 (57%) individuals were referred to their General Practitioner with a report of an increased CVD score - undetected high blood pressure in 120 (15%), undetected abnormal blood glucose in 70 (8%), undetected raised total cholesterol in 149 (18%), and CVD risk management review in 131 (16%). CONCLUSION: Using this systematic and targeted approach, there was a clear demand for this service from people of various ethnic backgrounds, of whom, one in two needed review from primary or secondary healthcare. Further work is required to assess the accuracy and clinical benefits of this community health screening approach.