Diagnosis of patients with heart failure with preserved ejection fraction in primary care : Cohort study

Aims Heart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure (HF), but low awareness and diagnostic challenges hinder identification in primary care. Our aims were to evaluate the recruitment and diagnostic strategy in the Optimise HFpEF cohort and compare with recent recommendations for diagnosing HFpEF. Methods and results Patients were recruited from 30 primary care practices in two regions in England using an electronic screening algorithm and two secondary care sites. Baseline assessment collected clinical and patient-reported data and diagnosis by history, assessment, and trans-thoracic echocardiogram (TTE). A retrospective evaluation compared study diagnosis with H2FPEF score and HFA-PEFF diagnostic algorithm. A total of 152 patients (86% primary care, mean age 78.5, 40% female) were enrolled; 93 (61%) had HFpEF confirmed. Most participants had clinical features of HFpEF, but those with confirmed HFpEF were more likely female, obese, functionally impaired, and symptomatic. Some echocardiographic findings were diagnostic for HFpEF, but no difference in natriuretic peptide levels were observed. The H2FPEF and HFA-PEFF scores were not significantly different by group, although confirmed HFpEF cases were more likely to have scores indicating high probability of HFpEF. Conclusions Patients with HFpEF in primary care are difficult to identify, and greater awareness of the condition, with clear diagnostic pathways and specialist support, are needed. Use of diagnostic algorithms and scores can provide systematic approaches to diagnosis but may be challenging to apply in older multi-morbid patients. Where diagnostic uncertainty remains, pragmatic decisions are needed regarding the value of additional testing versus management of presumptive HFpEF

Diagnosis of patients with heart failure with preserved ejection fraction in primary care: cohort study

Funder: NIHR Cambridge Clinical Research FacilityAbstract: Aims: Heart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure (HF), but low awareness and diagnostic challenges hinder identification in primary care. Our aims were to evaluate the recruitment and diagnostic strategy in the Optimise HFpEF cohort and compare with recent recommendations for diagnosing HFpEF. Methods and results: Patients were recruited from 30 primary care practices in two regions in England using an electronic screening algorithm and two secondary care sites. Baseline assessment collected clinical and patient‐reported data and diagnosis by history, assessment, and trans‐thoracic echocardiogram (TTE). A retrospective evaluation compared study diagnosis with H2FPEF score and HFA‐PEFF diagnostic algorithm. A total of 152 patients (86% primary care, mean age 78.5, 40% female) were enrolled; 93 (61%) had HFpEF confirmed. Most participants had clinical features of HFpEF, but those with confirmed HFpEF were more likely female, obese, functionally impaired, and symptomatic. Some echocardiographic findings were diagnostic for HFpEF, but no difference in natriuretic peptide levels were observed. The H2FPEF and HFA‐PEFF scores were not significantly different by group, although confirmed HFpEF cases were more likely to have scores indicating high probability of HFpEF. Conclusions: Patients with HFpEF in primary care are difficult to identify, and greater awareness of the condition, with clear diagnostic pathways and specialist support, are needed. Use of diagnostic algorithms and scores can provide systematic approaches to diagnosis but may be challenging to apply in older multi‐morbid patients. Where diagnostic uncertainty remains, pragmatic decisions are needed regarding the value of additional testing versus management of presumptive HFpEF

The effect of isometric exercise training on arterial stiffness: A randomized crossover controlled study.

Isometric exercise training (IET) is an effective intervention for the management of resting blood pressure (BP). However, the effects of IET on arterial stiffness remain largely unknown. Eighteen unmedicated physically inactive participants were recruited. Participants were randomly allocated in a cross-over design to 4 weeks of home-based wall squat IET and control period, separated by a 3-week washout period. Continuous beat-to-beat hemodynamics, including early and late systolic (sBP 1 and sBP 2, respectively) and diastolic blood pressure (dBP) were recorded for a period of 5 min and waveforms were extracted and analyzed to acquire the augmentation index (AIx) as a measure of arterial stiffness. sBP 1 (-7.7 ± 12.8 mmHg, p = 0.024), sBP 2 (-5.9 ± 9.9 mmHg, p = 0.042) and dBP (-4.4 ± 7.2 mmHg, p = 0.037) all significantly decreased following IET compared to the control period. Importantly, there was a significant reduction in AIx following IET (-6.6 ± 14.5%, p = 0.02) compared to the control period. There were also adjacent significant reductions in total peripheral resistance (-140.7 ± 65.8 dynes·cm-5, p = 0.042) and pulse pressure (-3.8 ± 4.2, p = 0.003) compared to the control period. This study demonstrates an improvement in arterial stiffness following a short-term IET intervention. These findings have important clinical implications regarding cardiovascular risk. Mechanistically, these results suggest that reductions in resting BP following IET are induced via favorable vascular adaptations, although the intricate details of such adaptations are not yet clear

The effect of isometric exercise training on arterial stiffness: A randomized crossover controlled study.

Isometric exercise training (IET) is an effective intervention for the management of resting blood pressure (BP). However, the effects of IET on arterial stiffness remain largely unknown. Eighteen unmedicated physically inactive participants were recruited. Participants were randomly allocated in a cross-over design to 4 weeks of home-based wall squat IET and control period, separated by a 3-week washout period. Continuous beat-to-beat hemodynamics, including early and late systolic (sBP 1 and sBP 2, respectively) and diastolic blood pressure (dBP) were recorded for a period of 5 min and waveforms were extracted and analyzed to acquire the augmentation index (AIx) as a measure of arterial stiffness. sBP 1 (-7.7 ± 12.8 mmHg, p = 0.024), sBP 2 (-5.9 ± 9.9 mmHg, p = 0.042) and dBP (-4.4 ± 7.2 mmHg, p = 0.037) all significantly decreased following IET compared to the control period. Importantly, there was a significant reduction in AIx following IET (-6.6 ± 14.5%, p = 0.02) compared to the control period. There were also adjacent significant reductions in total peripheral resistance (-140.7 ± 65.8 dynes·cm-5, p = 0.042) and pulse pressure (-3.8 ± 4.2, p = 0.003) compared to the control period. This study demonstrates an improvement in arterial stiffness following a short-term IET intervention. These findings have important clinical implications regarding cardiovascular risk. Mechanistically, these results suggest that reductions in resting BP following IET are induced via favorable vascular adaptations, although the intricate details of such adaptations are not yet clear

Characteristics of Patients with Heart Failure with Preserved Ejection Fraction in Primary Care: Cross-sectional analysis

Background: Many patients with heart failure with preserved ejection fraction (HFpEF) are undiagnosed, and UK general practice registers do not typically record HF sub-type. Improvements in management of HFpEF is dependent on improved identification and characterisation of patients in primary care. Aims: To describe a cohort of patients recruited from primary care with suspected HFpEF and compare patients in whom HFpEF was confirmed and refuted. Design and Setting: Baseline data from a longitudinal cohort study of patients with suspected HFpEF recruited from primary care in two areas of England. Methods: A screening algorithm and review were used to find patients on HF registers without a record of reduced ejection fraction. Baseline evaluation included cardiac, mental and physical function, clinical characteristics and patient reported outcomes. Confirmation of HFpEF was clinically adjudicated by a cardiologist. Results: Ninety-three (61%) of 152 patients were confirmed HFpEF. The mean age of patients with HFpEF was 79.3, 46% were female, 80% had hypertension, and 37% took 10 or more medications. Patients with HFpEF were more likely to be obese, pre-frail/frail, report more dyspnoea and fatigue, were more functionally impaired, and less active than patients in whom HFpEF was refuted. Few had attended cardiac rehabilitation. Conclusions: Patients with confirmed HFpEF had frequent multimorbidity, functional impairment, frailty and polypharmacy. Although comorbid conditions were similar between people with and without HFpEF, the former had more obesity, symptoms and worse physical function. These findings highlight the potential to optimise well-being through comorbidity management, medication rationalisation, rehabilitation, and supported self-management.NIHR School for Primary Care Research NIHR Cambridge Biomedical Research Centr

Low-dose interleukin 2 for the reduction of vascular inflammation in acute coronary syndromes (IVORY): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase II clinical trial.

Funder: Medical Research CouncilFunder: British Heart FoundationFunder: National Institute for Health Research (NIHR)INTRODUCTION: Inflammation plays a critical role in the pathogenesis of atherosclerosis, the leading cause of ischaemic heart disease (IHD). Studies in preclinical models have demonstrated that an increase in regulatory T cells (Tregs), which have a potent immune modulatory action, led to a regression of atherosclerosis. The Low-dose InterLeukin 2 (IL-2) in patients with stable ischaemic heart disease and Acute Coronary Syndromes (LILACS) study, established the safety of low-dose IL-2 and its biological efficacy in IHD. The IVORY trial is designed to assess the effects of low-dose IL-2 on vascular inflammation in patients with acute coronary syndromes (ACS). METHODS AND ANALYSIS: In this study, we hypothesise that low-dose IL-2 will reduce vascular inflammation in patients presenting with ACS. This is a double-blind, randomised, placebo-controlled, phase II clinical trial. Patients will be recruited across two centres, a district general hospital and a tertiary cardiac centre in Cambridge, UK. Sixty patients with ACS (unstable angina, non-ST elevation myocardial infarction or ST elevation myocardial infarction) with high-sensitivity C reactive protein (hsCRP) levels >2 mg/L will be randomised to receive either 1.5×106 IU of low-dose IL-2 or placebo (1:1). Dosing will commence within 14 days of admission. Dosing will comprise of an induction and a maintenance phase. 2-Deoxy-2-[fluorine-18] fluoro-D-glucose (18F-FDG) positron emission tomography/CT (PET/CT) scans will be performed before and after dosing. The primary endpoint is the change in mean maximum target to background ratios (TBRmax) in the index vessel between baseline and follow-up scans. Changes in circulating T-cell subsets will be measured as secondary endpoints of the study. The safety and tolerability of extended dosing with low-dose IL-2 in patients with ACS will be evaluated throughout the study. ETHICS AND DISSEMINATION: The Health Research Authority and Health and Care Research Wales, UK (19/YH/0171), approved the study. Written informed consent is required to participate in the trial. The results will be reported through peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT04241601.This work was funded by the Medical Research Council, grant number MR/N028015/1 and the British Heart Foundation Cambridge Centre of Excellence (RCAG/521)

Regulatory T-Cell Response to Low-Dose Interleukin-2 in Ischemic Heart Disease

BACKGROUND Atherosclerosis is a chronic inflammatory disease of the artery wall. Regulatory T cells (Tregs) limit inflammation and promote tissue healing. Low doses of interleukin (IL)-2 have the potential to increase Tregs, but its use is contraindicated in patients with ischemic heart disease. METHODS In this randomized, double-blind, placebo-controlled, dose-escalation trial, we tested lowdose subcutaneous aldesleukin (recombinant IL-2), given once daily for five consecutive days. In Part A, the primary endpoint was safety, and patients with stable ischemic heart disease were randomized to placebo or to one of 5 dose groups (range 0.3-3.0 x10 6 IU/day). In Part B, patients with acute non-ST elevation myocardial infarction or unstable angina were randomized to placebo or to one of 2 dose groups (1.5 and 2.5 x10 6 IU/day). The coprimary endpoints were safety and the dose required to increase circulating Tregs by 75%. Single-cell RNA-sequencing of circulating immune cells was used to provide mechanistic assessment of the effects of aldesleukin. RESULTS Forty-four patients were randomized in the study, 26 patients in Part A and 18 patients in Part B. In total, 3 patients withdrew prior to dosing; 27 received active treatment, and 14 received placebo. The majority of adverse events were mild. Two serious adverse events occurred, with one occurring after drug administration. In Parts A and B, there was a dosedependent increase in Tregs. In Part B, the estimated dose to achieve a 75% increase in Tregs was 1.46 x10 6 IU (95%CI 1.06 – 1.87). Single-cell RNA-sequencing demonstrated the engagement of distinct pathways and cell-cell interactions. CONCLUSION In this phase 1b/2a study, low-dose IL-2 expanded Tregs without adverse events of major concern. Larger trials are needed to confirm safety and to further evaluate efficacy of lowdose IL-2 as an anti-inflammatory therapy in patients with ischemic heart disease. (Funded by the Medical Research Council and the British Heart Foundation; ClinicalTrials.gov number, NCT03113773