Left Atrial Mechanics Following Preeclamptic Pregnancy.

BACKGROUND: Preterm preeclampsia is a pregnancy complication associated with myocardial dysfunction and premature cardiovascular disease morbidity and mortality. Left atrial (LA) strain is a noninvasive index of left ventricular end diastolic pressure and an early marker of heart failure risk. This study aimed to evaluate LA strain during the postpartum period in participants with and without preterm preeclampsia and to assess whether this varied in the presence of hypertension, cardiac dysfunction or both. METHODS: In this longitudinal cohort study, 321 women from 28 hospitals with preterm preeclampsia (cases) underwent cardiovascular assessment 6 months postpartum. This is a secondary analysis of the PHOEBE study (ISRCTN01879376). An uncomplicated pregnancy control group (n=30) was recruited from a single center for comparison. A full cross-sectional transthoracic echocardiogram was performed, and from these images, the myocardial strain of the left atrium, including reservoir, conduit, and contractile strain, as well as LA stiffness, were calculated. RESULTS: At 6 months postpartum, compared with controls, prior preeclampsia was associated with a significantly attenuated LA reservoir, conduit, and contractile strain, as well as increased LA stiffness (all P<0.001). LA strain was further reduced in preeclamptic women who had and had not developed hypertension, systolic, or diastolic dysfunction at 6 months postpartum (all P<0.05). CONCLUSIONS: LA mechanics were significantly attenuated at 6 months postpartum in participants with preterm preeclampsia, whether or not they remained hypertensive or had evidence of ventricular dysfunction. Further studies are needed to determine whether postnatal LA strain may identify women at greater risk for future cardiovascular disease.

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.

Myocardial performance index as a measure of global left ventricular function improves following isometric exercise training in hypertensive patients.

As the leading cause of cardiovascular disease and mortality, hypertension remains a global health problem. Isometric exercise training (IET) has been established as efficacious in reducing resting blood pressure (BP); however, no research to date has investigated its effects on the myocardial performance index (MPI). Twenty-four unmedicated hypertensive patients were randomized to 4 weeks of IET and a control period in a crossover design. Tissue Doppler imaging was used to acquire cardiac time intervals pre- and post-IET and during the control periods. IET significantly improved all measures of cardiac time intervals, including isovolumic relaxation time (83.1 ± 10.3 vs. 76.1 ± 11.2 ms, p = 0.006), isovolumic contraction time (84.8 ± 10.3 vs. 72.8 ± 6.4 ms, p < 0.001), ejection time (304.6 ± 30.2 vs. 321.4 ± 20.8 ms, p = 0.015) and the MPI (0.56 ± 0.09 vs. 0.47 ± 0.05, p < 0.001). This is the first study to demonstrate that IET significantly improves cardiac time intervals. These findings may have important clinical implications, highlighting the potential utility of IET in the management of cardiac health in hypertensive patients.

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.

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.

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 for patients with ischemic heart disease. METHODS: In this randomized, double-blind, placebo-controlled, dose-escalation trial, we tested low-dose subcutaneous aldesleukin (recombinant IL-2), given once daily for 5 consecutive days. In study part A, the primary end point was safety, and patients with stable ischemic heart disease were randomly assigned to receive placebo or to one of five dose groups (range, 0.3 to 3.0 × 106 IU daily). In study part B, patients with acute non-ST elevation myocardial infarction or unstable angina were randomly assigned to receive placebo or to one of two dose groups (1.5 and 2.5 × 106 IU daily). The coprimary end points were safety and the dose required to increase circulating Tregs by 75%. Single-cell RNA-sequencing of circulating immune cells was used to provide a mechanistic assessment of the effects of aldesleukin. RESULTS: Forty-four patients were randomly assigned to either study part A (n=26) or part B (n=18). In total, 3 patients withdrew before 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 dose-dependent increase in Tregs. In part B, the estimated dose to achieve a 75% increase in Tregs was 1.46 × 106 IU (95% confidence interval, 1.06 to 1.87). Single-cell RNA-sequencing demonstrated the engagement of distinct pathways and cell­cell interactions. CONCLUSIONS: In this phase 1b/2a study, low-dose IL-2 expanded Tregs without adverse events of major concern. Larger trials are needed to confirm the safety and to further evaluate the efficacy of low-dose IL-2 as an anti-inflammatory therapy for patients with ischemic heart disease. (Funded by the Medical Research Council, the British Heart Foundation, and others; ClinicalTrials.gov number, NCT03113773)

Characteristics of patients with heart failure with preserved ejection fraction in primary care: a 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 heart failure (HF) subtype. Improvements in management of HFpEF is dependent on improved identification and characterisation of patients in primary care. AIM: To describe a cohort of patients recruited from primary care with suspected HFpEF and compare patients in whom HFpEF was confirmed and refuted. DESIGN & SETTING: Baseline data from a longitudinal cohort study of patients with suspected HFpEF recruited from primary care in two areas of England. METHOD: A screening algorithm and review were used to find patients on HF registers without a record of reduced ejection fraction (EF). Baseline evaluation included cardiac, mental and physical function, clinical characteristics, and patient reported outcomes. Confirmation of HFpEF was clinically adjudicated by a cardiologist. RESULTS: In total, 93 (61%) of 152 patients were confirmed HFpEF. The mean age of patients with HFpEF was 79 years, 46% were female, 80% had hypertension, and 37% took ≥10 medications. Patients with HFpEF were more likely to be obese, pre-frail or 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. CONCLUSION: 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 wellbeing through comorbidity management, medication rationalisation, rehabilitation, and supported self-management.

Ambulatory blood pressure adaptations to high-intensity interval training: a randomized controlled study.

OBJECTIVE: Hypertension remains the leading cause of cardiovascular disease and premature mortality globally. Although high-intensity interval training (HIIT) is an effective nonpharmacological intervention for the reduction of clinic blood pressure (BP), very little research exists regarding its effects on ambulatory BP. The aim of this study was to measure alterations in ambulatory and clinic BP following HIIT in physically inactive adults. METHODS: Forty-one participants (22.8 ±â€Š2.7 years) were randomly assigned to a 4-week HIIT intervention or control group. The HIIT protocol was performed on a cycle ergometer set against a resistance of 7.5% bodyweight and consisted of 3 × 30-s maximal sprints separated with 2-min active recovery. Clinic and ambulatory BP was recorded pre and post the control period and HIIT intervention. RESULTS: Following the HIIT intervention, 24-h ambulatory BP significantly decreased by 5.1 mmHg in sBP and 2.3 mmHg in dBP (P = 0.011 and 0.012, respectively), compared with the control group. In addition, clinic sBP significantly decreased by 6.6 mmHg compared with the control group (P = 0.021), with no significant changes in dBP and mean BP (mBP). Finally, 24-h ambulatory diastolic, daytime sBP, mBP and dBP, and night-time sBP and mBP variability significantly decreased post-HIIT compared with the control group. CONCLUSION: HIIT remains an effective intervention for the management of BP. Our findings support enduring BP reduction and improved BP variability, which are important independent risk factors for cardiovascular disease.

Left atrial mechanics and aortic stiffness following high intensity interval training: a randomised controlled study.

PURPOSE: High intensity interval training (HIIT) has been shown to improve important health parameters, including aerobic capacity, blood pressure, cardiac autonomic modulation and left ventricular (LV) mechanics. However, adaptations in left atrial (LA) mechanics and aortic stiffness remain unclear. METHODS: Forty-one physically inactive males and females were recruited. Participants were randomised to either a 4-week HIIT intervention (n = 21) or 4-week control period (n = 20). The HIIT protocol consisted of 3 × 30-s maximal cycle ergometer sprints with a resistance of 7.5% body weight, interspersed with 2-min of active unloaded recovery, three times per week. Speckle tracking imaging of the LA and M-Mode tracing of the aorta was performed pre and post HIIT and control period. RESULTS: Following HIIT, there was significant improvement in LA mechanics, including LA reservoir (13.9 ± 13.4%, p = 0.033), LA conduit (8.9 ± 11.2%, p = 0.023) and LA contractile (5 ± 4.5%, p = 0.044) mechanics compared to the control condition. In addition, aortic distensibility (2.1 ± 2.7 cm2 dyn-1 103, p = 0.031) and aortic stiffness index (- 2.6 ± 4.6, p = 0.041) were improved compared to the control condition. In stepwise linear regression analysis, aortic distensibility change was significantly associated with LA stiffness change R2 of 0.613 (p = 0.002). CONCLUSION: A short-term programme of HIIT was associated with a significant improvement in LA mechanics and aortic stiffness. These adaptations may have important health implications and contribute to the improved LV diastolic and systolic mechanics, aerobic capacity and blood pressure previously documented following HIIT.