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Summary: Background: People with diabetes are at increased risk of hospitalisation, morbidity, and mortality following SARS-CoV-2 infection. Long-term outcomes for people with diabetes previously hospitalised with COVID-19 are, however, unknown. This study aimed to determine the longer-term physical and mental health effects of COVID-19 in people with and without diabetes. Methods: The PHOSP-COVID study is a multicentre, long-term follow-up study of adults discharged from hospital between 1 February 2020 and 31 March 2021 in the UK following COVID-19, involving detailed assessment at 5 and 12 months after discharge. The association between diabetes status and outcomes were explored using multivariable linear and logistic regressions. Findings: People with diabetes who survived hospital admission with COVID-19 display worse physical outcomes compared to those without diabetes at 5- and 12-month follow-up. People with diabetes displayed higher fatigue (only at 5 months), frailty, lower physical performance, and health-related quality of life and poorer cognitive function. Differences in outcomes between diabetes status groups were largely consistent from 5 to 12-months. In regression models, differences at 5 and 12 months were attenuated after adjustment for BMI and presence of other long-term conditions. Interpretation: People with diabetes reported worse physical outcomes up to 12 months after hospital discharge with COVID-19 compared to those without diabetes. These data support the need to reduce inequalities in long-term physical and mental health effects of SARS-CoV-2 infection in people with diabetes. Funding: UK Research and Innovation and National Institute for Health Research. The study was approved by the Leeds West Research Ethics Committee (20/YH/0225) and is registered on the ISRCTN Registry (ISRCTN10980107).

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

Background Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known.Objectives To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors.Methods In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health.Results From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86).Conclusion Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need.Trail registration number ISRCTN10980107.

Background and Aims: Intravenous iron therapies contain iron-carbohydrate complexes, designed to ensure iron becomes bioavailable via the intermediary of spleen and liver reticuloendothelial macrophages. How other tissues obtain and handle this iron remains unknown. This study addresses this question in the context of the heart., Methods: A prospective observational study was conducted in 12 patients receiving ferric carboxymaltose (FCM) for iron deficiency. Myocardial, spleen, and liver magnetic resonance relaxation times and plasma iron markers were collected longitudinally. To examine the handling of iron taken up by the myocardium, intracellular labile iron pool (LIP) was imaged in FCM-treated mice and cells., Results: In patients, myocardial relaxation time T1 dropped maximally 3 h post-FCM, remaining low 42 days later, while splenic T1 dropped maximally at 14 days, recovering by 42 days. In plasma, non-transferrin-bound iron (NTBI) peaked at 3 h, while ferritin peaked at 14 days. Changes in liver T1 diverged among patients. In mice, myocardial LIP rose 1 h and remained elevated 42 days after FCM. In cardiomyocytes, FCM exposure raised LIP rapidly. This was prevented by inhibitors of NTBI transporters T-type and L-type calcium channels and divalent metal transporter 1., Conclusions: Intravenous iron therapy with FCM delivers iron to the myocardium rapidly through NTBI transporters, independently of reticuloendothelial macrophages. This iron remains labile for weeks, reflecting the myocardium's limited iron storage capacity. These findings challenge current notions of how the heart obtains iron from these therapies and highlight the potential for long-term dosing to cause cumulative iron build-up in the heart., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Hypertensive pregnancy disorders are associated with adverse cardiac remodeling, which can fail to reverse in the postpartum period in some women. The Physician-Optimized Postpartum Hypertension Treatment trial demonstrated that improved blood pressure control while the cardiovascular system recovers postpartum associates with persistently reduced blood pressure. We now report the effect on cardiac remodeling., Methods: In this prospective, randomized, open-label, blinded end point trial, in a single UK hospital, 220 women were randomly assigned 1:1 to self-monitoring with research physician-optimized antihypertensive titration or usual postnatal care from a primary care physician and midwife. Participants were 18 years of age or older, with preeclampsia or gestational hypertension, requiring antihypertensives on hospital discharge postnatally. Prespecified secondary cardiac imaging outcomes were recorded by echocardiography around delivery, and again at blood pressure primary outcome assessment, around 9 months postpartum, when cardiovascular magnetic resonance was also performed., Results: A total of 187 women (101 intervention; 86 usual care) underwent echocardiography at baseline and follow-up, at a mean 258±14.6 days postpartum, of which 174 (93 intervention; 81 usual care) also had cardiovascular magnetic resonance at follow-up. Relative wall thickness by echocardiography was 0.06 (95% CI, 0.07-0.05; P <0.001) lower in the intervention group between baseline and follow-up, and cardiovascular magnetic resonance at follow-up demonstrated a lower left ventricular mass (-6.37 g/m 2 ; 95% CI, -7.99 to -4.74; P <0.001), end-diastolic volume (-3.87 mL/m 2 ; 95% CI, -6.77 to -0.98; P =0.009), and end-systolic volume (-3.25 mL/m 2 ; 95% CI, 4.87 to -1.63; P <0.001) and higher left and right ventricular ejection fraction by 2.6% (95% CI, 1.3-3.9; P <0.001) and 2.8% (95% CI, 1.4-4.1; P <0.001), respectively. Echocardiography-assessed left ventricular diastolic function demonstrated a mean difference in average E/E' of 0.52 (95% CI, -0.97 to -0.07; P =0.024) and a reduction in left atrial volumes of -4.33 mL/m 2 (95% CI, -5.52 to -3.21; P <0.001) between baseline and follow-up when adjusted for baseline differences in measures., Conclusions: Short-term postnatal optimization of blood pressure control after hypertensive pregnancy, through self-monitoring and physician-guided antihypertensive titration, associates with long-term changes in cardiovascular structure and function, in a pattern associated with more favorable cardiovascular outcomes., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04273854., Competing Interests: Disclosures L.M. and P.L. are supported by the National Institute for Health and Care Research Oxford Biomedical Research Centre. L.M. is a part-time employee of EMIS Group plc. P.L. is a founder and shareholder of a health care imaging company and a named inventor on patents related to cardiovascular imaging. R.M. has received blood pressure monitors for research from Omron and has worked with Omron and Sensyne on telemonitoring interventions for which licensing and consultancy fees have been paid to the University of Oxford. C.R. has received consultancy fees from Sensyne Health for work on telemonitoring products. J.K. is an executive committee member of the British Society of Cardiac Imaging and Cardiac Computed Tomography. The other authors report no conflicts.

Importance: Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment has yet proven effective to prevent transition to overt HF (stage C). The β3-adrenergic receptors (β3ARs) may represent a new target, as their activation attenuates LV remodeling., Objective: To determine whether activation of β3ARs by repurposing a β3AR agonist, mirabegron, is safe and effective in preventing progression of LV hypertrophy and diastolic dysfunction among patients with pre- or mild HF., Design, Setting, and Participants: The Beta3-LVH prospective, triple-blind, placebo-controlled phase 2b randomized clinical trial enrolled patients between September 12, 2016, and February 26, 2021, with a follow-up of 12 months. The trial was conducted at 10 academic hospitals in 8 countries across Europe (Germany, Poland, France, Belgium, Italy, Portugal, Greece, and the UK). Patients aged 18 years or older with or without HF symptoms (maximum New York Heart Association class II) were screened for the presence of LV hypertrophy (increased LV mass index [LVMI] of ≥95 g/m2 for women or ≥115 g/m2 for men) or maximum wall thickness of 13 mm or greater using echocardiography. Data analysis was performed in August 2022., Intervention: Participants were randomly assigned (1:1) to mirabegron (50 mg/d) or placebo, stratified by the presence of atrial fibrillation and/or type 2 diabetes, for 12 months., Main Outcomes and Measures: The primary end points were LVMI determined using cardiac magnetic resonance imaging and LV diastolic function (early diastolic tissue Doppler velocity [E/e'] ratio assessed using Doppler echocardiography) at 12 months. Patients with at least 1 valid measurement of either primary end point were included in the primary analysis. Safety was assessed for all patients who received at least 1 dose of study medication., Results: Of the 380 patients screened, 296 were enrolled in the trial. There were 147 patients randomized to mirabegron (116 men [79%]; mean [SD] age, 64.0 [10.2] years) and 149 to placebo (112 men [75%]; mean [SD] age, 62.2 [10.9] years). All patients were included in the primary intention-to-treat analysis. At 12 months, the baseline and covariate-adjusted differences between groups included a 1.3-g/m2 increase in LVMI (95% CI, -0.15 to 2.74; P = .08) and a -0.15 decrease in E/e' (95% CI, -0.69 to 0.4; P = .60). A total of 213 adverse events (AEs) occurred in 82 mirabegron-treated patients (including 31 serious AEs in 19 patients) and 215 AEs occurred in 88 placebo-treated patients (including 30 serious AEs in 22 patients). No deaths occurred during the trial., Conclusions: In this study, mirabegron therapy had a neutral effect on LV mass or diastolic function over 12 months among patients who had structural heart disease with no or mild HF symptoms., Trial Registration: ClinicalTrials.gov Identifier: NCT02599480.

Background: Hypertrophic cardiomyopathy (HCM) is characterized by increased left ventricular wall thickness, cardiomyocyte hypertrophy, and fibrosis. Adverse cardiac risk characterization has been performed using late gadolinium enhancement (LGE), native T1, and extracellular volume (ECV). Relaxation time constants are affected by background field inhomogeneity. T1ρ utilizes a spin-lock pulse to decrease the effect of unwanted relaxation. The objective of this study was to study T1ρ as compared to T1, ECV, and LGE in HCM patients., Methods: HCM patients were recruited as part of the Novel Markers of Prognosis in Hypertrophic Cardiomyopathy study, and healthy controls were matched for comparison. In addition to cardiac functional imaging, subjects underwent T1 and T1ρ cardiovascular magnetic resonance imaging at short-axis positions at 1.5T. Subjects received gadolinium and underwent LGE imaging 15-20 min after injection covering the entire heart. Corresponding basal and mid short axis LGE slices were selected for comparison with T1 and T1ρ. Full-width half-maximum thresholding was used to determine the percent enhancement area in each LGE-positive slice by LGE, T1, and T1ρ. Two clinicians independently reviewed LGE images for presence or absence of enhancement. If in agreement, the image was labeled positive (LGE + +) or negative (LGE --); otherwise, the image was labeled equivocal (LGE + -)., Results: In 40 HCM patients and 10 controls, T1 percent enhancement area (Spearman's rho = 0.61, p < 1e-5) and T1ρ percent enhancement area (Spearman's rho = 0.48, p < 0.001e-3) correlated with LGE percent enhancement area. T1 and T1ρ percent enhancement areas were also correlated (Spearman's rho = 0.28, p = 0.047). For both T1 and T1ρ, HCM patients demonstrated significantly longer relaxation times compared to controls in each LGE category (p < 0.001 for all). HCM patients also showed significantly higher ECV compared to controls in each LGE category (p < 0.01 for all), and LGE -- slices had lower ECV than LGE + + (p = 0.01)., Conclusions: Hyperenhancement areas as measured by T1ρ and LGE are moderately correlated. T1, T1ρ, and ECV were elevated in HCM patients compared to controls, irrespective of the presence of LGE. These findings warrant additional studies to investigate the prognostic utility of T1ρ imaging in the evaluation of HCM patients., (© 2021. The Author(s).)

Cardiac magnetic resonance (CMR) images play a growing role in the diagnostic imaging of cardiovascular diseases. Full coverage of the left ventricle (LV), from base to apex, is a basic criterion for CMR image quality and necessary for accurate measurement of cardiac volume and functional assessment. Incomplete coverage of the LV is identified through visual inspection, which is time-consuming and usually done retrospectively in the assessment of large imaging cohorts. This paper proposes a novel automatic method for determining LV coverage from CMR images by using Fisher-discriminative three-dimensional (FD3D) convolutional neural networks (CNNs). In contrast to our previous method employing 2D CNNs, this approach utilizes spatial contextual information in CMR volumes, extracts more representative high-level features and enhances the discriminative capacity of the baseline 2D CNN learning framework, thus achieving superior detection accuracy. A two-stage framework is proposed to identify missing basal and apical slices in measurements of CMR volume. First, the FD3D CNN extracts high-level features from the CMR stacks. These image representations are then used to detect the missing basal and apical slices. Compared to the traditional 3D CNN strategy, the proposed FD3D CNN minimizes within-class scatter and maximizes between-class scatter. We performed extensive experiments to validate the proposed method on more than 5,000 independent volumetric CMR scans from the UK Biobank study, achieving low error rates for missing basal/apical slice detection (4.9%/4.6%). The proposed method can also be adopted for assessing LV coverage for other types of CMR image data.

Aims: Progressive left ventricular (LV) remodelling with cardiac myocyte hypertrophy, myocardial fibrosis, and endothelial dysfunction plays a key role in the onset and progression of heart failure with preserved ejection fraction. The Beta3-LVH trial will test the hypothesis that the β 3 adrenergic receptor agonist mirabegron will improve LV hypertrophy and diastolic function in patients with hypertensive structural heart disease at high risk for developing heart failure with preserved ejection fraction., Methods and Results: Beta3-LVH is a randomized, placebo-controlled, double-blind, two-armed, multicentre, European, parallel group study. A total of 296 patients will be randomly assigned to receive either mirabegron 50 mg daily or placebo over 12 months. The main inclusion criterion is the presence of LV hypertrophy, that is, increased LV mass index (LVMi) or increased wall thickening by echocardiography. The co-primary endpoints are a change in LVMi by cardiac magnetic resonance imaging and a change in LV diastolic function (assessed by the E/e' ratio). Secondary endpoints include mirabegron's effects on cardiac fibrosis, left atrial volume index, maximal exercise capacity, and laboratory markers. Two substudies will evaluate mirabegron's effect on endothelial function by pulse amplitude tonometry and brown fat activity by positron emission tomography using 17F-fluorodeoxyglucose. Morbidity and mortality as well as safety aspects will also be assessed., Conclusions: Beta3-LVH is the first large-scale clinical trial to evaluate the effects of mirabegron on LVMi and diastolic function in patients with LVH. Beta3-LVH will provide important information about the clinical course of this condition and may have significant impact on treatment strategies and future trials in these patients., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: CMR T1 mapping is a quantitative imaging technique allowing the assessment of myocardial injury early after ST-segment-elevation myocardial infarction. We sought to investigate the ability of acute native T1 mapping to differentiate reversible and irreversible myocardial injury and its predictive value for left ventricular remodeling., Methods and Results: Sixty ST-segment-elevation myocardial infarction patients underwent acute and 6-month 3T CMR, including cine, T2-weighted (T2W) imaging, native shortened modified look-locker inversion recovery T1 mapping, rest first pass perfusion, and late gadolinium enhancement. T1 cutoff values for oedematous versus necrotic myocardium were identified as 1251 ms and 1400 ms, respectively, with prediction accuracy of 96.7% (95% confidence interval, 82.8% to 99.9%). Using the proposed threshold of 1400 ms, the volume of irreversibly damaged tissue was in good agreement with the 6-month late gadolinium enhancement volume ( r =0.99) and correlated strongly with the log area under the curve troponin ( r =0.80) and strongly with 6-month ejection fraction ( r =-0.73). Acute T1 values were a strong predictor of 6-month wall thickening compared with late gadolinium enhancement., Conclusions: Acute native shortened modified look-locker inversion recovery T1 mapping differentiates reversible and irreversible myocardial injury, and it is a strong predictor of left ventricular remodeling in ST-segment-elevation myocardial infarction. A single CMR acquisition of native T1 mapping could potentially represent a fast, safe, and accurate method for early stratification of acute patients in need of more aggressive treatment. Further confirmatory studies will be needed., (© 2017 The Authors.)

Background: Patients with treated HIV infection have clear survival benefits although with increased cardiac morbidity and mortality. Mechanisms of heart disease may be partly related to untreated chronic inflammation. Cardiovascular magnetic resonance imaging allows a comprehensive assessment of myocardial structure, function, and tissue characterization. We investigated, using cardiovascular magnetic resonance, subclinical inflammation and myocardial disease in asymptomatic HIV-infected individuals., Methods and Results: Myocardial structure and function were assessed using cardiovascular magnetic resonance at 1.5-T in treated HIV-infected individuals without known cardiovascular disease (n=103; mean age, 45±10 years) compared with healthy controls (n=92; mean age, 44±10 years). Assessments included left ventricular volumes, ejection fraction, strain, regional systolic, diastolic function, native T1 mapping, edema, and gadolinium enhancement. Compared with controls, subjects with HIV infection had 6% lower left ventricular ejection fraction (P<0.001), 7% higher myocardial mass (P=0.02), 29% lower peak diastolic strain rate (P<0.001), 4% higher short-tau inversion recovery values (P=0.02), and higher native T1 values (969 versus 956 ms in controls; P=0.01). Pericardial effusions and myocardial fibrosis were 3 and 4× more common, respectively, in subjects with HIV infection (both P<0.001)., Conclusions: Treated HIV infection is associated with changes in myocardial structure and function in addition to higher rates of subclinical myocardial edema and fibrosis and frequent pericardial effusions. Chronic systemic inflammation in HIV, which involves the myocardium and pericardium, may explain the high rate of myocardial fibrosis and increased cardiac dysfunction in people living with HIV., (© 2016 American Heart Association, Inc.)

Background: UK Biobank's ambitious aim is to perform cardiovascular magnetic resonance (CMR) in 100,000 people previously recruited into this prospective cohort study of half a million 40-69 year-olds., Methods/design: We describe the CMR protocol applied in UK Biobank's pilot phase, which will be extended into the main phase with three centres using the same equipment and protocols. The CMR protocol includes white blood CMR (sagittal anatomy, coronary and transverse anatomy), cine CMR (long axis cines, short axis cines of the ventricles, coronal LVOT cine), strain CMR (tagging), flow CMR (aortic valve flow) and parametric CMR (native T1 map)., Discussion: This report will serve as a reference to researchers intending to use the UK Biobank resource or to replicate the UK Biobank cardiovascular magnetic resonance protocol in different settings.

Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease with a frequency as high as 1 in 200. In many cases, HCM is caused by mutations in genes encoding the different components of the sarcomere apparatus. Hypertrophic cardiomyopathy is characterized by unexplained left ventricular hypertrophy, myofibrillar disarray, and myocardial fibrosis. The phenotypic expression is quite variable. Although most patients with HCM are asymptomatic, serious consequences are experienced in a subset of affected individuals who present initially with sudden cardiac death or progress to refractory heart failure. The Hypertrophic Cardiomyopathy Registry study is a National Heart, Lung, and Blood Institute-sponsored 2,750-patient, 44-site, international registry and natural history study designed to address limitations in extant evidence to improve prognostication in HCM (NCT01915615). In addition to the collection of standard demographic, clinical, and echocardiographic variables, patients will undergo state-of-the-art cardiac magnetic resonance for assessment of left ventricular mass and volumes as well as replacement scarring and interstitial fibrosis. In addition, genetic and biomarker analyses will be performed. The Hypertrophic Cardiomyopathy Registry has the potential to change the paradigm of risk stratification in HCM, using novel markers to identify those at higher risk., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Since cross-sectional brain-imaging studies demonstrating frontotemporal cerebral hypoactivity in violent offenders have generally been carried out around the time of trial and sentencing, the findings might be influenced by the stressful situation of the subjects. It seems that no group of offenders with this finding has yet been followed longitudinally. We have re-examined nine offenders convicted of lethal or near-lethal violence in whom single photon emission tomography (SPECT) previously had demonstrated frontotemporal hypoperfusion. The mean interval between the initial and the follow-up examination was 4 years. The initially observed hypoactivity was found to have remained virtually unchanged at follow-up: no mean change in the group exceeded 5% in 12 assessed regions of interest. Although preliminary due to the small sample size, this study suggests that frontotemporal brain hypoactivity is a trait rather than a state in perpetrators of severe violent crimes.

The change in cerebral rate of oxidative metabolism (CMR(O(2))) during neural activation may be estimated from blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) and arterial spin-labeling (ASL) fMRI measurements. The established method relies on an epoch of iso-metabolic blood flow increase, typically induced by CO2 breathing, to calibrate the BOLD-CBF relationship at resting-state CMR(O2). Here, we discuss the systematic bias in CMR(O2)-CBF data that can be introduced depending on the value derived for the calibration constant (M) from the CO2 breathing epoch. We demonstrate that the fidelity of BOLD-CBF data acquired during the neural activation task have low impact on the tightness of CMR(O2)-CBF coupling, as well as the coupling slope, when the derived calibration value is of a relatively moderate amplitude (M in the range of, or greater than, 10-15 at 1.5 T). Via the standard reformulation of a grid in BOLD-CBF space into the CMR(O2)-CBF plane, we demonstrate the non-linear transformation that takes place and the sources of systematic bias that result. We find that the outcome of a neurovascular coupling study may be predicted to a large extent purely from the value of the calibration constant, M, that is used. Our results suggest that the accurate determination of M is of greater importance than thought previously and indicate that BOLD-CBF data must always be supplied when considering CMR(O2)-CBF behavior in a particular brain region.

The heterogeneity of the initial insult and subsequent pathophysiology has made both the study of human head injury and design of randomised controlled trials exceptionally difficult. The combination of multimodality bedside monitoring and functional brain imaging positron emission tomography (PET) and magnetic resonance (MR), incorporated within a Neurosciences Critical Care Unit, provides the resource required to study critically ill patients after brain injury from initial ictus through recovery from coma and rehabilitation to final outcome. Methods to define cerebral ischemia in the context of altered cerebral oxidative metabolism have been developed, traditional therapies for intracranial hypertension re-evaluated and bedside monitors cross-validated. New modelling and analytical approaches have been developed.

ICM software was developed in 1986 in Warsaw, Poland and has been in use at the University of Cambridge Neurocritical Care Unit for 10 years collecting data from bed-side monitors in nearly 600 severely head injured patients and calculating secondary indices describing cerebral autoregulation and pressure-volume compensation. The new software ICM+ includes a much extended calculation engine that allows easy configuration and on-line trending of complex parameters. The program records raw signals, and calculates time trends of summary parameters. Configuration and analysis utilises arithmetic expressions of signal processing functions to calculate various statistical properties for each signal, frequency spectrums and derivatives, as well as correlations/cross-correlations between signals. The software allows configuration of several levels of analysis before calculating the final time trends. The final data are displayed in a variety of ways including simple time trends, as well as time window based histograms, cross histograms, correlations etc. All this allows complex information coming off the bed-side monitors to be summarized in a concise fashion and presented to medical and nursing staff in a simple way that alerts them to the development of various pathological processes. The system provides a universal tool for clinical and academic purposes. Its flexibility and advanced signal processing is specialized for the needs of multidisciplinary brain monitoring.

The method for the continuous assessment of cerebral autoregulation using slow waves of MCA blood flow velocity (FV) and cerebral perfusion pressure (CPP) or arterial pressure (ABP) has been introduced seven years ago. We intend to review its clinical applications in various scenarios. Moving correlation coefficient (3-6 min window), named Mx, is calculated between low-pass filtered (0.05 Hz) signals of FV and CPP or ABP (when ICP is not measured directly). Data from ventilated 243 head injuries and 15 patients after poor grade subarachnoid haemorrhage, 38 patients with Carotid Artery stenosis, 35 patients with hydrocephalus and fourteen healthy volunteers is presented. Good agreement between the leg-cuff test and Mx has been confirmed in healthy volunteers (r = 0.81). Mx also correlated significantly with the static rate of autoregulation and transient hyperaemic response test. Autoregulation was disturbed (p < 0.021) by vasospasm after SAH and worse in patients with hydrocephalus in whom CSF circulation was normal (p < 0.02). In head injury, Mx indicated disturbed autoregulation with low CPP (< 55 mmHg) and too high CPP (> 95 mmHg). Mx strongly discriminated between patients with favourable and unfavourable outcome (p < 0.00002). This method can be used in many clinical scenarios for continuous monitoring of cerebral autoregulation, predicting outcome and optimising treatment strategies.

Objectives: Disturbed cerebral autoregulation is believed to be associated with an unfavourable outcome following head injury. Previously, using ICP monitoring and transcranial Doppler ultrasonography, we investigated whether cerebral response to spontaneous variations in arterial pressure (ABP) or cerebral perfusion pressure (CPP) provide reliable information on cerebral autoregulatory reserve. In the present study we have correlated these methods with clinical findings., Methods: 188 head injured sedated and ventilated patients were studied daily. Waveforms of intracranial pressure (ICP), arterial pressure and transcranial Doppler flow velocity (FV) were captured over a half to two hour periods. Time averaged mean flow velocity (FV) and CPP were resolved. The correlation coefficient indices between FV and CPP (Mx) and between ICP and ABP (PRx) were calculated over 3 minutes epochs, and averaged for each investigation., Results: The relationship between indices of autoregulation and outcome (favourable-unfavourable) was significant and stronger than the association between admission GCS and outcome. With rigorously maintained CPP-oriented therapy relationship between CPP and outcome became non-significant. Mortality in patients with consistently disturbed autoregulation ranged 47%, while in patients with good autoregulation mortality was 11% (difference: p < 0.0001)., Conclusions: Positive values of indices of autoregulation, expressing positive association between slow waves of CPP and blood flow velocity or ABP and ICP, indicate disturbed autoregulation. These indices correlate with unfavourable outcome following head injury and should be used to guide intensive therapy.

Object: The goal of this study was to examine the relationship between cerebral autoregulation, intracranial pressure (ICP), arterial blood pressure (ABP), and cerebral perfusion pressure (CPP) after head injury by using transcranial Doppler (TCD) ultrasonography., Methods: Using ICP monitoring and TCD ultrasonography, the authors previously investigated whether the response of flow velocity (FV) in the middle cerebral artery to spontaneous variations in ABP or CPP provides reliable information about cerebral autoregulatory reserve. In the present study, this method was validated in 187 head-injured patients who were sedated and receiving mechanical ventilation. Waveforms of ICP, ABP, and FV were recorded over intervals lasting 20 to 120 minutes. Time-averaged mean FV and CPP were determined. The correlation coefficient index between FV and CPP (the mean index of autoregulation [Mx]) was calculated over 4-minute epochs and averaged for each investigation. The distribution of averaged mean FV values converged with the shape of the autoregulatory curve, indicating lower (CPP < 55 mm Hg) and upper (CPP > 105 mm Hg) thresholds of autoregulation. The relationship between the Mx and either the CPP or ABP was depicted as a U-shaped curve. Autoregulation was disturbed in the presence of intracranial hypertension (ICP > or = 25 mm Hg) and when mean ABP was too low (ABP < 75 mm Hg) or too high (ABP > 125 mm Hg). Disturbed autoregulation (p < 0.005) and higher ICP (p < 0.005) occurred more often in patients with unfavorable outcomes than in those with favorable outcomes., Conclusions: Autoregulation not only is impaired when associated with a high ICP or low ABP, but it can also be disturbed by too high a CPP. The Mx can be used to guide intensive care therapy when CPP-oriented protocols are used.

Positron emission tomography scans of patients with head injuries often show discrete areas of increased 18F-fluorodeoxyglucose uptake ("hot spots") when performed hours to days after the initial ictus. Using quantitative autoradiographic methods, the authors have investigated whether cerebral blood flow and glucose metabolism are uncoupled 2 hours after controlled head injury in an animal model, and whether any "hot spots" are accompanied by changes in cerebral glucose concentration. Experiments were performed on 18 anesthetized, ventilated (1.5% halothane in 2:1 nitrous oxide:oxygen) Sprague-Dawley rats weighing 300 to 330 g. A burr hole was made over the left parietal cortex, and all animals received a piston impact on the intact dura (2 mm in diameter, 2.0 m/sec, 2 mm in depth). All animals remained anesthetized and ventilated for a further 2 hours, after which quantitative autoradiography was used to determine either (1) local cerebral blood flow (LCBF) using 14C-iodoantipyrine, (2) local cerebral glucose utilization (LCGU) using 14C-deoxyglucose, or (3) local cerebral glucose content (LCGC) using 14C-methylglucose. Local CBF, LCGU, and LCGC were measured in five regions adjacent to the contusion, and values then were normalized on the contralateral cortex. Normalized LCBF, LCGU, or LCGC varied in parallel in ipsilateral cortex (no change) and in the ischemic core of the contusion (reduced). However, there were marked changes in the patterns observed in the boundary zone (within 1 mm of the contusion). In all six rats used for LCGU measurement, there were discrete areas of high metabolism, whereas in all six rats used for LCBF measurement, flow was universally depressed in the boundary zone. Of the six rats used for LCGC determination, there was a discrete area of high signal in only one. The authors conclude that there are discrete areas of uncoupling of cerebral blood flow and metabolism after head injury within 2 hours of cerebral contusion in the rat that cannot be explained by changes in cerebral glucose content in the majority of animals.

Previously, using transcranial Doppler ultrasonography, we investigated whether the hemodynamic response to spontaneous variations in cerebral perfusion pressure (CPP) provides reliable information about cerebral autoregulatory reserve. In the present study we have verified this method in 166 patients after head trauma. Waveforms of intracranial pressure (ICP), arterial pressure and transcranial Doppler flow velocity (FV) were captured daily over 0.5-2.0 hour periods. Time-averaged mean flow velocity (FV) and CPP were resolved. The correlation coefficient indices between FV and CPP (Mx) were calculated over 3 minutes epochs, and averaged for each investigation. An index of CBF (flow velocity diastolic to mean ratio) was calculated independently for each investigation. Mx depended on CPP (p < 0.0001) increasing to positive values when CPP decreased below 60 mm Hg. This threshold coincided with an averaged breakpoint for autoregulation, expressed by the index of CBF. Mx depended on outcome following head injury stronger than the Glasgow Coma Score on admission (ANOVA, F values 18 and 15 respectively; N = 166). In patients who died, cerebral autoregulation was disturbed during the first two days following injury. These results indicate an important role for the continuous monitoring of autoregulation following head trauma.

The method of direct calculation of cerebral perfusion pressure (CPP) as the difference between mean arterial pressure and intracranial pressure (ICP) produces a number, which not always adequately expresses brain perfusion. We investigated an alternative non-invasive method, based on waveform analysis of Transcranial Doppler blood flow velocity in Middle Cerebral Arteries (MCA). 25 consecutive head injured patients, paralysed, sedated and ventilated were studied. Intracranial pressure (ICP) arterial blood pressure (ABP) were monitored continuously. The left and right MCAs were insonated daily (116 measurements) using a purpose-built transcranial Doppler monitor (Deltex Ltd, Chichester, U.K.) with software capable of the non-invasive estimation of CPP. Time averaged values of ABP, mean and diastolic flow velocities (FVm, FVd) were calculated and CPPe was computed as: ABP*FVd/FVm + 14. An absolute difference between real CPP and CPPe was less than 10 mm Hg in 82% of measurements and less than 13 mm Hg in 90% of measurements. The method demonstrated a high potential to detect both short-term and long-term changes in CPP. The method is of potential benefit for the intermittent measurement and continuous monitoring of changes in brain perfusion pressure in situations where the direct measurement of CPP is not available or its reliability is in question.

Object: Plateau waves of intracranial pressure (ICP) are often recorded during intensive care monitoring of severely head injured patients. They are traditionally interpreted as meaningful secondary brain insults because of the dramatic decrease in cerebral perfusion pressure (CPP). The aim of this study was to investigate both the hemodynamic profile and the clinical consequences of plateau waves., Methods: One hundred sixty head-injured patients were studied using continuous monitoring of ICP; almost 20% of these patients exhibited plateau waves. In 96 patients arterial pressure, ICP, and transcranial Doppler (TCD) blood flow velocity were studied daily for 20 minutes to 3 hours. Sixteen episodes of plateau waves in eight patients were recorded and analyzed. The dramatic increase in ICP was followed by a profound fall in CPP (by 45%). In contrast, flow velocity fell by only 20%. Autoregulation was documented to be intact both before and after plateau but was disturbed during the wave (p < 0.05). Pressure-volume compensatory reserve was always depleted before the wave. Cerebrovascular resistance decreased during the wave by 60% (p < 0.05) and TCD pulsatility increased (p < 0.05). Plateau waves did not increase the probability of an unfavorable outcome following injury., Conclusions: The authors have confirmed that the plateau waves are a hemodynamic phenomenon associated with cerebrovascular vasodilation. They are observed in patients with preserved cerebral autoregulation but reduced pressure-volume compensatory reserve.

Objective: Cerebral critical closing pressure (CCP) has been defined as an arterial pressure threshold below which arterial vessels collapse. Hypothetically this is equal to intracranial pressure (ICP) plus the contribution from the active tone of cerebral arterial smooth muscle. The correlation of CCP with ICP, cerebral autoregulation, and other clinical and haemodynamic modalities in patients with head injury was evaluated., Method: intracranial pressure, arterial blood pressure (ABP) and middle cerebral artery blood flow velocity were recorded daily in ventilated patients. Waveforms were processed to calculate CCP, the transcranial Doppler-derived cerebral autoregulation index (Mx), mean arterial pressure (ABP), intracranial pressure (ICP), and cerebral perfusion pressure (CPP)., Results: Critical closing pressure reflected the time related changes in ICP during plateau and B waves. Overall correlation between CCP and ICP was mild but significant (R=0.41; p<0.0002). The mean difference between ABP and CCP correlated with CPP (R=0.57, 95% confidence interval (95% CI) for prediction 25 mm Hg). The difference between CCP and ICP, described previously as proportional to arterial wall tension, correlated with the index of cerebral autoregulation Mx (p<0.0002) and CPP (p<0.0001). However, by contrast with the Mx index, CCP-ICP was not significantly correlated with outcome after head injury., Conclusion: Critical closing pressure, although sensitive to variations in ICP and CPP, cannot be used as an accurate estimator of these modalities with acceptable confidence intervals. The difference CCP-ICP significantly correlates with cerebral autoregulation, but it lacks the power to predict outcome after head injury.

Object: The aim of the study was to assess how cerebrospinal fluid (CSF) pressure-volume compensation depends on cerebrovascular tone., Methods: In 26 New Zealand White rabbits, intracranial pressure (ICP), arterial blood pressure, and basilar artery blood flow velocity were measured continuously. Saline was infused into the cranial subarachnoid space to assess CSF compensatory parameters: the resistance to CSF outflow, the elastance coefficient, and the amplitude of the ICP pulsatile waveform. Infusions were repeated on two different levels of CO2 concentration in the arterial blood (PaCO2), at normotension and hypotension, and after the death of the animal. An increase in PaCO2 from a mean of 27 to 48 mm Hg was accompanied by an 18% increase in the resistance to CSF outflow (p<0.005) and a 64% increase (p<0.05) in the elastance coefficient. A decrease in arterial blood pressure from a mean of 100 to 51 mm Hg caused a 25% decrease in CSF outflow resistance (p<0.01) but did not affect the elastance coefficient. Postmortem, a 23% decrease in the CSF outflow resistance was associated with a 102% decrease in the elastance coefficient., Conclusions: Cerebrovascular parameters have a limited but significant impact on CSF infusion studies. The vascular component of ICP may be identified as a significant factor contributing to this phenomenon. During infusion studies, physiological parameters influencing vascular conditions should be maintained as stable as possible.

Objective: Cerebrovascular vasomotor reactivity reflects changes in smooth muscle tone in the arterial wall in response to changes in transmural pressure or concentration of carbon dioxide in blood. We have investigated whether slow waves in ABP and ICP may be used to derive an index which reflects reactivity of vessels to changes in arterial blood pressure., Methods: A method for the continuous monitoring of the association between slow spontaneous waves in ICP and AP has been adopted in a group of 98 head injured patients. ABP, ICP and transcranial Doppler blood flow velocity (FV) in the middle cerebral artery was recorded daily (20 to 120 minutes time periods). A Pressure-Reactivity Index (PRx) was calculated as a moving correlation coefficient between 40 consecutive samples of values for ICP and ABP averaged over 5 seconds. A moving correlation coefficient between spontaneous fluctuations of mean FV and CPP (Mx), which was previously reported to describe cerebral blood flow autoregulation, was also calculated. In an additional 25 patients, PRx was calculated and recorded continuously along with mean ICP, ABP and parameters describing ICP waveform., Results: A positive PRx correlated with high ICP (r = 0.366; p < 0.001), low admission GCS (r = 0.29; p < 0.01), and poor outcome at 6 months after injury (r = 0.48; p < 0.00001). During the first two days following injury, PRx was positive (p < 0.05) in patients with unfavourable outcome. The correlation between PRx and Mx (r = 0.63) was highly significant (p < 0.000001). Continuous recordings demonstrated that PRx was able to indicate individual thresholds of vascular reactivity for CPP, ICP, and ventilation parameters., Conclusion: Computer analysis of slow waves in ABP and ICP is able to provide a continuous index of cerebrovascular reactivity to changes in arterial pressure, which is of prognostic significance.

Time-dependent interactions between pressure, flow and volume of cerebral blood and cerebrospinal fluid were mathematically modelled. The model was designed to simulate blood inflow and storage, arteriolar and capillary blood circulation controlled by cerebral autoregulation, venous blood outflow and storage modulated by intracranial pressure, and cerebrospinal fluid production, storage and reabsorption. The software implementation of the model was used to calculate the response to a gradual decrease in cerebral perfusion pressure corresponding to either systemic hypotension or intracranial hypertension. We computed flow pulsatility index (PI) and short range correlation coefficients between systolic, diastolic and mean flow velocity (FVs,d,m) and mean cerebral perfusion pressure (CPP). In simulation, the changes in cerebral flow produced by intracranial hypertension and systemic hypotension were practically indistinguishable. The relationship between PI and CPP was reciprocal, independent of the state of autoregulation. The short range running correlation coefficients between FVs, FVm and CPP indicated both combined safe CPP range and preserved autoregulation, promising a clear clinical detection of "non-worsening" blood supply conditions. A similar procedure was applied to selected clinical data to illustrate the theoretical considerations.

Objectives: Cerebral haemodynamic responses to short and longlasting episodes of decreased cerebral perfusion pressure contain information about the state of autoregulation of cerebral blood flow. Mathematical simulation may help to elucidate which of the indices, that can be derived using transcranial Doppler ultrasonography and trends of intracranial pressure and blood pressure, are useful in clinical tests of autoregulatory reserve., Methods: Time dependent interactions between pressure, flow, and volume of cerebral blood and CSF were modelled using a set of non-linear differential equations. The model simulates changes in arterial blood inflow and storage, arteriolar and capillary blood flow controlled by cerebral autoregulation, venous blood storage and venous outflow modulated by changes in ICP, and CSF storage and reabsorption. The model was used to simulate patterns of blood flow during either short or longlasting decreases in cerebral perfusion pressure. These simulations can be considered as clinically equivalent to a short compression of the common carotid artery, systemic hypotension, and intracranial hypertension. Simulations were performed in autoregulating and non-autoregulating systems and compared with recordings obtained in patients., Results: After brief compression of the common carotid artery, a subsequent transient hyperaemia can be interpreted as evidence of intact autoregulation. During longlasting sustained hypoperfusion, a gradual increase in the systolic value of the blood flow velocity waveform along with a decrease in the diastolic value is specific for an autoregulating cerebrovascular system., Conclusion: Modelling studies help to interpret both clinical and experimental cerebral haemodynamic phenomena and their dependence on the state of autoregulation.

Dotarizine and Flunarizine are piperazine derivatives considered to be effective compounds for the treatment of various cerebrovascular disorders. In the present study the influence of these two drugs on changes in cerebral vessel diameter and blood flow velocity were measured and compared utilising transcranial Doppler sonography during hyperventilation in anaesthetized cats. Drugs were administered in 15 min intravenous infusions at a dose of 0.05 mg/kg/min. This investigation revealed that the 15 min intravenous administration of both compounds abolished the cerebral vasoconstrictor effects of hyperventilation and due to vasodilator effects they increased blood flow velocity to initial values. No statistically significant differences were found between the vasodilator effects of Dotarizine and Flunarizine. Results obtained suggest that Dotarizine, a novel piperazine derivative, has similar vasodilator and Ca2+ channel blocking effects on cerebrovascular reactivity compared to the widely clinically applied Flunarizine.