Heart rate and blood pressure variability : association with white matter lesions and cognitive function following stroke

Dementia presents a significant health care burden. Older post-stroke patients suffer high rates of dementia. Subcortical ischaemia may be an important mechanism of cognitive decline, particularly in older patients with cerebrovascular disease. It is hypothesised that abnormal heart rate and blood pressure variability will increase white matter lesion volume through hypoperfusion. This may lead to a subcortical pattern of cognitive decline characterised for example by deficits in attention and concentration. Stroke patients aged > 75 years and free of dementia had a series of cardiovascular autonomic, brain imaging and neuropsychometric investigations performed more than three months following incident stroke. Annual neuropsychometric assessment included CAMCOG score and measures of reaction time and concentration using a series of visual and numerical tasks presented on computer (Cognitive Drug Research Assessment System). Autonomic function is impaired in older stroke patients in the long term after stroke. These deficits are weakly associated with cross-sectional measures of sub-cortical performance but do not predict subsequent decline in cognitive function. Twenty-four hour blood pressure variability is associated with white matter disease and excessive nocturnal dipping is associated with impaired cognitive function. Again blood pressure variability does not help predict subsequent change in white matter lesion burden or cognitive function. This study provides limited support for the hypoperfusion theory of post-stroke cognitive impairment. However it does not indicate a role for heart rate and blood pressure variability in the mechanism of increasing white matter disease or decline in cognition in the two years following stroke.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Investigating the relationship between habitual physical activity and cardiovascular health in healthy and clinical populations

Physical activity (PA) is beneficial for arterial and autonomic health and, subsequently, cardiovascular disease risk. However, fundamental questions remain regarding the relationship between PA and health, the relative importance of the volume, intensity or composition of PA, and whether this differs in chronic conditions. Therefore, the aim of this thesis was to explore the influence of movement behaviours on key cardiovascular risk factors in healthy populations and those with T1D using novel methods and analysis techniques. Chapter 4 revealed that, contrary to expectation, the composition of daily movement and sleep behaviours was not associated with arterial stiffness in healthy children, with the reallocation of time between any behaviours not predicting significant change in arterial stiffness. It was hypothesised that this may be related to the measurement duration being insufficient to reflect habitual PA and its health-associated fluctuations. Therefore, a 28-day measurement period was used in Chapter 5, which revealed that, whilst there was minimal fluctuation in movement behaviours, PA metrics derived from 28 days were more strongly associated with cardiovascular health markers. Using a similar measurement protocol, children with type I diabetes (T1D) were found to engage in more light and less moderate-to-vigorous physical activity (MVPA) than healthy peers and were characterised by poorer arterial stiffness and autonomic function (Chapter 6). Importantly, Chapter 6 suggested that the intensity of PA was more influential than the volume. Subsequently, Chapter 7 supported this contention, revealing that the reallocation of time from any behaviour to MVPA was the most potent stimulus to cardiovascular health in T1D. Overall, this thesis demonstrates that the composition and the relative importance of the volume and intensity of PA must be considered when investigating the relationship with health. The findings highlight key targets for future interventions seeking to enhance the cardiovascular function of youth, especially in T1D

Pulse Rate Variability for the Assessment of Cardiovascular Changes

Pulse rate variability (PRV) describes the way pulse rate changes through time and is measured from pulsatile signals such as the photoplethysmogram (PPG). It has been proposed as a surrogate for heart rate variability (HRV). Nonetheless, the relationship between these variables is not entirely clear, probably due to both physiological and technical aspects involved in the extraction of PRV. Moreover, the effects of cardiovascular changes on PRV have not been elucidated. In this thesis, four studies were performed to (1) determine the best combination of some technical aspects for the extraction of PRV from PPG signals; (2) evaluate the relationship between PRV and HRV under different cardiovascular conditions; and (3) explore the effects of cardiovascular changes on PRV. First, PRV extraction gave lower errors when (1) signals were acquired for at least 120 s with a 256 Hz sampling rate and filtered with lower low cut-off frequencies and elliptic, equiripple or Parks-McClellan filter; (2) cardiac cycles were determined using the D2max algorithm and the a fiducial points; and (3) the Fast Fourier Transform was applied to obtain frequency spectra. Secondly, the relationship between HRV and PRV was found to be affected by cold exposure and changes in blood pressure, while PRV was found to be different at different body sites. Finally, PRV was affected by haemodynamic changes, such as target flow, stroke rate and blood pressure, both in an in-vitro model and in-vivo data. Additionally, PRV was found to be a potential tool for the estimation of blood pressure, with errors as low as 1:54 ± 0:17 mmHg, 1:07 ± 0:06 mmHg and 1:22 ± 0:09 mmHg for the estimation of systolic, diastolic and mean arterial pressure. Although more studies are needed to fully understand PRV and its clinical potential, PRV should not be regarded as the same as HRV, and it could be consider as a potential valuable biomarker for cardiovascular health

Advances in Electrocardiograms

Electrocardiograms have become one of the most important, and widely used medical tools for diagnosing diseases such as cardiac arrhythmias, conduction disorders, electrolyte imbalances, hypertension, coronary artery disease and myocardial infarction. This book reviews recent advancements in electrocardiography. The four sections of this volume, Cardiac Arrhythmias, Myocardial Infarction, Autonomic Dysregulation and Cardiotoxicology, provide comprehensive reviews of advancements in the clinical applications of electrocardiograms. This book is replete with diagrams, recordings, flow diagrams and algorithms which demonstrate the possible future direction for applying electrocardiography to evaluating the development and progression of cardiac diseases. The chapters in this book describe a number of unique features of electrocardiograms in adult and pediatric patient populations with predilections for cardiac arrhythmias and other electrical abnormalities associated with hypertension, coronary artery disease, myocardial infarction, sleep apnea syndromes, pericarditides, cardiomyopathies and cardiotoxicities, as well as innovative interpretations of electrocardiograms during exercise testing and electrical pacing

Systemic Amyloidosis – Insights by Cardiovascular Magnetic Resonance

Systemic amyloidosis is the exemplar infiltrative, extracellular disease. Although it is a multi-organ disorder, cardiac involvement drives prognosis. Survival is worst in the AL amyloidosis subtype. It can affect any age and any race. There is no direct test for amyloid burden and there is no treatment for amyloidosis, there is only treatment for the underlying condition. Earlier diagnosis permits prompt treatment and improves survival. A number of imaging modalities exist to non-invasively detect cardiac disease but all have limitations. Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) imaging provides the highest sensitivity for early detection. However, this also has its shortcomings. There is currently no non-invasive method of directly measuring amyloid burden in the extracellular space. New therapies are pending – but their development needs new surrogate endpoints and new tests are therefore desperately needed. T1 mapping permits tissue abnormalities to be directly visualised in a simple scan – the colour changes being instantly recognisable, either before contrast (pre contrast or native T1 mapping) or after, when the myocardial extracellular volume (ECV) can be measured. In a collaboration between the National Amyloidosis Centre and the Heart Hospital, I explored the possibility and potential that T1 mapping might measure cardiac (and other organ) involvement in systemic amyloidosis using EQ-MRI. In early clinical exploration in systemic AL amyloid, I showed that native myocardial T1 was elevated in cardiac amyloidosis and tracked disease, particularly early disease. Mean pre contrast myocardial T1 as measured by ShMOLLI was higher in patients at 1086 ± 90msec, compared to healthy volunteers of 958 ± 20msec (P 0.9 for both the FLASH IR and ShMOLLI techniques of T1 mapping and good agreement of ECV derived from both techniques. In pilot studies, I also demonstrated by serial scanning that changes (including regression) over time could be measured. In other organs, I showed that the amyloid burden could be measured and was higher in amyloidosis compared to healthy volunteer: ECV 0.32 vs 0.29 (P<0.001) for liver, 0.39 vs 0.34 (P<0.001) for spleen and 0.16 vs 0.09 (P<0.001) for skeletal muscle. These ECVs also tracked current conventional measures of disease severity by nuclear scintigraphy. These results demonstrate that the interstitial volume in patients with systemic AL amyloidosis can be measured non invasively in the heart, liver, spleen and skeletal muscle and that this correlates with existing markers of disease and survival. Pre contrast myocardial T1 was a good alternative measure for the heart. In conclusion, the work in this thesis has enabled a deeper understanding of cardiac amyloidosis, disease processes and stages. It has pioneered a new prognostic marker that is also able to identify some patients with cardiac involvement that were previously unrecognised. Novel subtypes are now recognised (e.g. cardiac amyloidosis with no LVH) and it has also allowed direct quantification of the liver and spleen. ECV is a new and powerful biomarker that has already been adopted by industry allowing development of new therapies and providing hope that an end to the scourge of this disease is near

Cardiovascular risk factors for perioperative myocardial injury

PhDBackground: Myocardial injury affects up to one in three patients undergoing non-cardiac surgery. However, very little is known about the underlying pathophysiology. In the general population, patients with elevated resting heart rate are at increased risk of cardiac events, mortality, heart failure and autonomic dysfunction, while hypertension is a well described risk factor for cardiovascular disease. I hypothesised that common abnormalities of heart rate or blood pressure were associated with myocardial injury after non-cardiac surgery. Methods: This thesis comprises a series of secondary analyses of data from five prospective multi-centre epidemiological studies of surgical patients. The main outcome of interest was myocardial injury, defined using objective measurement of cardiac troponin. I used logistic regression analysis to test for association between exposures and outcomes. Results: In a large international cohort, patients with high preoperative heart rate had increased risk of myocardial injury and patients with very low preoperative heart rate had reduced risk of myocardial injury. Patients with elevated preoperative pulse pressure had increased risk of myocardial injury, independent of existing hypertension or systolic blood pressure. High heart rate, or high or low systolic blood pressure during surgery, was associated with increased risk of myocardial injury. In a separate study, elevated preoperative heart rate was associated with cardiopulmonary and autonomic dysfunction, and reduced left ventricular stroke volume, suggestive of heart failure. Finally, autonomic dysfunction, identified using cardiopulmonary exercise testing, was associated with elevated preoperative heart rate, elevated plasma NT-Pro-BNP (indicative of heart failure) and postoperative myocardial injury. Conclusions: Elevated preoperative heart rate, autonomic dysfunction and subclinical heart failure may be part of a common phenotype associated with perioperative myocardial injury. Further research is needed to characterise the pathological processes responsible for myocardial injury, and to identify potential therapeutic targets.Medical Research Council British Journal of Anaesthesia Clinical Research Training Fellowship (grant number MR/M017974/1)

Cardiac manifestations of mitochondrial disease

PhD ThesisDue to critical dependence of the heart on oxidative metabolism, cardiac involvement in mitochondrial disease is common and may occur as the principal clinical manifestation or part of multisystem disease. The basic features of cardiac mitochondrial disease expression remain uncertain and no effective treatment exists. Previous research has suggested that cardiac involvement in mitochondrial disease is an important cause of morbidity and early mortality in paediatric populations. In this thesis, a retrospective study confirms the frequent occurrence of cardiac involvement in adults, and demonstrates a significant impact on survival; the importance of specific mt-tRNA mutations and age of symptom onset as predictors of cardiac involvement is also highlighted. Conversely, in children with end-stage cardiomyopathy of unknown aetiology, a prospective study identifies respiratory chain disease as an important cause of disease, altering patient management in a high-risk population in whom mitochondrial disease was not suspected. Using histochemical and immunohistochemical analysis of cardiac tissue, profound complex I deficiency is demonstrated in all cardiomyocytes displaying any evidence of COX-deficiency but also in cells without COX deficiency, supporting the primacy of this factor in patients with well-characterised mt-tRNA mutations. Differences in cardiac complex I expression between patients harbouring m.3243A>G and m.8344A>G mutations may impact on cardiac phenotype; chamber-specific respiratory chain abnormalities are noted and, while tissue segregation may play a role in frequency and severity of cardiac involvement, skeletal muscle mitochondrial DNA mutation load is not a consistent marker of risk. Advanced imaging techniques are used to demonstrate early concentric hypertrophic remodelling, and specific changes in intramyocardial strains and torsion, in patients harbouring the m.3243A>G or m.8344A>G mutations without clinical evidence of cardiac involvement. However, an endurance exercise interventional study shows that patients experience comparable cardiac hypertrophic and haemodynamic adaptations to sedentary controls and confirms the safety and efficacy of 16 weeks’ training.Wellcome Trust Clinical Research Training Fellowshi