Heart rate as a marker of incidence and prognosis of cardiovascular diseases in different populations: Evidence from Linked Electronic Health Records using the CALIBER platform and the 4C clinical cohort

Background: Resting heart rate (RHR) is an easily accessible clinical parameter. In spite of the well-established association between resting heart rate and mortality in men and women, potential links between the marker and more specific cardiovascular diseases (CVDs) have not yet been explored. No previous research has used clinically collected RHR measurements from primary care settings. Normal RHR values have not been firmly established, although this is crucial in clinical practice and promotion of personalised health care. Objectives: The main objectives of this PhD are to: -Examine the association between RHR and the onset of specific fatal and non-fatal cardiovascular diseases -Examine the association between RHR and the prognosis of people with coronary artery disease (CAD) --Investigate the association between RHR and the onset and prognosis of atrial fibrillation -Describe the establishment of a consented clinical cohort resource of patients with CAD (4C) -Compare electronic health records (EHR) processes and data with the 4C consented clinical cohort Methods: I used CALIBER, a linked electronic health records (EHR) platform that links primary and secondary care data, myocardial infarction disease registry and mortality data. Additionally, to establish a clinical cohort of people with CAD, I consented, recruited and collected anthropometric and biomarker data including RHR from patients attending chest pain clinics and angiography labs in London. Results: RHR was associated with myocardial and arrhythmic disorders, but not with coronary disease or peripheral arterial disease. An average RHR of >70bpm in the general population was associated with increased hazards of specific CVDs and mortality particularly in men and should not be considered as normal. Additionally, increased RHR was strongly associated with higher risk of cardiovascular outcomes not currently considered as primary endpoints in trials, such as heart failure. Finally, higher HR is strongly associated with atrial fibrillation in men, but not in women. Conclusions: EHR provides a wealth of primary care data, so far unexplored that give insight into associations of heart rate with CVDs in healthy and CAD populations. Average RHR of >70bpm in the general male population is associated with increased myocardial and arrhythmic disorders risk, but not with coronary disease. Disaggregation of CVDs into its constituent phenotypes contributes to our understanding of disease mechanisms with implications for clinical practice and interpretation of clinical trials

Clinically recorded heart rate and incidence of 12 coronary, cardiac, cerebrovascular and peripheral arterial diseases in 233,970 men and women: A linked electronic health record study

Background: In healthy population cohorts, resting heart rate above 90 bpm is associated with mortality from coronary heart disease, but it is not clear whether associations are present at lower heart rates or whether these associations differ between women. Methods: The CALIBER resource of linked electronic health records from primary care, hospitalisations, myocardial infarction registry and cause-specific mortality in the UK was used to assess associations between resting heart rate and 12 fatal and non-fatal coronary, cardiac, cerebral and peripheral vascular cardiovascular diseases and death using Cox proportional hazard models. Results: Among 233,970 patients, 29,690 fatal and non-fatal events occurred. Fully adjusted models showed that resting heart rate was not associated in men or women with cerebrovascular events. In men a resting heart rate of 70–79 bpm (29.1% of all men) versus less than 60 bpm was associated with an increased risk of heart failure (hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.26–2.16), unheralded coronary death (HR 1.65, 95% CI 1.13–2.41), total cardiovascular events (HR 1.22, 95% CI 1.15–1.28) and all-cause mortality (HR 1.39, 95% CI 1.22–1.58). Women with a higher resting heart rate level of 80–89 bpm versus 60 bpm had a higher risk of total cardiovascular disease events (HR 1.17, 95% CI 1.07–1.24) and all-cause mortality (HR 1.21, 95% CI 1.07–1.35) compared to a resting heart rate less than 60 bpm. The risk was also present at higher heart rates (>90 bpm) for heart failure and sudden cardiac death. Conclusions: A resting heart rate that clinicians currently consider as ‘normal’ in the general population is specifically associated with the incidence of certain major cardiovascular diseases and death, with the risk starting at lower resting heart rate levels in men compared to women. Further research is required to evaluate whether interventions to lower resting heart rate are warranted to prevent disease. The study is registered at: clinicaltrials.gov (ID: NCT01947361)

Drug eluting balloons for de novo coronary lesions - a systematic review and meta-analysis

The role of drug-eluting balloons (DEB) is unclear. Increasing evidence has shown a benefit for the treatment of in-stent restenosis. Its effect on de novo coronary lesions is more controversial. Several smaller randomized trials found conflicting results

Body-weight and psychological well-being in the UK general population

Background: While the consequences of body weight for physical health are well explored, the evidence for psychological well-being is less straightforward. An instrumental variable approach is used to address the endogenous relationship between body weight and well-being in the UK general population. Methods: Data from the Health Survey for England (2003, 2004 and 2006) are used to fit linear and ordered probit instrument variable models for a sample of 13 862 individuals, with frequent white meat consumption instrumenting for body-weight. Non-linearities in the relationship, robustness to weak instruments and relaxation of strict exogeneity assumption are further examined. Results: Accounting for endogeneity and conditional on health a protective effect on well-being is observed. A unit increase in body mass index (BMI) improves General Health Questionnaire (GHQ) by 0.17 (95% CI: 0.02-0.31) points and reduces the probability of reporting very low GHQ by 2.5% (95% CI: 0.01-0.05). Empirical testing showed that the instrument performs well, with increased meat consumption adding 0.58 points (95% CI: 0.42-0.74) to ones' BMI. Conclusions: We present support for the jolly-fat hypothesis, however, caution is recommended in drawing inferences. Further research needs to resolve the mixed findings in the literature

The economic and health impact of rare diseases: A meta-analysis

Objective Lack of medical and scientific knowledge on rare diseases (RD) often translates into limited research on them and a subsequent lack of understanding of their economic impact. This meta-analysis aims to fill this gap by evaluating the economic impact of RDs and exploring potential factors associated with the societal burden of RD. Methods Studies published between January 2010 and February 2017 were identified by searches in the PubMed platform. Thirty eligible studies were identified for inclusion, and nineteen studies were included in the meta-analysis and outcomes were explored. The cost categories include direct healthcare costs, direct non-healthcare formal costs, and direct non-healthcare informal costs. The patients’ health-related quality of life (QoL) dimensions examined include EQ-5D scores, VAS scores and Barthel index, and the carers’ utility outcomes include EQ-5d scores, VAS scores and Zarit scale. Random effects meta-regression models were used for modelling the impact of study and societal characteristics on cost. Results Across all RDs, mean direct healthcare (DH) costs ($16,513) account for the majority of direct costs (mainly driven by drug costs), followed by mean direct healthcare informal (€15,557) and mean direct healthcare formal (€4,579) costs. Body system affected by the RD, Gross Domestic Product (GDP) per capita and public health expenditure in country of study were the most significant determinants in predicting cost. In regards to QoL outcomes, patients with musculoskeletal diseases seem to have the lowest quality of life across EQ-5D scores, VAS scores and Barthel index. The burden on caregivers seemed to be associated with Autoimmune, followed by Musculoskeletal and Respiratory conditions. Conclusions This meta-analysis highlights the significant burden of RDs on the health care system and explicitly provides evidence for the magnitude of this impact. Such estimates are necessary to further the debate on priority setting around RDs and their comparison with other chronic diseases. Nevertheless, the large degree of cost variability across RDs might suggest that the use of umbrella terms to raise awareness around RDs’ societal impact might not be warranted

Cleaning products and respiratory health outcomes in occupational cleaners: a systematic review and meta-analysis

There is consistent evidence of increased respiratory symptoms in occupational cleaners; however, uncertainty remains on type of respiratory health effects, underlying causal agents, mechanisms and respiratory phenotypes. We aimed to conduct a systematic review and if possible, a meta-analysis of the available literature to characterise and quantify the cleaning-related respiratory health effects. We searched MEDLINE and EMBASE databases and included studies that evaluated the association of any respiratory health outcome with exposure to cleaning occupation or products in occupational cleaners. A modified GRADE was used to appraise the quality of included studies. We retrieved 1124 articles, and after applying our inclusion criteria, 39 were selected for the systematic review. We performed a meta-analysis of the 21 studies evaluating asthma which showed a 50% increased pooled relative risk in cleaners (meta-relative risk (RR)=1.50; 95% CI 1.44 to 1.56). Population-based cross-sectional studies showed more stable associations with asthma risk. No evidence of atopic asthma as dominant phenotype emerged. Also, we estimated a 43% increased risk (meta-RR=1.43; 95% CI 1.31 to 1.56) of chronic obstructive pulmonary disease. Evidence for associations with bronchial-hyper-responsiveness, lung function decline, rhinitis, upper and lower respiratory tract symptoms was weaker. In our systematic review and meta-analysis, we found that working as a cleaner is associated with an increased risk of reversible and even irreversible obstructive airway diseases. All studies lacked quantitative exposure assessment to cleaning products; this would help elucidate underlying causal agents and mechanisms. Exposure control and respiratory surveillance among cleaners is warranted to prevent the associated respiratory health burden. Trial registration number: CRD4201705915

Non-invasive ventilation and clinical outcomes in cystic fibrosis: Findings from the UK CF registry

Background: Non-invasive ventilation (NIV) for respiratory failure and airway clearance is an established intervention in cystic fibrosis (CF), but its therapeutic benefit on lung function and survival remains under-investigated. Methods: Using data from the UK CF Registry between 2007 and 2015, we explored the patterns of NIV use, and assessed changes in mean percent predicted FEV1 (ppFEV1) prior to and after NIV use, and the survival of patients on NIV. Results: Among 11,079 patients, 1107 had at least one record of NIV treatment. Incidence and prevalence of NIV was lower in children and followed non-linear temporal patterns. Adjusting for other risk factors, ppFEV1 rose by 0.70 (95%CI: -0.83, 2.24) after first NIV use in children. In adults with a low ppFEV1 (<40%) at initiation of treatment, NIV increased mean ppFEV1 by 2.60 (95% CI: 0.93, 4.27). Our analysis showed that NIV initiation is associated with an increased risk of death/transplant in both children (HR = 2.47; 95%CI: 1.20–5.08) and adults (HR = 1.96; 95% CI: 1.63–2.36) but effect was attenuated in children with low ppFEV1 (<40%). Conclusions: NIV usage in CF improves spirometric values but does not benefit survival. Further studies are required to better understand survival outcomes and ultimately improve NIV outcomes in CF

Incidence and risk factors of cancer in individuals with cystic fibrosis in the UK; a case-control study.

To assess cancer incidence in the UK cystic fibrosis (CF) population and determine the associated risk factors, we undertook a nested case-control study of patients with CF, registered with the UK CF Registry. Each case with a first reported cancer between 1999 and 2017 was matched with up to 4 controls: by age (±2-years) and year of cancer diagnosis. Conditional logistic regressions were adjusted for sex, lung function (FEV1%), CF related diabetes (CFRD), F508del status, transplant status, DIOS, gastro-oesophageal reflux disease, meconium ileus, Pseudomonas aeruginosa infection, pancreatic insufficiency, proton pump inhibitor (PPI) use, IV antibiotic days and BMI. Results: From 12,886 registered patients, 146 (1.1%) cases of malignancy were identified with 14.3% of cases occurring post solid organ transplant. Site of primary cancer was available for 98 patients: 22% were gastro-intestinal in origin (77% lower, 23% upper GI), 13% skin, 13% breast and 11% lymphomas/leukaemia. In univariable analysis, transplantation increased the odds of reporting any cancer by 2.46 times (95%CI: 1.3-4.6). CFRD also increased the odds of reporting any cancer (OR 2.35; CI: 1.37-4.0) and PPI use (OR 2.0; CI 1.28-3.19). In the multivariable models significant associations with CFRD and transplant remained, while PA infection, PPI use and being overweight showed increased, but statistically insignificant risks. The incidence of GI cancer was strongly associated with CFRD (OR=4.04; 1.47-11.1). Conclusions: We observed a high incidence of lower GI cancers in our cohort which was significantly affected by the presence of CFRD. Screening for gastrointestinal cancers could benefit patients at higher risk