Unfolding lipid profile- and sex-paradoxes in the epidemiology of subarachnoid haemorrhage

Introduction In cardiovascular diseases, high total cholesterol (TC) and male sex usually associate with elevated risk. However, studies of aneurysmal subarachnoid haemorrhages (aSAHs), report paradoxically that low TC and female sex elevate aSAH risk. Additionally, no population-based studies on the risk factors behind the most-fatal aSAH: sudden-death aSAHs, exist. This thesis aims to unfold these two paradoxes and aims to characterize the risk factors of sudden-death aSAHs using population-based cohort that includes also autopsy records of all sudden-death individuals. Methods A systematic review and meta-analysis identified the key studies included in the literature review and in hypothesis formation. The Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) check-list guided the reporting, and according to the Cochrane Collaboration guidelines, the review article focused on qualitative analysis because of high study heterogeneity. In cohort studies we followed prospectively 65 521 population-based FINRISK participants from medical registries since 1972 until the end of 2014. Participants enrolled at five-year intervals and provided 543 incident aSAHs, of which 98 were sudden-death aSAHs confirmed by computer tomography, spinal tap, or at autopsy. Baseline measurements at enrolment provided risk factors and potential confounders for the analyses and multiple imputations supplemented the missing values. The Cox regression, adjusted for the main risk factors and confounders, provided hazard ratios and a platform for population-attributable fraction, multiplicative effect modification, and additive effect modification analysis. Competing risks analysis mapped the associations between risk factors and aSAH during a long follow-up. Results Our systematic review found many high-risk-of-bias studies describing that low TC elevates aSAH risk, but it detected only two low-risk-of-bias studies, both indicating that high TC elevates aSAH risk. Our cohort study, which includes more-detailed lipid profile analyses, supports the review’s findings and suggests that the adverse lipid-profile plays a considerable role in aSAH development especially in men. Smoking had a linear dose-dependent association with aSAH in both sexes, and ex-smokers had reduced aSAH risk when compared to smokers. However, although smoking elevated aSAH risk more in women, female never-smokers were not at elevated risk, indicating that in women effect modification between sex and smoking explained the elevated risk. Along with high systolic blood pressure, smoking also elevates sudden-death aSAH risk more than it elevates risk for hospitalized aSAH. Conclusions Methodological limitations in earlier studies explain at least in part the paradoxical, risk-increasing association between low TC and aSAH. An adverse lipid profile is an important aSAH risk factor and accounts for a major fraction of all aSAHs in men. Vulnerability to smoking explains at least in part the paradoxically higher aSAH risk in women observed earlier. All levels of smoking elevate aSAH risk, and reducing or quitting smoking both reduce the risk. Future studies should focus on clarifying whether improving the lipid-profile reduces aSAH risk also in those carrying an unruptured intracranial aneurysm. In addition, they should study the reasons behind women´s vulnerability to smoking. Because a severe risk-factor profile elevates sudden-death aSAH risk more than it elevates hospitalized aSAH, hospital-based aSAH studies may underestimate the role played by risk factors. Public health policies focusing on reduction in classic cardiovascular risk factors at population level are likely to reduce both hospitalized and sudden-death aSAH incidence.Johdanto Kohonneen kokonaiskolesterolin ja miessukupuolen on usein kuvattu liittyvän suurentuneeseen sydän- ja verisuonitautiriskiin. Kirjallisuus kuitenkin paradoksaalisesti kuvaa näiden tekijöiden suojaavan sydän- ja verisuonitauteihin kuuluvalta aneurysmaattiselta lukinkalvonalaiselta verenvuodolta (aSAV). Myöskään vaarallisimman, äkkikuolemaan johtavan aSAV:n riskitekijöistä ei ole väestötason julkaisuja. Tämä väitöskirja pyrki selvittämään mainittujen paradoksien taustoja sekä ruumiinavaustietoja hyödyntäen kartoittamaan väestötasolla äkkikuolemaan johtavan aSAV:n riskitekijöitä. Menetelmät Ensimmäisessä osatyössä artikkelien systemaattinen katsaus tunnisti väitöskirjan kannalta tärkeimmät artikkelit ja loi pohjan hypoteesien muodostamiselle. Artikkelien suurten keskinäisten erojen vuoksi katsaus keskittyi Cochrane-verkoston suositusten mukaan laadulliseen tarkasteluun. Tulokset raportoitiin systemaattisten katsausten ja meta-analyysien raportointisuosituksen (PRISMA) mukaisesti. Kohorttitutkimuksissa seurasimme terveydenhuollon rekistereistä 65 521 henkilöä, jotka osallistuivat FINRISK-tutkimukseen vuosien 1972 ja 2014 välillä. Uusi kohortti kerättiin joka viides vuosi, ja koko seurannan aikana tunnistimme 543 aSAV:a, joista 98 johti äkkikuolemaan. Äkkikuolemaan johtaneet aSAV:t tunnistettiin tietokonetomografialla, lumbaalipunktiolla tai ruumiinavaustiedoista. Riskitekijät mitattiin seurannan alussa ja tutkimuksessa huomioitiin sekä aSAV:n tunnetut riskitekijät, että mahdolliset sekoittavat tekijät. Puuttuvat riskitekijätiedot täydennettiin tarvittaessa moni-imputaatiomentelmällä. Aineiston analyysissä käytettiin Coxin mallia, josta johdettiin riskitekijöiden hasardisuhde-estimaatit, väestön riskiosuus sekä multiplikatiiviset ja additiiviset efektin muunnokset, joilla tutkittiin riskitekijöiden vaikutuksen eroa miesten ja naisten välillä. Pitkän seuranta-ajan vuoksi analyysejä täydennettiin kilpailevien riskien mallilla, joka huomioi muista kuin aSAV:sta johtuneet kuolemat seurannan aikana. Tulokset Systemaattisessa katsauksessa havaittiin, että suuren harhariskin tutkimukset raportoivat aSAV:n riskitekijäksi etupäässä matalan kolesterolin, kun taas pienen harhariskin tutkimukset raportoivat riskitekijäksi korkean kolesterolin. Kohorttitutkimuksessamme, jossa tarkasteltiin kattavasti lipidiprofiilia, havaittiin että epäedullinen lipidiprofiili (korkea LDL ja matala HDL) on merkittävä aSAV:n riskitekijä etenkin miehillä. Tupakointimäärällä oli lineaarinen yhteys aSAV:in ilmaantuvuuteen sekä miehillä että naisilla ja riski lisääntyi mitä enemmän osallistujat polttivat, kun taas tupakoinnin lopettaneilla aSAV-riski oli seurannan aikana pienempi kuin tupakoijilla. Lisäksi havaitsimme, että tupakointi lisäsi naisten aSAV-riskiä enemmän kuin miehillä, eikä tupakoimattomien naisten aSAV-riski ollut koholla tupakoimattomiin miehiin verrattuna. Tämä viittaisi siihen, että sukupuoli muuntaa tupakan ja aSAV:n välistä yhteyttä ja että tämä yhteys on voimakkaampi naisilla. Lisäksi tupakointi ja korkea verenpaine lisäsivät äkkikuolemaan johtavaa aSAV-riskiä enemmän kuin sairaalahoitoon johtavaa aSAV-riskiä. Johtopäätökset Aiemmin havaittu paradoksaalinen yhteys matalan kolesterolin ja aSAV:n välillä selittyy ainakin osittain aikaisempien tutkimusten puutteellisilla tutkimusmenetelmillä. Epäedullinen lipidiprofiili lisäsi aSAV-riskiä sekä miehillä että naisilla ja etenkin miehillä sen riskiosuus väestössä oli huomattava. Tulevien tutkimusten tulisi selvittää, voidaanko epäedullista lipidiprofiilia parantamalla vähentää aSAV-riskiä myös potilailla, joilla aneurysma on jo todettu. Naisten herkkyys tupakan haitoille selittää ainakin osittain aiemmissa tutkimuksissa havaitun naisten suurentuneen aSAV-riskin. Jatkotutkimusten tulisi kartoittaa syytä miksi tupakka lisää naisten aSAV-riskiä. Koska epäedullinen riskitekijäprofiili lisää äkkikuolemaan johtavan aSAV:n riskiä enemmän kuin sairaalaan johtavan aSAV:n riskiä, saattavat vain sairaala-aineiston sisältävät tutkimukset aliarvioida riskitekijöiden roolin. Kansanterveyspoliittiset päätökset, jotka johtavat klassisten sydän- ja verisuonitautien riskitekijöiden vähenemiseen väestötasolla, johtavat todennäköisesti niin äkkikuolemaan kuin sairaalahoitoon johtavan aSAV:n esiintyvyyden pienenemiseen

Comment on "A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk"

A 27-protein signature has been proposed to predict cardiovascular disease, but its applicability in clinical decision-making remains unclear

Adverse lipid profile elevates risk for subarachnoid hemorrhage : A prospective population-based cohort study

Background and aims: Studies report that both high and low total cholesterol (TC) elevates SAH risk. There are few prospective studies on high-density lipoproteins (HDL-C) and low-density lipoproteins (LDL-C), and apparently none concerns apolipoproteins A and B. We aimed to clarify the association between lipid profile and SAH risk. Methods: The National FINRISK study provided risk-factor data recorded at enrolment between 1972 and 2007. During 1.52 million person-years of follow-up until 2014, 543 individuals suffered from incident hospitalized SAH or outside-hospital-fatal SAH. Cox proportional hazards model was used to calculate the hazard ratios and multiple imputation predicted ApoA1, ApoB, and LDL-C values for cohorts from a time before apolipoprotein-measurement methods were available. Results: One SD elevation (1.28 mmol/l) in TC elevated SAH risk in men (hazard ratio (HR) 1.15 (95% CIs 1.00-1.32)). Low HDL-C levels increased SAH risk, as each SD decrease (0.37 mmol/l) in HDL-C raised the risk in women (HR 1.29 (95% CIs 1.07-1.55)) and men (HR 1.20 (95% CIs 1.14-1.27)). Each SD increase (0.29 g/l) in ApoA1 decreased SAH risk in women (HR 0.85 (95% CIs 0.74-0.97)) and men (HR 0.88 (95% CIs 0.76-1.02)). LDL-C (SD 1.07 mmol/l) and ApoB (SD 0.28 g/l) elevated SAH risk in men with HR 1.15 (95% CIs 1.01-1.31) and HR 1.26 (95% CIs 1.10-1.44) per one SD increase. Age did not change these findings. Conclusions: An adverse lipid profile seems to elevate SAH risk similar to its effect in other cardiovascular diseases, especially in men. Whether SAH incidence diminishes with increasing statin use remains to be studied. (C) 2018 Elsevier B.V. All rights reserved.Peer reviewe

Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases

Publisher Copyright: © 2022, The Author(s).Immune system and blood–brain barrier dysfunction are implicated in the development of Alzheimer’s and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827 immune system- and blood–brain barrier-related biomarkers and identified 127 potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-β, tau and α-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n = 339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer’s disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49–0.88, P = 0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases.Peer reviewe

Systematic comparison of family history and polygenic risk across 24 common diseases

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Cholesterol as a Risk Factor for Subarachnoid Hemorrhage : A Systematic Review

Background The role played by total cholesterol (TC) in risk for subarachnoid hemorrhage (SAH) is unclear because studies report both high and low TC each as a risk factor. We performed a systematic review to clarify associations between lipid profile and SAH. Methods Our literature search comprised Pubmed, Scopus, and Cochrane Library databases with no language, publication year, or study type limitations. The Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) checklist guided our reporting. Data forms adapted from the Critical Appraisal Skills Program (CASP), and Cochrane Collaboration guidelines provided a platform for risk-of-bias evaluation. We used a random effects model to calculate pooled estimates and assessed heterogeneity with I-2-statistics. Results Of the final 21 studies reviewed, 12 were prospective and 9 retrospective. All studies assessed TC, four assessed HDL, and none LDL in risk for SAH. Heterogeneity among all, retrospective, and Asian studies was high (I-2 = 79.5%, I-2 = 89.0%, and I-2 = 84.3%) and considerable in prospective (I-2 = 46.0%). We therefore focused on qualitative analysis and found that only two studies had a low risk of bias. According to these studies high TC increases risk for SAH in men, whereas the role of HDL remained unclear. Conclusion The low-risk-of-bias studies suggest that elevated TC levels elevate risk for SAH in men. Due to the high prevalence of hypercholesterolemia, population attributable risk (PAR) of hypercholesterolemia may exceed the PARs of smoking and hypertension in men. Apart from diabetes and obesity, the risk-factor profile of SAH seems to resemble that of other cerebrovascular diseases, at least in men.Peer reviewe

Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c : The Whitehall II Cohort Study

Background: It is unclear whether replacing oral glucose tolerance test (OGTT) with hemoglobin A1c (HbA1c) measurement for diagnosing diabetes is justified. We aimed to assess the proportion of OGTT-diagnosed diabetes cases that can be confirmed by HbA1c and to examine whether individuals with OGTT diagnosis but nondiagnostic HbA1c are at higher risk of macrovascular and microvascular disease. Methods: Participants were 5773 men and women from the population-based Whitehall II prospective cohort study in the United Kingdom. New OGTT diabetes cases diagnosed in clinical examinations in 2002 to 2004 and 2007 to 2009 were assessed for HbA1c confirmation (>= 6.5%) in these and subsequent clinical examinations in 2012 to 2013 and 2015 to 2016. All participants were followed up for major cardiovascular events through linkage to electronic health records until 2017 and for incident chronic kidney disease (estimated glomerular filtration ratePeer reviewe

Modifications to residential neighbourhood characteristics and risk of 79 common health conditions: a prospective cohort study.

BACKGROUND: Observational studies have identified a link between unfavourable neighbourhood characteristics and increased risk of morbidity, but it is unclear whether changes in neighbourhoods affect future disease risk. We used a data-driven approach to assess the impact of neighbourhood modification on 79 health outcomes. METHODS: In this prospective cohort study, we used pooled, individual-level data from two Finnish cohort studies: the Health and Social Support study and the Finnish Public Sector study. Neighbourhood characteristics (mean educational level, median income, and employment rate of residents, and neighbourhood green space) and individual lifestyle factors of community-dwelling individuals were assessed at baseline (at different waves starting between 1998 and 2013). We repeated assessment of neighbourhood characteristics and lifestyle factors approximately 5 years from each baseline assessment, after which follow-up began for health conditions diagnosed according to the WHO International Classification of Diseases for 79 common health conditions using linkage to electronic health records. We used Cox proportional hazard regression models to compute adjusted hazard ratios (HRs) of incident disease associated with neighbourhood characteristics and changes in neighbourhood characteristics over time and logistic regression analysis to compute adjusted odds of association between changes in neighbourhood characteristics and individual lifestyle factors. FINDINGS: 114 786 individuals (87 012 [75·8%] women; mean age 44·4 years [SD 11·1]) had complete data and were included in this cohort study. During 1·17 million person-years at risk, we recorded 164 368 new-onset health conditions and 3438 deaths. Favourable changes in neighbourhood characteristics were associated with reduced risk of all-cause mortality and incidence of 19 specific health conditions. Unfavourable changes were correspondingly associated with increased risk of mortality and 27 specific health conditions. Among participants who did not move residence during the observation period, relative to individuals who continually lived in disadvantaged neighbourhoods, those who experienced favourable modifications in neighbourhood characteristics had a lower risk of future diabetes (HR 0·84, 95% CI 0·75-0·93), stroke (0·49, 0·29-0·83), skin disease (0·72, 0·53-0·97), and osteoarthritis (0·87, 0·77-0·99). Living in a neighbourhood with improving characteristics was also associated with improvements in individual-level health-related lifestyle factors. Among participants who lived in advantaged residential environments at baseline, unfavourable changes in neighbourhood characteristics were associated with an increased risk of diabetes, stroke, skin disease, and osteoarthritis compared with individuals who lived in advantaged neighbourhoods throughout the study period. INTERPRETATION: Favourable modifications to residential neighbourhoods showed robust, longitudinal associations with a range of improvements in health outcomes, including improved health behaviours and reduced risk of cardiometabolic, infectious, and orthopaedic conditions. FUNDING: UK Medical Research Council, US National Institute on Aging, NordForsk, and Academy of Finland

Long‐term risk of dementia following hospitalization due to physical diseases: A multicohort study

Introduction Conventional risk factors targeted by prevention (e.g., low education, smoking, and obesity) are associated with a 1.2‐ to 2‐fold increased risk of dementia. It is unclear whether having a physical disease is an equally important risk factor for dementia. Methods In this exploratory multicohort study of 283,414 community‐dwelling participants, we examined 22 common hospital‐treated physical diseases as risk factors for dementia. Results During a median follow‐up of 19 years, a total of 3416 participants developed dementia. Those who had erysipelas (hazard ratio = 1.82; 95% confidence interval = 1.53 to 2.17), hypothyroidism (1.94; 1.59 to 2.38), myocardial infarction (1.41; 1.20 to 1.64), ischemic heart disease (1.32; 1.18 to 1.49), cerebral infarction (2.44; 2.14 to 2.77), duodenal ulcers (1.88; 1.42 to 2.49), gastritis and duodenitis (1.82; 1.46 to 2.27), or osteoporosis (2.38; 1.75 to 3.23) were at a significantly increased risk of dementia. These associations were not explained by conventional risk factors or reverse causation. Discussion In addition to conventional risk factors, several physical diseases may increase the long‐term risk of dementia.Peer reviewe