Cardiovascular disease and all-cause mortality Influence of fitness, fatness and genetic factors. Gabriel Högström - PDF

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Cardiovascular disease and all-cause mortality Influence of fitness, fatness and genetic factors Gabriel Högström Institutionen för samhällsmedicin och rehabilitering Umeå 2017 Responsible publisher under

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Cardiovascular disease and all-cause mortality Influence of fitness, fatness and genetic factors Gabriel Högström Institutionen för samhällsmedicin och rehabilitering Umeå 2017 Responsible publisher under Swedish law: the Dean of the Medical Faculty This work is protected by the Swedish Copyright Legislation (Act 1960:729) ISBN: ISSN: Elektronisk version tillgänglig på Tryck/Printed by: UmU-Tryckservice, Umeå, Jan Umeå, Sverige 2017 Till farmor TABLE OF CONTENTS TABLE OF CONTENTS... I ABSTRACT... III ABBREVIATIONS... V ORIGINAL PAPERS... VII SAMMANFATTNING PÅ SVENSKA... VIII INTRODUCTION... 1 OBESITY... 3 Definitions of obesity... 3 Epidemiology... 4 The pathophysiology of obesity... 5 DIABETES Overview Definition and diagnostic criteria Epidemiology Risk factors for type II diabetes Pathophysiology of diabetes ATHEROSCLEROSIS Introduction Fat metabolism The development of an atherosclerotic plaque Risk factors for atherosclerosis Cardiovascular disease AEROBIC FITNESS Introduction Definitions of fitness Aerobic fitness and physical activity: two sides of the same coin? The genetic component of fitness Low aerobic fitness as a risk factor for disease Protective mechanisms of high aerobic fitness FAT BUT FIT Aerobic fitness vs. obesity Metabolic fitness vs. obesity RATIONALE AND AIM I Project rationale Aims MATERIALS AND METHODS Databases Study populations Baseline testing procedures Data collection during follow-up Statistical methods RESULTS Results of Study I Results of Study II Results of Study III Results of Study IV DISCUSSION Aerobic fitness as a life-long indicator of health Protective mechanisms of aerobic fitness Fat but fit Aerobic fitness and diabetes Aerobic fitness versus physical activity Limitations Clinical implications Future research SUMMARY AND CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES... 68!! II ABSTRACT Background Low aerobic fitness and obesity are associated with atherosclerosis, and therefore greatly increase the risk of cardiovascular disease (CVD) and early death. It has long been known that atherosclerosis my begin early in life. Despite this fact, it remains unknown how obesity and aerobic fitness early in life influence the risks of atherosclerosis, CVD and death. Furthermore, it is unknown whether high aerobic fitness can compensate for the risks associated with obesity, and how genetic confounding affects the relationships of aerobic fitness with CVD and all-cause mortality. Thus, the main aims of this thesis were to investigate the associations of aerobic fitness in late adolescence with myocardial infarction (Study I), stroke (Study II) and all-cause mortality (Study III), and how genetic confounding influences the relationships of aerobic fitness with CVD, diabetes and death (Study IV). Methods The study population comprised up to 1.3 million men who participated in mandatory Swedish military conscription. During conscription, all conscripts underwent highly standardized tests to assess aerobic fitness, body mass index, blood pressure and cognitive function. A physician also examined all conscripts. Data on subjects diagnoses, death and socioeconomic status during follow-up were retrieved using record linkage. Subjects were subsequently followed until the study endpoint, date of death or date of any outcome of interest. Associations between baseline variables and the risks of adverse outcomes were assessed using Cox s proportional hazard models. Genetic confounding of the relationships between aerobic fitness and diabetes, CVD and death was assessed using a twin population and a paired logistic regression model. Results In Study I, low aerobic fitness at conscription was associated with an increased risk of myocardial infarction (MI) during follow-up (hazard ratio [HR] 0.82 per standard deviation increase). Similarly, in Study II, high aerobic fitness reduced the risk of stroke (HR 0.84 for ischemic stroke, HR 0.82 for hemorrhagic stroke; P for all), and obesity was associated with an increased risk of stroke (HR 1.15 for ischemic stroke, HR 1.18 for hemorrhagic stroke; P for all). In Study III, high aerobic fitness was also associated with reduced all-cause mortality later in life (HR 0.49, P III 0.001). High aerobic fitness exerted the strongest protection against death from substance and alcohol abuse, suicide and trauma (HRs 0.20, 0.41 and 0.52, respectively; P for all). Obese individuals with aerobic fitness were at higher risk of MI and all-cause mortality than were normal-weight individuals with low fitness (Studies I and III). In Study IV, fit twins had no reduced risk of CVD or death during follow-up compared with their unfit twin siblings (odds ratio 1.11, 95% confidence interval ), regardless of how large the difference in fitness was. However, the fitter twins were protected against diabetes during follow-up. Conclusions Already early in life, aerobic fitness is a strong predictor of CVD and allcause mortality later in life. In contrast to the fat but fit hypothesis, it seems that high aerobic fitness cannot fully compensate for the risks associated with obesity. The associations of aerobic fitness with CVD and allcause mortality appear to be mediated by genetic factors. Together, these findings have implications for the view of aerobic fitness as a causal risk factor for CVD and early death. IV ABBREVIATIONS AFT Accelerated failure time AGE Advanced glycation end product ANN Artificial neural network ApoB Apolipoprotein B BMI Body mass index BPA Bisphenol A camp Cyclic adenosine monophosphate CI Confidence interval CT Computed tomography CVD Cardiovascular disease DXA Dual-energy X-ray absorptiometry DZ Dizygotic ECG - Electrocardiography FFA Free fatty acid GWAS Genome-wide association study HDL High-density lipoprotein HDR Hospital Discharge Registry HR Hazard ratio ICD International Classification of Diseases IGF Insulin-like growth factor IL Interleukin LDL Low-density lipoprotein V LISA Longitudinal Integration Database for Health Insurance and Labor Market Studies LPL Lipoprotein lipase MCSR Military Conscription Service Registry MI Myocardial infarction MZ Monozygotic NCDR National Cause of Death Registry OR Odds ratio PAR Population attributable risk PPAR-α Peroxisome proliferator-activated receptor alpha SAT Subcutaneous adipose tissue SD Standard deviation SEK Swedish crown T2DM Type II diabetes mellitus TG Triglyceride TNF-α Tumor necrosis factor-alpha VAT Visceral adipose tissue VEGF Vascular endothelial growth factor VLDL Very-low-density lipoprotein VO 2max Maximal oxygen consumption WC Waist circumference WHO World Health Organization W MAX Maximal Watts per second VI ORIGINAL PAPERS I. Högström G, Nordström A, Nordström P (2014) High aerobic fitness in late adolescence is associated with a reduced risk of myocardial infarction later in life: a nationwide cohort study in men. Eur Heart J, (44): p II. Högström G, Nordström A, Eriksson M, Nordström P (2015) Risk factors assessed in adolescence and the later risk of stroke in men: a 33-year follow-up study. Cerebrovasc Dis, (1): p III. Högström G, Nordström A, Nordström P (2015) Aerobic fitness in late adolescence and the risk of early death: a prospective cohort study of 1.3 million Swedish men. Int J Epidemiol, 2015: 17(24) p IV. Högström G, Nordström A, Nordström P (2016) The risks of Cardiovascular Disease and Death in Twin Pairs with Discrepant Aerobic Fitness: A nationawide Cohort Study. Submitted for publication. VII SAMMANFATTNING PÅ SVENSKA Hjärt-kärlsjukdom är idag den vanligaste dödsorsaken och förorsakar också flest fall av långsiktig funktionsnedsättning. Den vanligaste formen av hjärt-kärlsjukdom är ischemisk hjärtsjukdom. Akut ischemisk hjärtsjukdom, eller hjärtinfarkt, inträffar när ett av hjärtats kranskärl täpps igen. Slaganfall, eller stroke, är den näst vanligaste formen av hjärtkärlsjukdom, vilken också leder till flest fall av permanent funktionsnedsättning. En stroke kan antingen bero på att ett blodkärl i hjärnan täpps igen, en så kallad ischemisk stroke, eller att ett blodkärl i hjärnan brister och börja blöda, en så kallad hemorragisk stroke. En majoritet av all hjärt-kärlsjukdom beror på ateroskleros, vilket avser inlagring av fett i och förkalkning av blodkärlen. Ateroskleros är en process som sannolikt börjar redan i tonåren för att sedan utvecklas i tysthet och göra sig hörd först senare i livet, i form av exempelvis en hjärtinfarkt eller en stroke. Låg fysisk prestationsförmåga, alltså låg kondition, är en av de starkaste riskfaktorerna för ateroskleros, hjärt-kärlsjukdom och för tidigt död. Likaså är fetma förknippat med accelererad ateroskleros, förhöjd risk att drabbas av hjärtkärlsjukdom och för tidig död. Trots att ateroskleros är ett förlopp som börjar så tidigt som i tonåren är det idag otillräckligt undersökt hur låg kondition samt fetma tidigt i livet interagerar och påverkar risken för hjärt-kärlsjukdom och tidig död. Vidare har det de senaste åren spekulerats i huruvida riskökningen för sjukdom och död förknippad med fetma kan kompenseras av en hög kondition. Denna hypotes har kallats fat but fit och gör gällande att en person med fetma som har en hög kondition har samma eller till och med lägre risk för hjärt-kärlsjukdom och död i jämförelse med en normalviktig person med låg kondition. Underlaget för denna hypotes har emellertid flera brister och ytterligare studier med mer precisa mått och större studiebefolkning vore av värde. Slutligen så används ofta kondition som ett riskmått, och används då ofta som en uppskattning av fysisk aktivitet. Vidare har studier som undersökt kopplingen mellan kondition och sjukdom översatt sina resultat till rekommendationer gällande fysisk aktivitet. Tvillingstudier har dock indikerat att konditionen har en påtaglig ärftlig komponent. Om sambandet mellan kondition och sjukdom samt död också kan förklaras av denna ärftliga komponent är idag okänt. VIII Syftet med den här avhandlingen var att undersöka tre huvudsakliga frågeställningar: I. Hur låg kondition och övervikt tidigt i livet påverkar risken för hjärt-kärlsjukdom och för tidig död senare i livet. II. Skyddar hög kondition överviktiga individer från att drabbas av hjärt-kärlsjukdom och att dö jämfört med normalviktiga personer med låg kondition? III. Hur påverkar ärftliga faktorer sambandet mellan kondition, hjärt-kärlsjukdom, diabetes och död? Samtliga studier i denna avhandling har utgått från det svenska mönstringsregistret. Under mönstringen fick alla rekryter genomgå flertalet tester och undersökningar, bland annat mättes kondition, kroppsmasseindex (BMI), muskelstyrka, intelligens, blodtryck och en läkarundersökning genomfördes. I studierna som ligger till grund för denna avhandling har upp till 1.3 miljoner av de personer som deltog i mönstringen studerats. Testresultaten från mönstringen har kopplats till risken för att insjukna i hjärtinfarkt (Studie I), stroke (Studie II) och risken för att dö (Studie III). För att undersöka arvets inverkan på sambandet mellan kondition, sjukdom och död jämfördes tvillingpar där tvillingsyskonen hade olika kondition. Den vältränade tvillingen jämfördes med sitt mindre vältränade syskon med avseende på risken att insjukna i typ-2 diabetes, hjärt-kärlsjukdom eller att dö (Studie IV). I Studie I konstaterades att hög kondition vid mönstringen skyddade mot hjärtinfarkt senare i livet (HR 0.82 per ökning av en standardavvikelse, P 0.05). I Studie II kunde vi visa att kondition tidigt i livet också skyddade mot både ischemisk och hemorragisk stroke (HR 0.84 och 0.82 per standardavvikelse för ischemisk respektive hemorragisk stroke, P 0.05 för båda). I studie III jämfördes den femtedel av rekryterna med högst kondition med femtedelen som hade lägst kondition. De mest vältränade hade 51 % lägre risk att dö i jämförelse med de minst vältränade. I både Studie I och III jämfördes obesa individer (med ett BMI 30) som hade hög kondition med normalviktiga individer (med ett BMI mellan 18.5 och 25) med avseende på risk för hjärtinfarkt och död. I båda studierna hade de överviktiga individerna högre risk än de normalviktiga. I Studie IV jämfördes vältränade tvillingsyskon med sina mindre vältrande tvillingsyskon med avseende på risken för hjärt-kärlsjukdom, diabetes och död. Vältränade tvillingar hade inte en lägre risk för IX hjärtkärlsjukdom och död än sina otränade tvillingsyskon. Detta samband kvarstod när bara tvillingar med stor skillnad i kondition jämfördes. De mer vältränade tvillingarna var dock skyddade mot diabetes under uppföljningstiden. Sammanfattningsvis har studierna i denna avhandling visat att låg kondition och fetma redan tidigt i livet är kopplat till risken för hjärtkärlsjukdom. Hypotesen fat but fit kunde inte bekräftas vare sig för risken att drabbas av hjärtinfarkt eller att dö i förtid. Resultaten från tvillingparen antyder vidare att kopplingen mellan kondition och risken för hjärt-kärlsjukdom samt död förmedlas via arvet. Studien visade också att hög kondition skyddar mot diabetes oberoende av arvet. Dessa fynd har implikationer för det förmodade kausala sambandet mellan fysisk kapacitet, sjukdom och död. X INTRODUCTION Cardiovascular disease (CVD) is the world s leading cause of death and the leading contributor to long-term disability. [1] Low aerobic fitness and obesity are two of the strongest predictors of CVD and all-cause mortality. [2, 3] It is presently unknown how aerobic fitness early in life is associated with the risks of CVD and death later in life, and whether high aerobic fitness can compensate for obesity in terms of the risks of disease and death. Finally, the importance of genetic heritage with respect to the associations of aerobic fitness with CVD and all-cause mortality is unclear. Aerobic fitness is defined as an individual s ability to perform a strenuous activity, usually determined by a maximal performance exercise test. Apart from characterizing an individual s physical status, aerobic fitness is also a strong indicator of health. In selected studies, aerobic fitness outperformed all classical risk factors in the prediction of CVD and allcause mortality. [2] Obesity, defined as body mass index (BMI) 30 kg/m 2, is also a strong risk factor for CVD and all-cause mortality. [3] Atherosclerosis is the underlying cause of most cases of CVD. This inflammatory and progressive condition likely begins early in life; it is unknown, however, how obesity and low aerobic fitness early in life impact the risks of CVD and death later in life. Whereas low aerobic fitness increases the risks of disease and death, high aerobic fitness exerts a protective effect. The protective effect of high aerobic fitness in relation to obesity has been the topic of several recent studies. The central question has been whether high aerobic fitness can fully compensate for the hazards of obesity. Selected studies have found that high aerobic fitness does indeed compensate for obesity, launching the fat but fit hypothesis. [4-9] Although some studies have delved into this matter, population-wide studies with reliable measurements of both obesity and aerobic fitness are lacking. Aerobic fitness is a commonly used risk factor, often used synonymously with habitual physical activity. However, twin studies have demonstrated that fitness is largely a genetic trait, with little influence from physical activity. [10, 11] A remaining question is how genetic factors influence the associations of aerobic fitness with CVD and death. 1 The present thesis aimed to answer three principal questions: I. How do aerobic fitness and obesity in late adolescence influence the risks of CVD and all-cause mortality later in life? Specifically, how does aerobic fitness relate to myocardial infarction (MI), stroke and all-cause mortality? II. Is the fat but fit hypothesis true, i.e., can high aerobic fitness compensate for the hazards of obesity? III. How does genetic confounding affect the relationships of aerobic fitness with CVD and all-cause mortality? 2 OBESITY Definitions of obesity The World Health Organization s (WHO s) definition of excess body fat or obesity is based on the BMI, which is expressed as body weight (in kilograms) divided by height (in meters) squared. BMIs 18.5 to 24.9 kg/m 2 are considered to represent normal weight, BMIs 25 kg/m 2 are considered to represent overweight and BMIs 30 kg/m 2 are considered to represent obesity. Obesity can be divided further into grade I ( kg/m 2 ), grade II ( kg/m 2 ) and grade III ( 40 kg/m 2 ; severe obesity). [12] It is important to note that some studies have suggested that the categories specified above are not suitable for certain ethnicities and age groups. [13, 14] Obesity can also be defined based on the amount of fat tissue located in the abdominal region, often referred to as abdominal fat mass. Waist circumference (WC) is an easily accessible measure for the assessment of abdominal fat mass. According to the National Institute of Health, WCs 102 cm for men and 88 cm for women constitute obesity. [15] The relationship between waist and hip circumferences can also be used to define obesity. Waist-to-hip ratios 0.9 and 0.85 for men and women, respectively, serve as the central obesity criteria released by the WHO. [16] Although definitions based on total fat mass and specific fat placement are yet to be formulated, several methods do exist that provide very accurate measurements of body fatness and its location. Among these, dual-energy X-ray absorptiometry (DEXA) is considered to be the gold standard. Using X-rays of different energies, a DXA scan provides very precise measurement of body fat percentage and bone mineral density; it can also be used to assess visceral and gynoid fat mass. [17] Other methods include magnetic resonance imaging and computed tomography (CT), both of which illustrate the anatomical distribution of fat, bioelectric impedance and the plethysmograph ( BodPod ). [18, 19] 3 Figure 1. Results from different measurements of body composition components: a DXAscan (left) and an MRI scan (right) that assess the amount and placement of VAT, SAT, lean soft tissue (LST) and skeletal muscle (SM) among others. Image source: Prado et al., 2014, J Parenter Enteral Nutr. [20] Epidemiology Obesity is becoming more common. Between 1980 and 2008, the global mean BMI increased steadily: 0.4 kg/m 2 per decade for men and 0.5 kg/m 2 for women. During this time period, the number of obese adult individuals almost doubled. [21] Trends have been similar in Sweden, where the prevalence of obesity has doubled since [22] This global trend of obesity affects not only adults, but also children, in whom the prevalence of obesity has increased 60% since 1990 and is expected to reach a 116% increase in [23] Previously a phenomenon of the industrialized world, childhood obesity now affects children in developing countries as well. In 2010, an estimated 43 million preschool children were overweight or obese, of whom 35 million lived in the developing world. Relative increases in the number of overweight children are also greater in developing countries; in Africa, a 49% increase is projected to occur by [23] The wave of childhood obesity is a cause for concern, as excess body fat early in life often perpetuates into adulthood. [24] In light of these developments, the WHO has declared that obesity is a global epidemic. [25] 4 The fear of obesity stems from its close relation to disease. Strong, graded associations have been observed between obesity and type II diabetes, CVD, depression, dementia and several forms of cancer. [26-30] By extension, these associations translate into increased all-
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