metabola krav. Tidigare arbete visade att både hospitaliseringar och förekomsten av diagnosen hjärtsvikt ökat bland unga patienter liksom kardiomyopati diagnoserna. Nyligen publicerade studier visade att mortaliteten hos patienter med hjärtsvikt fort-farande är hög.
Syfte: Validera kardiomyopatidiagnoserna i Västra Götaland. Undersöka
mortalitets-trender och risker för död över tid i olika åldersgrupper. Beskriva patienter <55 år avseende patientkarakteristika, utfall och mortalitetsrisker med detaljerad beskrivning av könsskillnader.
Metoder och Resultat: I delarbete I validerades kardiomyopatidiagnoserna i Västra
Götaland genom granskning av medicinska journaler på tre sjukhus från 1989 till 2009. Validiteten av diagnoserna var hög (86%) liksom användning av ultraljud som undersöknings metod (99.7%). I delarbete II användes patientregistret, dödsorsaksre-gistret och populationsredödsorsaksre-gistret. Vi fann överlag sjunkande mortalitet mellan tidspe-rioder 1987-2002 och 2003-2014, framförallt bland patienter <65år medan förbätt-ringen hos äldre var minimal. Mortalitetsrisken ökade framförallt hos patienter <65 år i samma tidsperioder. I delarbete III och IV har vi använt data från Rikssviktsregistret samt samma register som i delarbete II. Patienter <55 år hade högre förekomst av all samsjuklighet och dödlighet jämfört med kontroller. Obesitas, kardiomyopatier och kongenital hjärtsjukdom var vanligare hos patienter <55 år. Den högsta mortalitets-risken hittades hos de allra yngsta patienterna som också förlorade fl est levnadsår. Medianöverlevnaden vid till exempel 30 år var 56.3 år jämfört med kontrollernas 82.4 år vilket ger 26.1 förlorade levnadsår. Med åldern minskade mortalitetsrisken och de förlorade levnadsåren. Mortalitetsrisken hos patienterna jämfört med kontrollerna var nästan dubbelt så hög hos unga kvinnor som hos män. Förväntad livslängd hos kvin-nor är högre än hos män varför kvinkvin-nor förlorade fl er levnadsår än män. Komorbidite-ter, speciellt cancer, var associerad med ökad mortalitetsrisk hos båda könen.
Slutsatser: Vi fann hög validitet av kardiomyopatidiagnoserna, vilket stödjer
hypote-sen att ökning av sjukdomen möjligen har skett. Mortaliteten hos patienter med hjärt-svikt har förbättrats framförallt hos patienter <65 år, medan hos patienter som är äldre är förbättringen marginell. Jämfört med kontroller ses en ökning av mortalitetsrisken över tid, mest uttalad hos de yngsta patienterna. De allra yngsta patienterna hade högst mortalitetsrisk och förlorade levnadsår upp till 26 år i median, båda minskande med ökande ålder. Kvinnor med hjärtsvikt <55 år hade dubbel så hög mortalitetsrisk som män även om skillnaden inte var signifi kant.
ACKNOWLEDGEMENTS
I hereby want to express my sincere gratitude and appreciation to family, friends, col-leagues and co-workers involved in the work of this thesis. In particular I would like to thank:
Professor Maria Schaufelberger, my main supervisor for introducing me to the re-search world and giving me the chance to grow in my own way. Thank you for all the lessons! I higly value the advices, vast knowledge and all the time you invested!
Professor Annika Rosengren, my co-supervisor for shearing your enormous know-ledge of epidemiology, statistics and writing skills that have been helpful and valuable all the way.
Professor Yüksel Peker, my co-supervisor for your support and catching enthusiasm for research.
Professor Ulf Dahlström, Associate Professor Magnus Edner, Associate Professor
Urban Alehagen, Associate Professor Masuma Novak, Associate Professor Lena Björck and Sandra Lindström co-authors for encouraging and rewording co-operation
while working together on my thesis.
Tatiana Zverkova Sandström, co-author for your enormous patience and guidance in
statistics, nerveless for all nice talks and all your support on my way.
Professor Michael Fu, for your encouragement and valuable advices during my sci-entifi c and clinical work.
To all former and present fellow PhD students for all the creative and amazing time we spent together. Thanks for all your support, encouragement and laughters!
To Erik Thunström, for the enormous support and huge enthusiasm for research!
Sven-Eric Hägelind and Annika Odenstedt for your generous time and availability
during my learning process.
Eva Thydén and Ulrica Granberg-Forslund for all the administrative support during
my PhD period. Special thanks to Eva for the engagement and profesional help with the fi nal presentation of the this thesis.
Professor Mikael Dellborg, Head of the Research Unit at Sahlgrenska University Hos-pital/Östra that assured an excellent research milieu.
Associate Professor Helen Sjöland, Head of the department for Cardiology at Sahl-grenska University Hospital/Östra for all the support in my scientifi c determinations and providing PhD students research time and possibility to complete their studies.
Senior Professor Karl Swedberg for supporting my fi rst steps as a resident in cardiol-ogy and lighting the spark for research.
To all my friends, colleagues and co-workers at the Cardiology department and Medi-cal clinic at Sahlgrenska University Hospital/Östra for all your support!
To my friends Tanja and Hrvoje, Marija and Ante, Cristiana and Daniel, Mahia and
Tobbe, Camilla and Thomas for your support, all the valuable advices and most of all
the discussions, laughs and the time we have shared.
To my family ujko Ratko, ujko Ante, Birgitta, Tina och Daniel with their families for beliving in me and supporting me from the fi rst day in Sweden.
To my family in Croatia, especially my grandmother Marija for all the love and for teaching me patience and compassion for others.
My mother Angela, father Miki and brother Ivo Mise for your endless love and support in everything I decide to do! Thank you for teaching me perseverance and work ethic.
My beloved husband Toni, thank you for always believing in me, for all your patience, uncounditional support and love!
My wonderful children Klara, Emanuela and Vincent, you are my strength, my inspi-ration, my motivation, my everything!
The studies and the work with this thesis was supported by the Swedish Research Council, the Swedish Heart and Lung foundation, the Swedish state under the agree-ment concerning research and education of doctors, Västra Götaland Region, Gothen-burg Medical Society, Cardiology Research Foundation, Medicine Clinic, Sahlgrenska University Hospital/Östra.
REFERENCES
1. Hobbs FD, Kenkre JE, Roalfe AK, Davis RC, Hare R, Davies MK. Impact of heart failure and left ventricular systolic dysfunction on quality of life: a cross-sectional study compar-ing common chronic cardiac and medical disorders and a representative adult population. Eur Heart J. 2002;23(23):1867-76.
2. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European heart journal. 2016;37(27):2129-200.
3. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of conges-tive heart failure: the Framingham study. The New England journal of medicine. 1971;285(26):1441-6.
4. Harlan WR, oberman A, Grimm R, Rosati RA. Chronic congestive heart failure in coro-nary artery disease: clinical criteria. Annals of internal medicine. 1977;86(2):133-8. 5. Carlson KJ, Lee DC, Goroll AH, Leahy M, Johnson RA. An analysis of physicians’
rea-sons for prescribing long-term digitalis therapy in outpatients. Journal of chronic dis-eases. 1985;38(9):733-9.
6. Eriksson H, Caidahl K, Larsson B, Ohlson LO, Welin L, Wilhelmsen L, et al. Cardiac and pulmonary causes of dyspnoea--validation of a scoring test for clinical-epidemiological use: the Study of Men Born in 1913. European heart journal. 1987;8(9):1007-14. 7. Guidelines for the diagnosis of heart failure. The Task Force on Heart Failure of the
Eu-ropean Society of Cardiology. EuEu-ropean heart journal. 1995;16(6):741-51.
8. Roger VL. Epidemiology of heart failure. Circulation research. 2013;113(6):646-59. 9. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, et al. The
global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. Journal of the American College of Cardiology. 2014;63(12):1123-33.
10. Ryder S, Fox K, Rane P, Armstrong N, Wei CY, Deshpande S, et al. A Systematic Review of Direct Cardiovascular Event Costs: An International Perspective. PharmacoEconom-ics. 2019;37(7):895-919.
11. Metra M, Teerlink JR. Heart failure. Lancet (London, England). 2017;390(10106):1981-95.
12. Bleumink GS, Knetsch AM, Sturkenboom MC, Straus SM, Hofman A, Deckers JW, et al. Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prog-nosis of heart failure The Rotterdam Study. European heart journal. 2004;25(18):1614-9. 13. Paren P, Schaufelberger M, Bjorck L, Lappas G, Fu M, Rosengren A. Trends in preva-lence from 1990 to 2007 of patients hospitalized with heart failure in Sweden. European journal of heart failure. 2014;16(7):737-42.
14. Seferovic PM, Stoerk S, Filippatos G, Mareev V, Kavoliuniene A, Ristic AD, et al. Orga-nization of heart failure management in European Society of Cardiology member coun-tries: survey of the Heart Failure Association of the European Society of Cardiology in collaboration with the Heart Failure National Societies/Working Groups. European jour-nal of heart failure. 2013;15(9):947-59.
15. Zarrinkoub R, Wettermark B, Wändell P, Mejhert M, Szulkin R, Ljunggren G, et al. The epidemiology of heart failure, based on data for 2.1 million inhabitants in Sweden. Eur J Heart Fail. 2013.
16. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93(9):1137-46. 17. Barasa A, Schaufelberger M, Lappas G, Swedberg K, Dellborg M, Rosengren A. Heart
failure in young adults: 20-year trends in hospitalization, aetiology, and case fatality in Sweden. European heart journal. 2014;35(1):25-32.
18. http://www.who.int/nmh/publications/ncd-status-report-2014/en/ (2014, assessed 28 March 2018.
19. Kindblom JM, Bygdell M, Sonden A, Celind J, Rosengren A, Ohlsson C. BMI change during puberty and the risk of heart failure. Journal of internal medicine. 2018;283(6):558-67.
20. Chaparro MP, Ivarsson A, Koupil I, Nilsson K, Haggstrom J, de Luna X, et al. Regional inequalities in pre-pregnancy overweight and obesity in Sweden, 1992, 2000, and 2010. Scandinavian journal of public health. 2015;43(5):534-9.
21. Rosengren A, Aberg M, Robertson J, Waern M, Schaufelberger M, Kuhn G, et al. Body weight in adolescence and long-term risk of early heart failure in adulthood among men in Sweden. European heart journal. 2017;38(24):1926-33.
22. Robertson J, Schaufelberger M, Lindgren M, Adiels M, Schioler L, Toren K, et al. Higher Body Mass Index in Adolescence Predicts Cardiomyopathy Risk in Midlife. Circulation. 2019;140(2):117-25.
23. Shafazand M, Schaufelberger M, Lappas G, Swedberg K, Rosengren A. Survival trends in men and women with heart failure of ischaemic and non-ischaemic origin: data for the period 1987-2003 from the Swedish Hospital Discharge Registry. European heart journal. 2009;30(6):671-8.
24. Sidney S, Quesenberry CP, Jr., Jaffe MG, Sorel M, Nguyen-Huynh MN, Kushi LH, et al. Recent Trends in Cardiovascular Mortality in the United States and Public Health Goals. JAMA cardiology. 2016;1(5):594-9.
25. Taylor CJ, Ordonez-Mena JM, Roalfe AK, Lay-Flurrie S, Jones NR, Marshall T, et al. Trends in survival after a diagnosis of heart failure in the United Kingdom 2000-2017: population based cohort study. BMJ (Clinical research ed). 2019;364:l223.
26. Zarrinkoub R, Wettermark B, Wandell P, Mejhert M, Szulkin R, Ljunggren G, et al. The epidemiology of heart failure, based on data for 2.1 million inhabitants in Sweden. Euro-pean journal of heart failure. 2013;15(9):995-1002.
27. Lindmark K, Boman K, Olofsson M, Tornblom M, Levine A, Castelo-Branco A, et al. Epidemiology of heart failure and trends in diagnostic work-up: a retrospective, popula-tion-based cohort study in Sweden. Clinical epidemiology. 2019;11:231-44.
28. Redfi eld MM. Heart failure--an epidemic of uncertain proportions. The New England journal of medicine. 2002;347(18):1442-4.
29. Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. Journal of the American College of Cardiology. 2004;43(3):317-27.
30. Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. Journal of the American College of Cardiology. 2007;50(8):768-77.
31. Stalhammar J, Stern L, Linder R, Sherman S, Parikh R, Ariely R, et al. The burden of pre-served ejection fraction heart failure in a real-world Swedish patient population. Journal of medical economics. 2014;17(1):43-51.
32. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet (London, England). 2003;362(9386):777-81.
33. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, et al. Irbe-sartan in patients with heart failure and preserved ejection fraction. The New England journal of medicine. 2008;359(23):2456-67.
34. van Veldhuisen DJ, Cohen-Solal A, Bohm M, Anker SD, Babalis D, Roughton M, et al. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: Data From SENIORS (Study of Effects of Nebivolol In-tervention on Outcomes and Rehospitalization in Seniors With Heart Failure). Journal of the American College of Cardiology. 2009;53(23):2150-8.
35. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, et al. Spironolactone for heart failure with preserved ejection fraction. The New England journal of medicine. 2014;370(15):1383-92.
36. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an in-dividual patient-level analysis of double-blind randomized trials. European heart journal. 2018;39(1):26-35.
37. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. European heart journal. 2006;27(19):2338-45.
38. Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation. 2006;114(5):397-403.
39. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profi le of heart failure. Nature reviews Cardiology. 2011;8(1):30-41.
40. Jhund PS, Macintyre K, Simpson CR, Lewsey JD, Stewart S, Redpath A, et al. Long-term trends in fi rst hospitalization for heart failure and subsequent survival between 1986 and 2003: a population study of 5.1 million people. Circulation. 2009;119(4):515-23.
41. Bueno H, Ross JS, Wang Y, Chen J, Vidan MT, Normand SL, et al. Trends in length of stay and short-term outcomes among Medicare patients hospitalized for heart failure, 1993-2006. Jama. 2010;303(21):2141-7.
42. Crespo-Leiro MG, Anker SD, Maggioni AP, Coats AJ, Filippatos G, Ruschitzka F, et al. European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year follow-up outcomes and differences across regions. European journal of heart failure. 2016;18(6):613-25.
43. Wong CM, Hawkins NM, Ezekowitz JA, Jhund PS, Savu A, MacDonald MR, et al. Heart Failure in Young Adults Is Associated With High Mortality: A Contemporary Population-Level Analysis. The Canadian journal of cardiology. 2017;33(11):1472-7.
44. Global, regional, and national life expectancy, all-cause mortality, and cause-specifi c mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet (London, England). 2016;388(10053):1459-544.
45. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the Euro-pean Society of Cardiology (ESC). EuroEuro-pean heart journal. 2014;35(39):2733-79. 46. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, et al. Classifi cation
of the cardiomyopathies: a position statement from the European Society Of Cardiol-ogy Working Group on Myocardial and Pericardial Diseases. European heart journal. 2008;29(2):270-6.
47. Maggioni AP, Dahlstrom U, Filippatos G, Chioncel O, Leiro MC, Drozdz J, et al. EU-RObservational Research Programme: the Heart Failure Pilot Survey (ESC-HF Pilot). European journal of heart failure. 2010;12(10):1076-84.
48. Report of the WHO/ISFC task force on the defi nition and classifi cation of cardiomyopa-thies. British heart journal. 1980;44(6):672-3.
49. Hudson RE. The cardiomyopathies: order from chaos. The American journal of cardiol-ogy. 1970;25(1):70-7.
50. Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O’Connell J, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiol-ogy Task Force on the Defi nition and Classifi cation of cardiomyopathies. Circulation. 1996;93(5):841-2.
51. Thiene G, Corrado D, Basso C. Cardiomyopathies: is it time for a molecular classifi ca-tion? European heart journal. 2004;25(20):1772-5.
52. Chioncel O, Lainscak M, Seferovic PM, Anker SD, Crespo-Leiro MG, Harjola VP, et al. Epidemiology and one-year outcomes in patients with chronic heart failure and pre-served, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry. European journal of heart failure. 2017;19(12):1574-85.
53. The survival of patients with heart failure with preserved or reduced left ventricu-lar ejection fraction: an individual patient data meta-analysis. European heart journal. 2012;33(14):1750-7.
54. Wong CM, Hawkins NM, Jhund PS, MacDonald MR, Solomon SD, Granger CB, et al. Clinical characteristics and outcomes of young and very young adults with heart failure:
tality and Morbidity). Journal of the American College of Cardiology. 2013;62(20):1845-54.
55. Wong CM, Hawkins NM, Petrie MC, Jhund PS, Gardner RS, Ariti CA, et al. Heart failure in younger patients: the Meta-analysis Global Group in Chronic Heart Failure (MAG-GIC). European heart journal. 2014;35(39):2714-21.
56. Reijneveld SA. Age in epidemiological analysis. Journal of epidemiology and commu-nity health. 2003;57(6):397.
57. https://www.un.org/en/development/desa/population/publications/pdf/ageing/WorldPop-ulationAgeing2013.pdf.
58. Lund LH, Claggett B, Liu J, Lam CS, Jhund PS, Rosano GM, et al. Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesar-tan across the entire ejection fraction spectrum. European journal of heart failure. 2018. 59. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Colvin MM, et al. 2017 ACC/
AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Associa-tion Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e61.
60. Faris RF, Flather M, Purcell H, Poole-Wilson PA, Coats AJ. Diuretics for heart failure. The Cochrane database of systematic reviews. 2012(2):Cd003838.
61. Effects of enalapril on mortality in severe congestive heart failure. Results of the Coop-erative North Scandinavian Enalapril Survival Study (CONSENSUS). The New England journal of medicine. 1987;316(23):1429-35.
62. Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The New England journal of medicine. 1991;325(5):293-302.
63. Yusuf S, Pitt B, Davis CE, Hood WB, Jr., Cohn JN. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The New England journal of medicine. 1992;327(10):685-91.
64. The Cardiac Insuffi ciency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet (London, England). 1999;353(9146):9-13.
65. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. The New England journal of medicine. 1996;334(21):1349-55.
66. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet (London, England). 1999;353(9169):2001-7.
67. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. The New England journal of medicine. 2001;345(23):1667-75. 68. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of
spi-ronolactone on morbidity and mortality in patients with severe heart failure. Random-ized Aldactone Evaluation Study Investigators. The New England journal of medicine. 1999;341(10):709-17.
69. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplere-none in patients with systolic heart failure and mild symptoms. The New England journal of medicine. 2011;364(1):11-21.
70. Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet (London, England). 2010;376(9744):875-85.
71. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angioten-sin-neprilysin inhibition versus enalapril in heart failure. The New England journal of medicine. 2014;371(11):993-1004.
72. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, et al. Ef-fect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. The New England journal of medicine. 1986;314(24):1547-52.
73. The effect of digoxin on mortality and morbidity in patients with heart failure. The New England journal of medicine. 1997;336(8):525-33.
74. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. The New England journal of medicine. 2005;352(15):1539-49.
75. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, et al. Amiodarone or