umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Biobank Research.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
Show others and affiliations
2017 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 6, no 12, article id e007160Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Aortic stenosis (AS) has different clinical phenotypes, including AS with or without concomitant coronary artery disease (CAD). It is unknown whether these phenotypes share the same risk factors. In particular, lipoprotein(a) [Lp(a)] and apolipoproteins (Apo) are associated with AS, but it is unknown whether these associations differ among phenotypes. In this prospective analysis we examined the impact of Lp(a) and Apo in subgroups of patients with AS.

METHODS AND RESULTS: We identified 336 patients (mean age at survey 56.7 years, 48% female) who underwent surgery for AS after a median 10.9 years (interquartile range 9.3 years), participants in 1 of 3 large population surveys. For each patient, 2 matched referents were allocated. Lp(a) and Apo were analyzed in the baseline samples. Uni- and multivariable logistic regression analyses were used to estimate risks related to a 1 (ln) standard deviation increase in Lp(a) and the ratio of Apo B to Apo A1 (Apo B/A1 ratio). High levels of Lp(a) predicted surgery for AS in 203 patients with concomitant CAD (odds ratio [95% confidence intervals]) (1.29 [1.07-1.55]), but not in 132 patients without CAD (1.04 [0.83-1.29]) in the fully adjusted model. Similarly, a high Apo B/A1 ratio predicted surgery in patients with concomitant CAD (1.43 [1.16-1.76]) but not in those without CAD (0.87 [0.69-1.10]).

CONCLUSIONS: High levels of Lp(a) and a high Apo B/A1 ratio were associated with surgery for AS in patients with concomitant CAD but not in those with isolated AS. This finding may lead to a new avenue of research for targeted risk factor interventions in this population.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017. Vol. 6, no 12, article id e007160
Keywords [en]
aortic stenosis, aortic valve surgery, apolipoproteins, lipoprotein(a), prospective cohort study, risk markers
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:umu:diva-143323DOI: 10.1161/JAHA.117.007160ISI: 000418951100046PubMedID: 29246959OAI: oai:DiVA.org:umu-143323DiVA, id: diva2:1168354
Available from: 2017-12-20 Created: 2017-12-20 Last updated: 2019-05-21Bibliographically approved
In thesis
1. Cardiovascular risk factors in aortic stenosis
Open this publication in new window or tab >>Cardiovascular risk factors in aortic stenosis
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Kardiovaskulära riskfaktorer vid aortastenos
Abstract [en]

Introduction: Aortic stenosis (AS) is the most common hemodynamic significant valvular heart disease and affects about 2% of the population. The incidence increases with age. When symptoms of the stenotic aortic valve disease eventually occur the 2-year mortality exceeds 50%. Aortic valve replacement (AVR) by surgery or by catheter intervention is the only known treatment. The causes of AS are only partly known, despite that the disease has been known since the beginning of 17th century. In younger individuals, a bicuspid valve is present in about 80% of the cases. The traditional cardiovascular risk-factors for ischemic heart disease have been linked to AS, and the histology of the stenotic aortic valve and the atherosclerotic plaques shares several features such as inflammation, lipid deposition and calcification. High levels of the lipoprotein Lp(a) has been linked to both atherosclerosis and AS, and a causal relation with AS is supported by Mandelian randomisation. End-stage renal disease is associated with increased risk of AS but if early impairment increases the risk is not known.

Material and methods: We identified 799 patients with surgery for valvular heart disease and/or disease of the ascending aorta with a prior participation in one of three large population based health surveys in northern Sweden (Västerbotten Intervention Program [VIP], MONItoring Of trends and Determinants in CArdivascular Disease survey [MONICA], and the Mammary Screening Project [MSP]). For each case, four referents matched by age, gender, type and date of survey, and geographical area were randomly selected. From the health surveys, data on cardiovascular risk-factors and health history as well as measurements of anthropometry, blood pressure, glucose and cholesterol levels were retrieved. Each case was carefully validated and data from pre- and perioperative assessments were collected. The presence of coronary artery disease (CAD) was determined from the preoperative coronary angiogram. Apolipoproteins B and A1, Lp(a), creatinine and cystatin C were analysed in samples obtained at the initial survey. As this is a matched case-referent study where cases and referents had the same follow-up duration within strata, logistic regression using the conditional maximum likelihood routine designed for matched analysis was used to estimate odds ratios (ORs) with 95% confidence intervals. Studied variables were tested in uni- and multivariable models.

Results: Paper 1: Of the identified 799 cases with questionnaires, 322 were primarily operated for AS, 91 for aortic regurgitation, 181 for mitral regurgitation, 131 for disease of ascending aorta, 52 for CAD (and for concomitant valvular or aortic disease). The remaining 22 had various indications for valvular heart surgery and were excluded. Altogether 38% of patients were women. Aortic stenosis: Hypertension (OR 1.87 [1.37–2.54]), diabetes (OR 1.78 [1.01–3.11]) and total cholesterol (OR 1.64 [1.07–2.49]) were associated with future AVR. After exclusion of concomitant CAD, none of the these risk-factors remained significant. Aortic regurgitation: None of the cardiovascular risk-factors was associated with increased risk for aortic regurgitation demanding surgery, whereas high levels of cholesterol were associated with reduced risk for surgery (OR 0.29 [0.12–0.71]). Mitral regurgitation: High levels of cholesterol associated with surgery for mitral regurgitation (OR 1.74 [1.01–3.00]), but not in those without CAD. Disease of the ascending aorta: Hypertension (OR 2.42 [1.44–4.06]) and previous smoking (OR 1.97 (1.12–3.49]) related to increased risk for surgery of the ascending aorta, whereas diabetes was inversely associated with surgery (OR 0.09 [0.01–0.73]). Excluding CAD, only diabetes remained protective (OR 0.24 [0.07–0.81]). Paper 2: 322 patients underwent AVR, and 70 had surgery before the age of 60 years and 252 had surgery after 60 years of age. After exclusion of patients with CAD, 49 and 82 patients remained in these age groups. Arterial hypertension associated with future AVR in those operated before the age of 60 years regardless of concomitant CAD or not (OR 3.40 [1.45–7.93] and OR 5.88 [1.46–23.72]). In those older than 60 years at surgery and with concomitant CAD, all traditional cardiovascular risk factors associated with surgery, but in those without concomitant CAD, only impaired fasting glucose (IFG) was associated with surgery (OR 3.22 [1.19–8.76]). Paper 3: 336 patients having surgery for AS. Lipoprotein(a) [Lp(a)] was independently associated with surgery in those with concomitant CAD (OR 1.29 [1.07–1.55]), but not in those without CAD. A high Apo B/A1 ratio was associated with surgery in patients with CAD (OR 1.43 [1.16–1.76]), but not in those without. Paper 4: The same cohort as in paper 3 was examined. Renal function was estimated by the ratio between glomerular filtration rates (eGFR) obtained from cystatin C and creatinine, and a low ratio indicates early impairment of renal function (“shrunken pore syndrome”). A high ratio independently associated with lower risk for future AVR (OR 0.84 [0.73–0.97]). Protective effect was seen in women but not in men (0.74 [0.60–0.92] and 0.93 [0.76 [0.76–1.13], respectively). After stratification for CAD, the association remained significant in women with CAD but not in men with CAD (0.60 [0.44–0.83] and 0.96 [0.76 [0.75–1.23], respectively).

Conclusion: The traditional cardiovascular risk-factors associated with future surgery for valvular heart disease and for surgery of the ascending aorta, however with a clear difference if there was concomitant CAD or not. Arterial hypertension was a major risk factor for surgery for AS in younger patients without CAD, whereas impaired fasting glucose (IFG) associated with surgery in elderly patients without CAD. High levels of Lp(a) and a high Apo B/A1 ratio were associated with future AVR only in patients with concomitant CAD. Similarly, early renal impairment expressed as low ratio of eGFR by cystatin C and by creatinine (“shrunken pore”) associated with future AVR.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2018. p. 63
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1941
Keywords
Valvular heart disease, aortic stenosis, bicuspid aortic valve, cardiovascular risk factors, hypertension, diabetes mellitus, smoking, hypercholesterolemia, obesity, shrunken pore, renal failure
National Category
Cardiac and Cardiovascular Systems
Research subject
Epidemiology; Cardiology
Identifiers
urn:nbn:se:umu:diva-144306 (URN)978-91-7601-825-5 (ISBN)
Public defence
2018-02-23, Sal B, NUS 1D-Tandläkarhögskolan, Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2018-02-02 Created: 2018-01-31 Last updated: 2018-06-09Bibliographically approved
2. Metabolic risk markers and relative survival in patients with aortic stenosis requiring surgery
Open this publication in new window or tab >>Metabolic risk markers and relative survival in patients with aortic stenosis requiring surgery
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Aortic stenosis (AS) is the most common valve disorder requiring surgery in developed countries. The etiology of AS is only partly known.  Identification of new biomarkers in prospective studies could lead to novel insights in the etiology of AS, and possibly lead to improved clinical management. Long term observed survival after aortic valve surgery has improved over the last decades despite an ageing population presenting with more comorbidities. Whether this is reflected in improved relative survival is not known. We evaluated if biomarkers associated prospectively with AS requiring surgery, and if these associations differed between genders, time to surgery and the presence of coronary artery disease (CAD). We also assessed long term observed and relative survival after aortic valve surgery with and without concomitant coronary artery by-pass surgery (CABG).

Methods and results: Study I: We prospectively studied the impact of lipoprotein (a)(Lp[a]) and apolipoproteins (Apo) in subgroups of AS. During a 20-year period, 336 patients with prior participation in large population-based surveys in northern Sweden were operated due to AS plus CABG when indicated. For each case two referents were matched. Data from the baseline survey were collected and included data on cardiovascular risk factors, health history, measurements of anthropometry, blood pressure, blood glucose and blood lipid levels were retrieved. Data from pre- and perioperative assessments were also collected. The presence of CAD was determined from the coronary angiogram. Elevated levels of Lp(a) and an elevated Apo B/Apo A 1 ratio were independently associated with future surgery for AS, but only in patients with concomitant CAD (OR 1.29, 95 % CI 1.07-1.55 and 1.43, 95 % CI 1.16-1.76 respectively). Study II: The same patient cohort as in study I was used. A panel of 92 cardiovascular candidate proteins were analysed with the multiplex proximity extension assay in samples obtained at baseline. Six circulating proteins (growth differentiation factor 15[GDF-15], galectin-4, von Willebrand factor [vWF], interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9, [PCSK9]) were associated with future surgery for AS in patients with concurrent CAD (ORs ranged from 1.25 to 1.37 per SD increase in the protein signal). In the validation study with 106 additional cases, the association of all but one, (interleukin 17 receptor A), of these proteins were replicated in patients with AS and concurrent CAD but not in those without concurrent CAD. Study III: In the same patient cohort as in study I and II we evaluated if troponin T (TnT) and C-reactive protein (CRP) associated prospectively with future surgery for AS. TnT was independently associated with surgery for AS in patients both with (OR 1.22, 95 % CI 1.02-1.46) and without concomitant CAD (1.39, 95% CI 1.05-1.84). CRP was not associated with surgery for AS (OR 1.06, 95 % CI 0.92-1.23). Study IV: 4970 patients between 2005 and 2016 from three Swedish heart surgery centres, undergoing aortic valve replacement (AVR) due to either AS or aortic regurgitation in conjunction with CABG when indicated, were followed up. All-cause mortality, as well as both observed and relative survival, was analysed with focus on age, sex, type of valve prosthesis and the impact of concomitant CABG. Median follow-up was 4.7 years (2.3-7.6). 30-day mortality was 2.3 %. Long-term survival with 30-day mortality excluded was 96.6 %, 82.7 %, 57.6 % after 1, 5 and 10 years respectively. Relative survival rates (adjusting for the background mortality in the general Swedish population based on age, sex and year) were 99.6 %, 99.5 % and 90.6 % after 1, 5 and 10 years respectively. Age had a negative influence on observed survival (p<0.001) but was associated with better relative survival (relative mortality rate [RMR] 0.74, 95 % CI 0.71 - 0.77). Women had a lower observed mortality than men (p<0.001) but a lower relative survival (RMR 1.17, 95 % CI 1.02-1.35). Combined surgery (AVR+CABG) was not significantly associated with higher mortality (p=0.43) in a multivariable adjusted analysis. The presence of bicuspid morphology was associated with lower observed mortality compared with tricuspid valve, and a relative survival matching that in the general population.

Conclusion: I. Plasma levels of Lp(a) and the Apo B/Apo A 1 ratio were independently associated with future surgery for AS but only in patients with concomitant CAD. This finding suggests that patients with AS have different phenotypes and may open a new avenue of research on targeted risk factor interventions in this population. II. Five circulating proteins – GDF-15, galectin-4, vWF, transferrin receptor protein 1, and PCSK9 – were associated with the need for aortic valve surgery several years later. The role of these proteins should be investigated in future studies. III. Elevated plasma levels of TnT were independently associated with future surgery for AS, irrespective of the presence of concomitant CAD, which could indicate that the myocardium is subject to mechanical stress already in the subclinical stage of AS. This may be used as a clinical tool for identification of patients with subclinical AS who could benefit from early intervention. Elevated CRP levels did not associate with future AVR. IV. Relative survival following AVR was particularly good in the elderly matching that in the general population underlining the benefits of aortic valve surgery in properly selected patients. Women had decreased relative survival compared to men. This should be explored in future studies. Adding CABG to an AVR procedure was not associated with increased risk. Bicuspid valve morphology was associated with lower observed mortality compared with tricuspid valve morphology, and with a relative survival matching that of the general population.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2019. p. 85
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2028
Keywords
aortic stenosis, aortic valve surgery, coronary artery disease, prospective cohort study, risk markers, lipoprotein (a), apolipoproteins, proteomics, troponin T, C-reactive protein, relative survival, observed survival
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:umu:diva-159032 (URN)978-91-7855-051-7 (ISBN)
Public defence
2019-06-14, Sal B, Unod T, 9 tr, Norrlands Universitetssjukhus, 13:00 (English)
Opponent
Supervisors
Available from: 2019-05-24 Created: 2019-05-16 Last updated: 2019-05-24Bibliographically approved

Open Access in DiVA

fulltext(984 kB)68 downloads
File information
File name FULLTEXT01.pdfFile size 984 kBChecksum SHA-512
5bb81fd27a1a0a4f7292f4be1fd8fd96982ca7d757e1ace1d488b87690f3624c7bf90b8c1db77df7224f77c863165ef54a87bdd3e795c9d236069092fc0494e2
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Ljungberg, JohanHolmgren, AndersBergdahl, Ingvar A.Hultdin, JohanNorberg, MargaretaNäslund, UlfJohansson, BengtSöderberg, Stefan

Search in DiVA

By author/editor
Ljungberg, JohanHolmgren, AndersBergdahl, Ingvar A.Hultdin, JohanNorberg, MargaretaNäslund, UlfJohansson, BengtSöderberg, Stefan
By organisation
CardiologyMedicineDepartment of Biobank ResearchClinical chemistryEpidemiology and Global Health
In the same journal
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
Cardiac and Cardiovascular Systems

Search outside of DiVA

GoogleGoogle Scholar
Total: 68 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 267 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf