OBJECTIVES: Due to age-related differences in aortic valve structure, it is likely that the pathophysiology of aortic stenosis (AS) and associated risk factors differ between age groups. Here we prospectively studied the influence of traditional cardiovascular risk factors on AS development requiring surgery among patients without concomitant coronary artery disease (CAD) and stratified for age.

DESIGN: This study included 322 patients, who had prior to surgery for AS participated in population-based surveys, and 131 of them had no visible CAD upon preoperative coronary angiogram. For each case, we selected four referents matched for age, gender, and geographic area. To identify predictors for surgery, we used multivariable conditional logistic regression with a model including arterial hypertension (or measured blood pressure and antihypertensive medication), cholesterol levels, diabetes, body mass index (BMI), and smoking.

RESULTS: In patients without CAD, future surgery for AS was associated with arterial hypertension and elevated levels of diastolic blood pressure in patients younger than 60 years at surgery (odds ratio [95% confidence interval]), (3.40 [1.45-7.93] and 1.60 [1.09-2.37], respectively), and with only impaired fasting glucose tolerance in patients 60 years or older at surgery (3.22 [1.19-8.76]).

CONCLUSION: Arterial hypertension and elevated diastolic blood pressure are associated with a risk for AS requiring surgery in subjects below 60 years of age. Strict blood pressure control in this group is strongly advocated to avoid other cardiovascular diseases correlated to hypertension. If hypertension and elevated diastolic blood pressure are risk factors for developing AS requiring surgery need further investigations. Notably, elevated fasting glucose levels were related to AS requiring surgery in older adults without concomitant CAD.

Recently, a new approach was proposed to detect mild impairment in renal function: a reduced ratio between estimated glomerular filtration rate (eGFR) calculated by cystatin C and eGFR calculated by creatinine. We aimed to evaluate if this ratio is associated with aortic stenosis (AS) requiring surgery. We identified 336 patients that first participated in population surveys and later underwent surgery for AS (median age [interquartile range] 59.8 [10.3] years at survey and 68.3 [12.7] at surgery, 48% females). For each patient, two matched referents were allocated. Cystatin C and creatinine were determined in stored plasma. eGFR(cystatin C) and eGFR(creatinine) and their ratio were estimated. Conditional logistic regression analyses were used to estimate the risk (odds ratio (OR) with [95% confidence interval (CI)]) related to one (ln) standard deviation increase in the ratio between eGFR(cystatin C) and eGFR(creatinine). A high ratio was associated with lower risk for AS requiring surgery (OR [95% CI]) (OR 0.84 [0.73-0.97]), especially in women (0.74 [0.60-0.92] vs. 0.93 [0.76-1.13] in men). After further stratification for coronary artery disease (CAD), the association remained in women with CAD but not in women without CAD (0.60 [0.44-0.83] and 0.89 [0.65-1.23], respectively). In conclusion, a high ratio between eGFR(cystatin C) and eGFR(creatinine) was associated with lower risk for surgery for AS, especially in women. Mild impairment of renal function is thus associated with future risk for AS requiring surgery.

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.

Background: Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case-control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights. Methods: Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study. Results: Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease. Conclusions: We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.

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.

Background: Risk factors for developing heart valve and ascending aortic disease are based mainly on retrospective data. To elucidate these factors in a prospective manner, we have performed a nested case-referent study using data from large, population-based surveys. Methods and Results: A total of 777 patients operated for heart valve disease or disease of the ascending aorta had previously participated in population-based health surveys in Northern Sweden. Median time (interquartile range) from survey to surgery was 10.5 (9.0) years. Primary indications for surgery were aortic stenosis (41%), aortic regurgitation (12%), mitral regurgitation (23%), and dilatation/dissection of the ascending aorta (17%). For each case, referents were allocated, matched for age, sex, and geographical area. In multivariable models, surgery for aortic stenosis was predicted by hypertension, high cholesterol levels, diabetes mellitus, and active smoking. Surgery for aortic regurgitation was associated with a low cholesterol level, whereas a high cholesterol level predicted surgery for mitral regurgitation. Hypertension, blood pressure, and previous smoking predicted surgery for disease of the ascending aorta whereas diabetes mellitus was associated with reduced risk. After exclusion of cases with coronary atherosclerosis, only the inverse associations between cholesterol and aortic regurgitation and between diabetes mellitus and disease of the ascending aorta remained. Conclusions: This is the first truly prospective study of traditional cardiovascular risk factors and their association with valvular heart disease and disease of the ascending aorta. We confirm the strong association between traditional risk factors and aortic stenosis, but only in patients with concomitant coronary artery disease. In isolated valvular heart disease, the impact of traditional risk factors is varying.

Background:  Due to age-related differences in aortic valve structure, it is likely that the pathophysiology of aortic stenosis and associated risk factors differ between age groups. Here we prospectively studied the influence of traditional cardiovascular risk factors on aortic stenosis development among patients without concomitant coronary artery disease, and stratified for age. 

Methods: This study included 131 patients from previous population-based surveys, who underwent surgery for aortic stenosis and had no visible coronary arteriosclerosis upon preoperative coronary angiogram. The younger group included 49 patients of <60 years old at surgery: median age, 54.4 years; median follow-up, 8.7 years. The older group included 82 patients of ≥60 years old at surgery: median age, 71.3 years; median follow-up, 11.0 years. For each case, we selected four referents matched for age, gender, and geographic area. To identify predictors for surgery, we used multivariable conditional logistic regression with a model including arterial hypertension, cholesterol levels, diabetes, BMI, and smoking. 

Results:  Future surgery for aortic stenosis was associated with arterial hypertension and elevated levels of diastolic blood pressure in the younger group (odds ratio, 3.40; 95% confidence interval, 1.45–7.93, and odds ratio 1,60; 95% confidence interval, 1.09–2.37, respectively), and with only impaired fasting glucose tolerance in the older group (odds ratio, 3.22; 95% confidence interval, 1.19–8.76). 

Conclusion: Arterial hypertension and elevated diastolic blood pressure are associated with a risk for aortic stenosis development in subjects below 60 years of age. Strict blood pressure control in this group are strongly advocated to avoid other cardiovascular diseases correlated to hypertension. If hypertension and elevated diastolic blood pressure are risk for developing aortic stenosis need further investigations. Notably, elevated fasting glucose levels were related to aortic stenosis in older adults without concomitant coronary artery disease. 

Introduction 

Renal insufficiency is a known risk factor for cardiovascular disease. However, it is unknown if early impairment in renal function is associated with increased risk for aortic stenosis (AS). Recently a new approach was proposed to detect early impairment in renal function by using the ratio between glomerular filtration rate (GFR) calculated by cystatin C and GFR calculated by creatinine. 

Purpose 

To evaluate if the ratio between GFR cystatin C and GFR creatinine is associated with increased risk for AS requiring surgery and further, to evaluate if the ratio associates with survival. 

Methods 

We identified 334 patients that underwent surgery for AS after participation in population surveys (median age (interquartile range) 59.4 (10.3) years at survey and 68.3 (12.7) at surgery, 48% females). For each patient, two matched referents were allocated. Circulating levels of cystatin C and creatinine were determined at baseline (survey). Estimated glomerular filtration rates (eGFR) were calculated using the CAPA and Lund-Malmö-Revised formulas. Uni- and multivariable conditional logistic regression analyses were used to estimate the risk (odds ratio (OR) with [95% confidence interval]) related to one (ln) standard deviation increase in cystatin C, creatinine, eGFR cystatin C, eGFR creatinine, and in the ratio between eGFR cystatin C and eGFR creatinine, respectively. 

Results 

A high ratio was associated with lower risk for AS requiring surgery (OR 0.84 [0.73–0.97]). After stratification for sex, this 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 further stratification for CAD, the association remained in women with CAD, but the effect was not seen in men with CAD (0.60 [0.44–0.83] and 0.96 [0.76 [0.75–1.23]). A high ratio was associated with longer survival in the entire cohort (HR 0.84 [0.75–0.95]). 

Conclusion 

A high ratio between eGFR based on cystatin C and eGFR based on creatinine was associated with lower risk for surgery for AS in those with CAD with a clear sex-difference. Early renal impairment is thus associated with future risk for AS requiring surgery. Further, a high ratio relates to longer survival.