Abstract
Background
There is currently no medical therapy that can slow down/stop the progression of aortic stenosis (AS). Novel drugs lowering lipoprotein(a) (Lp[a]), a proinflammatory particle linked to AS development, are currently under evaluation, but the proportion of patients with AS and elevated Lp(a) who might benefit from such therapy is not known.
Objectives
The authors sought to characterize the prevalence of high Lp(a) in patients with AS to determine the role of future Lp(a)-lowering therapies.
Methods
In a nonselected Canadian population of AS patients seen in our specialized valve clinic, we assessed Lp(a) levels. High Lp(a) level was defined as an Lp(a) ≥100 nmol/L as per the Canadian Cardiovascular Society’s Lipid Guidelines.
Results
Lp(a) levels were measured in 162 patients (mean age: 75 ± 10 years, 43% female, mean pressure gradient: 29 ± 14 mm Hg). Mean Lp(a) was 69 ± 79 nmol/L (median: 24 nmol/L, IQR: 19-91 nmol/L), and 39 patients (24%) had a high Lp(a) level. There were no differences in the mean Lp(a) or in the proportion of high Lp(a) levels with respect to sex, age, or AS severity (all P > 0.20).
Conclusions
In this cross-sectional series of unselected AS patients followed in a valve clinic, only 1 in every 4 patients had a significantly elevated Lp(a) level. Novel Lp(a)-lowering therapies may have limited applicability to most patients with AS and highlight the need for further research into understanding the pathophysiology of AS and developing medical therapies targeting different pathways.
Key words: aortic stenosis, lipoprotein (a)
Central Illustration
Aortic stenosis (AS) is the most common form of valvular heart disease in developed countries.1 As the disease prevalence is expected to continue rising, so too will the number of patients requiring surgical or transcatheter valve intervention. AS is linked to inflammation and cardiovascular risk factors, including hypercholesterolemia, in situ cholesterol deposition, and low-density lipoprotein oxidation, but the current therapeutic options for hyperlipidemia—statin medications—have been shown to be ineffective in preventing AS progression.2, 3, 4, 5, 6
Lipoprotein(a) (Lp[a]) is a low-density lipoprotein that is genetically determined and associated with inflammation, atherogenesis, calcification, and thrombosis.7 Elevated levels of Lp(a) are increasingly being recognized as a risk factor for atherosclerotic cardiovascular disease.8, 9, 10 Lp(a) and its encoding gene have now been well established as an independent risk factor for AS.11, 12, 13 Beyond AS prevalence, Lp(a) may potentially increase the likelihood of AS progression, as suggested in a recent meta-analysis.11 Critically, standard medications for hypercholesterolemia, including statins, are ineffective in reducing Lp(a) levels, with only proprotein convertase subtilisin/kexin type 9 inhibitors having some lowering effect, albeit modest.14, 15, 16, 17 The development of novel Lp(a)-lowering therapies might allow for preventative treatment of AS and are currently being evaluated in randomized controlled trials. Previous population studies have suggested that approximately 25% of individuals have a clinically significant Lp(a) level,18 but in patients with AS, this prevalence is unknown. Characterizing this prevalence is of utmost importance to determine the magnitude of the AS population that might potentially benefit from novel Lp(a)-lowering agents and understand the generalizability of ongoing randomized controlled trials. In the present study, we evaluated the distribution of Lp(a) levels in an unselected cohort of patients seen in our valve clinic and investigated the impact of age, sex, and AS severity.
Methods
Study population
We measured Lp(a) levels in consecutive AS patients referred to the University of Ottawa Heart Institute valve clinic (a tertiary center located in Ottawa, Ontario, Canada, providing cardiac care to approximately 1.5 million inhabitants) irrespective of disease severity and symptoms. All patients had a clinical evaluation and comprehensive transthoracic echocardiogram within 6 weeks. Exclusion criteria were rheumatic disease, a history of radiotherapy, or prior infective endocarditis. Clinical and echocardiographic information as presented in Table 1 was extracted from clinical notes. The study was approved by our ethics review board, and all patients signed an informed consent form.
Table 1.
Baseline Medical Clinical and Echocardiographic Results of the Population Overall and According to Lipoprotein (a) (Lp[a]) Levels (Lower or ≥100 nmol/L)
| Overall (n = 162) | Low Lp(a) (n = 123) | High Lp(a) (n = 39) | P Value | |
|---|---|---|---|---|
| Age, y | 75 ± 10 | 74 ± 10 | 76 ± 9 | 0.23 |
| Female | 69 (43%) | 50 (41%) | 19 (49%) | 0.46 |
| Smoker | 74 (46%) | 60 (49%) | 14 (36%) | 0.20 |
| Dyslipidemia | 81 (50%) | 64 (52%) | 17 (44%) | 0.46 |
| Diabetes | 40 (25%) | 34 (28%) | 6 (15%) | 0.14 |
| Hypertension | 105 (65%) | 78 (63%) | 27 (69%) | 0.57 |
| Prior acute coronary syndrome | 39 (24%) | 29 (24%) | 10 (26%) | 0.83 |
| Stroke or transient ischemic attack | 20 (12%) | 14 (11%) | 6 (15%) | 0.58 |
| Peripheral arterial disease | 9 (6%) | 7 (6%) | 2 (5%) | 1.00 |
| Lung disease | 32 (20%) | 24 (20%) | 8 (21%) | 1.00 |
| Atrial fibrillation | 24 (15%) | 19 (15%) | 5 (13%) | 0.80 |
| Creatinine, μmol/L | 90 ± 35 | 92 ± 38 | 84 ± 25 | 0.25 |
| Left ventricular ejection fraction <50% | 10 (6%) | 7 (5%) | 3 (8%) | 0.45 |
| Mean pressure gradient, mm Hg | 29 ± 14 | 31 ± 14 | 27 ± 12 | 0.21 |
| Aortic valve area, cm2 | 1.05 ± 0.25 | 1.05 ± 0.28 | 1.07 ± 0.26 | 0.42 |
Values are mean ± SD or n (%).
Lp(a) measurement
Lp(a) levels were measured using particle-enhanced immunoturbidometric assay, which was run in cobas 8000 c 502 module machines and expressed in nmol/L. All assays were performed in similar conditions using a morning blood draw with fasting for at least 8 hours. Occasionally, the lab would report Lp(a) levels as >240 nmol/L or <20 nmol/L. In such cases, the patient’s Lp(a) was recorded as 241 nmol/L and 19 nmol/L, respectively, for calculating the mean/median value.
Echocardiographic evaluation
All patients underwent a comprehensive clinically indicated transthoracic echocardiogram examination completed by registered technicians and interpreted by level 3 echocardiographers. The severity of AS was evaluated based on the peak velocity, mean pressure gradient (MPG), and aortic valve area (AVA) calculated using the continuity equation.19 For the purpose of our study, mild, moderate, and severe AS were defined as an AVA ≥1.5 cm2, 1.5 to 1.0 or ≤1.0 cm2, respectively, or an MPG <20 mm Hg, 20 to 40 mm Hg, or ≥40 mm Hg, respectively.19 Left ventricle ejection fraction was assessed using the biplane Simpson method or visual estimate.
Statistical analysis
Continuous variables are expressed as mean ± SD, median (IQR), or number of patients (percentage) as appropriate. Histograms are used to express the distribution of Lp(a) levels and the proportion of cases with high Lp(a) levels, which was defined as patients with a value ≥100 nmol/L as per the Canadian Cardiovascular Society’s Lipid Guidelines.20 Lp(a) levels and the proportion of patients with high Lp(a) were also compared with respect to age, sex, and severity of valve disease using Wilcoxon and chi-square analysis, respectively. Analyses were repeated using the Lp(a) cutoff value proposed by the American College of Cardiology and American Heart Association (Lp[a] ≥125 nmol/L).21 Statistical analyses were performed using the JMP Pro 17 (SAS Institute).
Results
Study population
Lp(a) level was measured in 162 patients with various AS severities. The mean age was 75 ± 10 years, 76% were aged 70 or older, and 43% were female. The mean aortic valve MPG was 29 ± 14 mm Hg, and the mean AVA was 1.05 ± 0.27 cm2. Based on AVA, 5% of patients presented with mild AS, 49% with moderate AS, and 48% with severe AS. These proportions were 25%, 55%, and 20%, respectively when MPG was used to classify AS severity. Main comorbidities and baseline echo data of the study population are presented in Table 1.
Lp(a) distribution
Overall
The distribution of Lp(a) was not normal and is shown in Figure 1. The median Lp(a) level was 24 nmol/L (IQR: 19-91 nmol/L). Thirty-nine patients (24%) had a high Lp(a) level based on the Canadian guidelines (≥100 nmol/L) and 34 patients (21%) based on the American guidelines (≥125 nmol/L). Twenty-four patients (15%) had an Lp(a) level ≥200 nmol/L.
Figure 1.
Distribution of Lipoprotein (a) Levels in Patients With Aortic Stenosis Overall and According to Sex
Lp(a) distribution followed a “U” curve in both sexes. Notably, only 24% of patients had an Lp(a) ≥100 nmol/L, and only 21% had a level ≥125 nmol/L. Lp(a) = lipoprotein (a).
According to sex
The median IQR of Lp(a) level in male and female patients were 26 nmol/L, IQR: 19-88 nmol/L and 21 nmol/L, IQR: 19-124 nmol/L, respectively. There was no statistically significant difference between Lp(a) levels in the male and female patients (P = 0.83), nor was there a statistically significant difference in the proportion of men and women with high Lp(a) levels (22% vs 28%, respectively, P = 0.46) (Figure 2).
Figure 2.
Proportion of Patients With High Lipoprotein (a) Levels (≥100 nmol/L) in Overall and According to Sex, Age, and Valve Anatomy
In the total population, 24% of patients had high Lp(a). This proportion was comparable across the sex, age, and AS severity of groups. AS = aortic stenosis; Lp(a) = lipoprotein (a).
According to age
In patients <70 years of age, median Lp(a) level was 59 ± 65 nmol/L (23 nmol/L, IQR: 19-82 nmol/L), and high Lp(a) was present in 21% of patients. In patients aged 70 years or older, the median Lp(a) level was 24 nmol/L, IQR: 19-102 nmol/L, and 25% had a high Lp(a) level. There was no difference in Lp(a) levels in patients ≥70 and <70 years of age (P = 0.53) or in the proportion of cases with high Lp(a) levels (P = 0.67) (Figure 2).
According to AS severity
There was no statistically significant difference in Lp(a) levels between patients with severe AS and nonsevere AS (median: 19 nmol/L, IQR: 19-68 nmol/L vs median: 30 nmol/L, IQR: 19-119 nmol/L, P = 0.24). In patients with severe AS (based on AVA), 19% had a high Lp(a) level compared to 28% in patients with nonsevere AS (P = 0.20). When MPG was used to define severe AS (MPG ≥40 mm Hg), there likewise was no statistically significant difference between Lp(a) level or proportion of high Lp(a) cases. There was no correlation between Lp(a) level and AS severity either assessed using MPG (R = −0.06, P = 0.45) or AVA (R = 0.03, P = 0.75) (Figure 3).
Figure 3.
Correlation Between Lipoprotein (a) Levels and Severity of Aortic Stenosis Assessed Using the Mean Pressure Gradient
No correlation was observed between Lp(a) level and severity of aortic stenosis. Lp(a) = lipoprotein (a).
Discussion
In this unselected cross-sectional series of AS patients seen in a specialized valve clinic, 24% of patients had a high Lp(a) level with no significant differences observed with respect to sex (22% in male, 28% in female), age (21% vs 25% in patients <70 years and ≥70 years, respectively), or AS severity (19% vs 28% in patients with severe and nonsevere AS). Our results highlight potential generalizability concerns with ongoing trials on Lp(a)-lowering agents and the significant proportion of AS patients who may not benefit from such pharmacotherapy (Central Illustration).
Central Illustration.
Lipoprotein (a) Distribution in Aortic Stenosis
Only one-quarter of patients with aortic stenosis presented with high Lp(a). Lp(a) = lipoprotein (a).
Lp(a) and AS occurrence
Lp(a) levels are determined through the LPA gene. This gene codes for Kringle domains, with Kringle domain 2 (KIV2) being causally linked to Lp(a) levels.22 With respect to atherosclerotic cardiovascular disease, Mendelian randomization using data from the Copenhagen City Heart Study, the Copenhagen General Population Study, and the Copenhagen Ischemic Heart Disease Study found that doubling genetically determined Lp(a) levels increased risk of myocardial infarction by 22% with increased HRs for those with high Lp(a) and low KIV2 repeats.10 Similarly, a case-control study using data from Europe identified specific LPA gene variants that had lower KIV2 repeats, higher Lp(a) levels, and a higher risk of atherosclerotic cardiovascular disease.23 One single nucleotide polymorphism in the LPA gene, rs10455872, was of particular importance for cardiovascular disease due to its effect on KIV2.
Lp(a) is increasingly being recognized as a risk factor in the development of AS. The rs10455872 polymorphism has been linked to aortic valve calcification and aortic valve stenosis. Using genome-wide data from the Framingham Heart Study cohort, the Age Gene/Environment Study cohort, and the Multi-Ethnic Study of Atherosclerosis cohort, rs10455872 was shown to increase the odds of aortic valve calcification by a factor of 2.24 Previous research has also established a concentration-dependent link between Lp(a) levels and risk of occurrence of AS,13,25, 26, 27 and Lp(a) independently predicts the degree of aortic valve calcification (calcium scoring).28,29
Lp(a) and AS progression
Lp(a) is a risk factor for AS events and potentially for disease progression,12,28,30 although the evidence on this association is debated. A subanalysis from the FOURIER trial found that higher Lp(a) levels informed a higher risk of AS events.12 A similar finding was seen in the ASTRONOMER trial, where disease progression was the fastest in patients with the highest tertile of Lp(a).30 Nevertheless, a Rotterdam population study did not find an association between Lp(a) and AS progression, despite redemonstrating an association with the development of new valve calcification.29 In a recent meta-analysis including 757 patients across 5 longitudinal studies, the highest Lp(a) tertile showed more rapid AS progression based on peak velocity (+41%, estimate, 1.41; 95% CI, 1.13-1.75) and (+57%, estimate, 1.57; 95% CI, 1.18-2.10).11 The association was preserved when Lp(a) concentration was considered as a continuous variable. Interestingly, the meta-analysis found no association between Lp(a) levels and progression based on AVA. Overall, Lp(a) is accepted as a risk factor for AS occurrence, with some evidence to suggest a potential role in AS progression.
Lp(a) distribution
Lp(a) distribution in the general population has been previously presented, but little is known about its distribution in unselected patients with AS. In a large database study of over 500,000 patients in the United States, 24% had an Lp(a) level >50 mg/dL (equivalent to 100 nmol/L in the Canadian Cardiovascular Society Lipid Guidelines; mg/dL can be converted to nmol/L by multiplying by 2.5).18 In a second study with nearly 50,000 patients with known atherosclerotic cardiovascular disease, 28% of patients had Lp(a) >50 mg/dL.31 Lp(a) levels have been shown to vary across ethnicities, as observed in the INTERHEAT study,32 which evaluated Lp(a) levels in patients with the first myocardial infarction and controls. African American and Latin American populations generally had the highest proportion of individuals with an Lp(a) >50 mg/dL; however, even in these groups, the highest prevalence was 27%. Therefore, the Lp(a) distribution in our AS population seems to align with that of the general population.
In our cohort, female patients had a similar proportion of cases with Lp(a) ≥100 nmol/L compared to males, 28% and 22%, respectively. Women usually tend to present with higher Lp(a) levels and a slightly higher proportion of high Lp(a) levels than men.18 A recent study of Lp(a) levels in Chinese patients with carotid atherosclerosis found that 8% of women had levels >50 mg/dL compared to 6% of men.33 The lack of a statistical difference in our cohort may be related to our small sample size, but overall, the magnitude of the difference is small and unlikely to affect our main results, that is, only a minority of both male and female patients present with a high Lp(a) level.
We did not observe any difference in Lp(a) distribution according to age. Likewise, the proportion of high Lp(a) levels did not differ between patients <70 years of age and those 70 years or older (21% and 25%, respectively). Previous research on age and Lp(a) has shown that levels remain stable over a lifetime, and thus only 1 measurement is recommended.34 The absence of an association between age and Lp(a) levels was also seen in the Copenhagen City Heart Study, wherein patients with myocardial infarction did not have significant interaction between Lp(a) level and age.10
Patients with nonsevere and severe AS also presented with similar Lp(a) levels and proportion of patients with high Lp(a) levels. It is worth noting that our study is cross-sectional and not longitudinal in design, and therefore no conclusion can be drawn on the potential association between Lp(a) level and AS progression.
Study strengths and limitations
While a strength of our study is that all patients, regardless of disease severity and symptoms were included for analysis, there are several limitations that should be noted. This was a single-center cross-sectional study with a relatively small sample size and mostly Caucasian patients. However, patients were consecutively enrolled in our cohort irrespective of comorbidities and past medical history which reflect real life practice. Further, our results were very similar in any subgroup analyzed, suggesting that the results are robust. We found no association between Lp(a) levels and AS severity, either assessed using MPG or AVA. Nevertheless, only 24 patients presented with an Lp(a) ≥200 nmol/L, and we cannot formally exclude an association between very high Lp(a) values and severe AS. Finally, we were not able to assess the impact of valve anatomy as the number of patients with a bicuspid aortic valve was too small (16 patients, 10% of the cohort). This aspect should be examined in future research. Nevertheless, excluding patients with bicuspid aortic valve resulted in similar results across the total population, and with respect to sex, age, and AS severity.
Clinical implications
AS is one of the few cardiac conditions without any preventative medical therapies, and clinical trials are actively exploring whether dedicated Lp(a)-lowering agents can be used for preventing/slowing AS progression. There are currently 4 trials listed on clinicaltrials.gov evaluating this indication (NCT05646381: A Randomized Double-blind, Placebo-controlled, Multicenter Trial Assessing the Impact of Lipoprotein[a] Lowering With Pelacarsen [TQJ230] on the Progression of Calcific Aortic Valve Stenosis [Lp(a)FRONTIERS CAVS]. NCT04968509: Effect of PCSK9 InhibitorS On Calcific Aortic Valve DiseasE [EPISODE]. NCT03051360: PCSK9 Inhibitors in the Progression of Aortic Stenosis. NCT02109614: Early Aortic Valve Lipoprotein[a] Lowering Trial [EAVaLL]). Among these trials, the Lp(a) value inclusion/exclusion value is specified in 2 trials. One trial will include patients with Lp(a) ≥175 nmol/L, while the other is enrolling patients with Lp(a) >50 mg/dL (equivalent to 100 nmol/L). Thus, our findings highlight that while Lp(a)-lowering therapies, if proven effective, would represent a major breakthrough, their benefit may be limited to a small subset of the AS population and that the majority of AS patients will remain without effective preventative therapy. Our results further emphasize the need for ongoing research into understanding the pathophysiology of AS and developing medical therapies targeting different pathways than Lp(a).35
Conclusions
In this unselected cross-sectional series of AS patients seen in a specialized valve clinic, only 1 of every 4 patients had a high Lp(a) level. The incidence of a high Lp(a) level did not vary with age, sex, or AS severity. Our results suggest that even if Lp(a)-lowering therapies are proven to be beneficial, most patients with AS may not be eligible for such therapy.
Funding support and author disclosures
This study was funded by the UOHIAMO AFP Innovations Fund (UOH-20-004). Dr Messika-Zeitoun received a research grant from Edwards Lifesciences and is a consultant for Predisurge. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Acknowledgments
The authors deeply thank the nurses and research coordinators of the University of Ottawa Heart Institute Centre for Valvular Heart Disease.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
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