The Role of Emerging Risk Factors in Cardiovascular Outcomes
Curr Atheroscler Rep
The Role of Emerging Risk Factors in Cardiovascular Outcomes
Ben Lacey 0 1
William G. Herrington 0 1
David Preiss 0 1
Sarah Lewington 0 1
Jane Armitage 0 1
Abbreviations APOC 0 1
CETP CI CKD CRP eGFR FGF 0 1
HDL IL Lp 0 1
/LPA Lp-PLA 0 1
LDL LPL NT-proBNP 0 1
0 MRC Population Health Research Unit (MRC PHRU) , Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF , UK
1 Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford , Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF , UK
Purpose of Review This review discusses the recent evidence for a selection of blood-based emerging risk factors, with particular reference to their relation with coronary heart disease and stroke. Recent Findings For lipid-related emerging risk factors, recent findings indicate that increasing high-density lipoprotein cholesterol is unlikely to reduce cardiovascular risk, whereas reducing triglyceride-rich lipoproteins and lipoprotein(a) may be beneficial. For inflammatory and hemostatic biomarkers, genetic studies suggest that IL-6 (a pro-inflammatory cytokine) and several coagulation factors are causal for cardiovascular disease, but such studies do not support a causal role for C-reactive protein and fibrinogen. Patients with chronic kidney disease are at high cardiovascular risk with some of this risk not mediated by blood pressure. Randomized evidence (trials or Mendelian) suggests homocysteine and uric acid are unlikely to be key causal mediators of chronic kidney disease-associated risk and sufficiently large trials of interventions which modify mineral bone disease biomarkers are Ben Lacey, William G. Herrington and David Preiss would like to share first authorship; Sarah Lewington and Jane Armitage are joint contributors.
Epidemiology; Atherosclerosis; Vascular disease; Coronary heart disease; Stroke; Risk factors
Tissue plasminogen activator
tumour necrosis factor-α
von Willebrand factor
Major risk factors for cardiovascular disease include, but are
not limited to, cigarette smoking, blood pressure, blood lipids,
diabetes mellitus and adiposity [1–5, 6 ]. The causality of
these ‘classic’ risk factors is well established and they are
commonly used to assess absolute cardiovascular risk in the
general population [7–9]. Over the last few decades, however,
other risk factors (commonly blood-based biomarkers) have
been identified with potentially important implications for
cardiovascular disease prevention, either through improved risk
prediction or for treating cardiovascular disease (Table 1) [6 ,
10]. For many of these risk factors, their causal relevance to
cardiovascular disease is not well established and research is
ongoing. This review will discuss the recent evidence for a
selection of blood-based emerging risk factors, with particular
reference to their relation with major cardiovascular
outcomes, namely coronary heart disease and stroke.
Total cholesterol, low-density lipoprotein (LDL) cholesterol,
high-density lipoprotein (HDL) cholesterol and non-HDL
cholesterol (calculated as the difference between total
cholesterol and HDL cholesterol) display robust log-linear
associations with, and are considered classic predictors of,
cardiovascular disease [4, 11]. All commonly used cardiovascular risk
scores contain various combinations of these routinely
measured lipids . It has been demonstrated that the predictive
capacities of apolipoprotein B100 and apolipoprotein A1 are
very similar to non-HDL cholesterol and HDL cholesterol,
respectively . Robust data from monogenic conditions like
familial hypercholesterolemia, randomized trials (most
notably of statin therapy) and genetic studies have confirmed that
LDL cholesterol is causally related to cardiovascular disease,
and cardiovascular outcome trials of new powerful LDL
cholesterol lowering therapies are starting to emerge [12–16].
Recent studies have also provided further insights into the
relevance of HDL cholesterol, triglycerides, lipoprotein(a)
and lipoprotein-associated phospholipase A2 to the
development of cardiovascular disease.
HDL Cholesterol, Apolipoprotein A1 and Triglycerides
The inverse associations of HDL cholesterol and
apolipoprotein A1 with cardiovascular disease have led to the
Emerging risk factors for atherosclerotic cardiovascular
development of various therapeutic approaches to increase
their levels [11, 17, 18]. While some early fibrate trials
(medicines which reduce triglyceride, modestly increase HDL
cholesterol and reduce LDL cholesterol) suggested cardiovascular
benefit, recent larger studies of HDL cholesterol-raising
therapies have yielded little or no benefit [19, 20 ].
Cholesterolester transfer protein (CETP) inhibitors are able to increase
HDL cholesterol by 30–120%, though it should be noted that
potent CETP inhibitors also modestly reduce LDL
cholesterol. Despite evidence from genetic studies indicating
that those with genetically determined lower CETP activity
may be at lower cardiovascular risk , three major
outcomes trials of CETP inhibitors have shown no benefit [22,
23]. Results for the final ongoing major trial are expected in
2017. Of the three agents which failed, dalcetrapib (a weak
inhibitor of CETP) has offered the purest test of the ‘HDL
hypothesis’ given that it increases HDL cholesterol by 30%
but has no effect on LDL cholesterol levels. In the
DalOUTCOMES trial conducted in 15,871 participants
following a recent acute coronary syndrome, dalcetrapib had
no effect on cardiovascular events compared to placebo over
2.6 years . Recent analyses of genetic variants have
suggested that higher genetically determined HDL cholesterol is
not associated with lower cardiovascular risk [14 , 24],
implying that therapeutic interventions designed solely to increase
HDL cholesterol are unlikely to provide cardiovascular
benefit. It has also been announced that the development of
apolipoprotein A1 Milano, an HDL mimetic given by weekly
intravenous infusion, has been halted due to failure to reduce
coronary atherosclerosis as measured by intravascular
By contrast with HDL cholesterol, triglyceride levels are
only weakly associated with, and do not improve prediction
of, cardiovascular disease after adjustment for classic risk
factors including HDL cholesterol . However, recent
Mendelian randomization studies (Fig. 1) have suggested that
triglyceride-rich lipoproteins may be causally implicated in
the development of cardiovascular disease. Lipoprotein lipase
and apolipoprotein C3 are intimately involved in triglyceride
metabolism. Genetic polymorphisms in both the LPL and
APOC3 genes which result in higher triglyceride
concentrations have been demonstrated to be associated with increased
risk of myocardial infarction, while approaches combining
data from multiple variants that affect triglyceride levels have
yielded similar results [14 , 26–28]. An injectable antisense
oligonucleotide to apolipoprotein C3 is currently under
investigation in clinical trials to determine its effect on triglycerides,
though not yet on cardiovascular disease risk .
Lipoprotein(a) (Lp[a]) is a lipoprotein similar in structure to
LDL but with the addition of apolipoprotein(a) which is
covalently bound to the apolipoprotein B of the lipoprotein. The
apolipoprotein(a) varies in size depending on the number of
kringle repeats that it contains. Lp(a) levels are highly heritable
and are considerably higher in black individuals than in whites
[30, 31]. Levels of Lp(a) are positively associated with coronary
heart disease in a curvilinear fashion with a clear increase above
1 μmol/L , a relationship largely unaffected by adjustment
for classic cardiovascular risk factors. Lp(a) appears to have a
weaker association with stroke. It is not clear whether Lp(a)
meaningfully improves the prediction of cardiovascular events.
However, studies of genetic polymorphisms in the LPA gene
indicate that Lp(a) is causally implicated in the development of
cardiovascular disease (Fig. 2) . An injectable antisense
oligonucleotide to apolipoprotein(a) has been developed and
shown to reduce circulating Lp(a) by around 70% in early phase
clinical trials [33 ].
Lipoprotein-Associated Phospholipase A2
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a
mediator expressed in atherosclerotic plaque which increases the
production of pro-inflammatory and pro-apoptotic mediators.
A case-control analysis of 1740 participants in the WOSCOPS
trial cohort demonstrated that those in the highest quintile of
Lp-PLA2 mass were at double the risk of a coronary event
compared to those in the lowest quintile . Subsequent
meta-analyses confirmed that Lp-PLA2, whether measured
as mass or activity, is modestly associated with risk of
coronary events . However, genetic and clinical trial evidence
has established that inhibition of this pathway is unlikely to
provide cardiovascular benefit [36, 37]. For example,
darapladib, an inhibitor of Lp-PLA2, failed to reduce
cardiovascular events in the STABILITY trial of 15,828 patients
with stable coronary heart disease over 3.7 years .
Inflammatory processes play an important role in the
pathogenesis of atherosclerotic vascular disease . Yet, there is
only limited evidence for the causal relevance of circulating
inflammatory biomarkers on risk of vascular disease, and
clinical trials of drugs specifically targeting inflammatory
pathways are ongoing [39, 40].
C-reactive protein (CRP) is an acute-phase reactant,
synthesized primarily in the liver and released into the blood in
response to tissue injury or infection. A large meta-analysis
of individual participant data reported that 1-standard
deviation (SD) higher loge CRP concentration was associated
with 37% (95% CI 27–48%) higher risk of coronary heart
disease and 27% (15–40%) higher risk of ischemic stroke,
after adjusting for classic vascular risk factors .
However, a meta-analysis of Mendelian randomization
studies found that genes encoding for CRP were not
associated with risk of coronary heart disease (risk ratio for
coronary heart disease 1.00 [95% CI 0.90–1.13] per 1-SD
higher genetically raised loge CRP) . In light of these
findings, CRP is unlikely to be causally related to vascular
disease, but it may still have some utility in improving the
Fig. 1 Mendelian randomization
and randomized controlled trial
designs compared. Reproduced
with permission from: Davey
Smith G, Ebrahim S. Mendelian
Randomization: Genetic Variants
as Instruments for Strengthening
Causal Inference in Observational
Studies. In: Biosocial Surveys,
National Research Council of the
National Academy of Sciences,
2008. Courtesy of National
Academies Press, Washington,
predictive ability of cardiovascular risk scores (although
the added value appears small) .
Interleukin(IL)-6 is a pro-inflammatory cytokine that acts
high in the inflammatory pathways (an ‘upstream’
inflammatory biomarker) with effects that include stimulation of
Fig. 2 Association of the LPA Genotype Score with the Lp(a)
Lipoprotein Level and the Risk of Coronary Disease in the
PROCARDIS Cohort. The odds ratios (squares, with the size inversely
proportional to the sampling variation) are for the association of the LPA
genotype score (no variant alleles, one variant allele, or two variant
alleles) with the risk of coronary disease, as measured with the use of
‘floating absolute risks’ which summarize the sampling variation for the
three genotype scores without the selection of an arbitrary baseline
genotype score. The vertical lines indicate 95% confidence intervals.
Reproduced with permission from: Clarke R, Peden JF, Hopewell JC,
et al. Genetic variants associated with Lp(a) lipoprotein level and
coronary disease. N Engl J Med. 2009;361(26):2518–2528. Copyright
© 2009 Massachusetts Medical Society. Reprinted with permission
from Massachusetts Medical Society
hepatic acute-phase reactants, such as CRP . It has
been found to be strongly associated with coronary heart
disease risk: a meta-analysis of 17 studies (5730 cases and
19,038 controls) reported an odds ratio for coronary heart
disease, adjusting for several classic vascular risk and
correcting for within-person variability, of 1.83 (95% CI
1.56–2.14) per 1-SD increase in usual IL-6 values .
Furthermore, meta-analyses of Mendelian randomization
studies of an IL-6 receptor variant (Asp358Ala), with
effects consistent to IL-6 receptor blockade, have reported a
decreased risk of coronary heart disease per allele,
supporting the causal role of the IL-6 pathway in coronary
heart disease [46 , 47 ].
Other Pro-Inflammatory Cytokines
There is more limited evidence for the association of other
pro-inflammatory cytokines with vascular disease. A
recent large meta-analysis assessed the association between
coronary heart disease risk and several other
proinflammatory cytokines, including IL-18, matrix
metalloproteinase-9, soluble CD40 ligand and tumour necrosis
factor-α (TNF-α) . Positive associations were
described for IL-18 and TNF-α only, with relative risks of
coronary heart disease per 1-SD higher levels of 1.13
(95% CI 1.05–1.20) and 1.17 (1.09–1.25), respectively.
These associations have yet to be assessed reliably in
Mendelian randomized studies. However, a Mendelian
randomized analysis of the gene encoding a different
cytokine, the IL-1 receptor antagonist, reported a per-allele
odds ratio for coronary heart disease of 1.03 (95% CI
1.02–1.04) but no association with ischemic stroke (odds
ratio 1.00 [0.98–1.02]) . Trials are ongoing of drugs
targeting the signalling pathways of IL-1, as well as those
for IL-6 and TNF-α [39, 40, 50].
Biomarkers of Hemostasis and Thrombosis
Several circulating biomarkers of hemostasis and thrombosis
are strongly associated with risk of vascular disease.
Mendelian randomization studies support a causal role for a
number of factors involved with coagulation pathways,
consistent with the efficacy of anticoagulant drugs in reducing
atherosclerotic vascular events .
The most extensively studied hemostatic biomarker is
fibrinogen, the major circulating clotting factor by mass. A
metaanalysis of prospective observational studies reported that,
after adjusting for classic vascular risk factors, 1-g/L increase
in usual plasma fibrinogen was associated with a 82% (95%
CI 60–106%) higher risk of coronary heart disease and 82%
(54–116%) higher risk of stroke . Mendelian
randomization studies, however, have not supported the causality of this
association. A large meta-analysis of such studies reported a
relative risk of coronary heart disease of 1.00 (95% CI 0.95–
1.04) per higher-fibrinogen allele . Inflammatory and
hemostatic processes are interrelated and the strong
observational associations of fibrinogen and vascular risk may, in part,
reflect its regulation by pro-inflammatory cytokines, such as
IL-6 . As with CRP, however, fibrinogen may still be a
useful adjunct to standard cardiovascular risk scores .
Tissue Plasminogen Activator, D-dimer and von
Several prospective studies have described associations of
other hemostatic factors and vascular disease. In particular,
increased circulating levels of tissue plasminogen activator
(t-PA), D-dimer and von Willebrand factor (VWF) have been
associated with increased coronary heart disease risk [54–57].
A meta-analysis of prospective population-based studies
found relative risks for coronary heart disease per 1-SD higher
baseline levels of 1.13 (95% CI 1.06–1.21) with t-PA, 1.23
(1.16–1.32) with D-dimer and 1.16 (1.10–1.22) for VWF .
However, there was strong potential for residual confounding
in this meta-analysis and, as such, the relation with coronary
heart disease is still uncertain. The largest single study in this
meta-analysis, which adjusted for a more comprehensive set
of potential confounders, reported somewhat shallower
associations (relative risks per 1-SD higher baseline levels of 1.07
[95% CI 0.99–1.14] with t-PA, 1.06 [1.00–1.13] with D-dimer
and 1.08 [1.02–1.15] for VWF) .
Other Hemostatic Factors
A genetic study of the effect of seven polymorphisms, all of
which alter hemostatic pathways, reported strong associations
with coronary heart disease risk for two genes both encoding
for coagulant factors . Per-allele relative risks for coronary
heart disease of factor V (G1691A) and prothrombin (factor II;
G20210A) were 1.17 (95% CI 1.08–1.28) and 1.31 (1.12–
1.52), respectively. There was no evidence of an association
with several platelet receptors (GP1a, GP1bα and GPIIIa) and
the findings for genetic variants of plasminogen activator
inhibitor-1 (PAI-1; a protein involved in fibrinolysis) were
inconclusive as there was strong evidence of publication bias.
There is limited evidence for the associations between other
biomarkers of hemostasis and vascular disease .
Troponin and natriuretic peptides are released into the
circulation from cardiac tissue even under physiological
conditions, suggesting that they may be attractive cardiovascular
biomarkers. The increasing availability of high-sensitivity
assays for troponin in routine biochemistry laboratories (where
it is typically used for the diagnosis of myocardial infarction)
alongside brain natriuretic peptide (especially N-terminal
prob-type natriuretic peptide [NT-proBNP] which is usually
measured when left ventricular failure is suspected), indicates that
these assays could be easily incorporated into routine
cardiovascular risk screening if they are demonstrated to predict risk
The Natriuretic Peptides Studies Collaboration combined
data from 40 studies for 95,000 participants without
cardiovascular disease at baseline. Those with NT-proBNP levels in
the highest tertile were at double the risk of suffering a
coronary event, stroke, or developing heart failure [60 ]. Addition
of NT-proBNP to a risk model with classical risk factors
yielded modest improvements in cardiovascular risk
prediction, similar in scale to that provided by HDL cholesterol and
superior to CRP. Neprilysin inhibitors (e.g. sacubitril) are
agents which inhibit the degradation of natriuretic peptides
a n d o t h e r e n d o g e n o u s v a s o a c t i v e p e p t i d e s . T h e
PARADIGM-HF trial, conducted in 8442 patients with heart
failure, confirmed that neprilysin inhibition (when added to
renin-angiotensin system blockade) reduces hospitalization
and death due to heart failure but probably has little effect
on the risk of stroke or myocardial infarction .
Data regarding the predictive capacity of high sensitivity
troponin (both troponin-T and troponin-I) in those without
cardiovascular disease are more limited than for NT-proBNP.
In one major study, troponin-T levels were related to outcomes
in 9698 participants without cardiovascular disease aged 54 to
74 years . One third had measurable troponin-T. There
was a graded increase in cardiovascular events at
progressively higher levels of troponin-T compared to those with
unmeasurable levels and the authors concluded that its predictive
capacity was similar to that of NT-proBNP.
Chronic Kidney Disease and Kidney-Related Factors
Chronic kidney disease (CKD) is defined and staged by severity
of reduced renal function, usually quantified using estimated
glomerular filtration rate (eGFR) . Its prevalence reaches
10% in populations where old age or diabetes are common .
CKD is independently associated with substantially increased
risk of cardiovascular disease, with progressively more
advanced CKD associated with progressively higher risk [65, 66].
The spectrum of cardiovascular disease which manifests in
people with CKD is wide and includes both arterial and cardiac
disease. Common presentations of arterial disease in those with
CKD include intimal atherosclerotic lesions ,
nonatheromatous non-calcified arterial stiffening , and heavy
medial calcification  (see Wheeler et al.  for a
comprehensive review). Correspondingly, people with CKD are at
increased risk of coronary artery disease and structural heart
disease [66, 71, 72]. CKD is also associated with increased stroke
risk, and for large vessel stroke, there is some Mendelian
randomization evidence that this association may be one of cause
and effect. .
Every 30% decrement in eGFR is associated with about a
30% increase in risk of a cardiovascular event, so that a reduction
in eGFR from 60 to 10 mL/min/1.73m2 is associated with about
fourfold increased risk of cardiovascular disease . The
kidneys have a key role in modulating blood pressure which is a
clear mechanism by which CKD causes increased risk of
cardiovascular disease . Each 10 mL/min/1.73m2 lower eGFR is
associated with about a 5 mmHg higher systolic blood pressure
, so a reduction in eGFR from 60 to 10 mL/min/1.73m2
would be expected to increase SBP by at least 20 mmHg,
approximately doubling cardiovascular risk [2, 74]. The effect of
CKD on blood pressure might therefore account for up to about
one half of the association between CKD and cardiovascular
A range of emerging risk factors which correlate with
reduced renal function have been proposed to mediate the
remaining CKD-associated cardiovascular risk which is not
explained by blood pressure. However, the precise roles are not
yet fully elucidated and quantified. For some, including
homocysteine and uric acid, a body of evidence now suggests
they are unlikely to be key causal mediators of arterial disease.
Other risk factors remain potential candidates, including
mediators of accelerated arterial calcification and certain lipid
abnormalities. Details of the evidence supporting each of
these mechanisms are provided below, with an emphasis on
effects on coronary artery disease.
Homocysteinuria is a rare inherited disorder of metabolism
which causes high blood homocysteine concentration and
premature cardiovascular disease. Reduced renal function leads to
moderately increased blood homocysteine concentrations and it
is estimated that a 5 μmol/L increase in homocysteine is
observed for each 10 mL/min/1.73m2 lower eGFR. Observational
studies suggest such a change might increase coronary risk by
about 20% . However, Mendelian randomization
experiments have been negative, and a meta-analysis of trials testing
homocysteine lowering using folate supplementation found no
evidence of benefit on major cardiovascular events [77, 78].
Moderate elevations of homocysteine therefore seem unlikely
to be causally associated with coronary artery disease.
Blood uric acid concentration also increase as renal function
falls, and positive associations between uric acid levels and
coronary artery disease have been observed [79, 80]. Each 10 mL/min/
1.73m2 lower eGFR is associated with about a 10–15 μmol/L
increase in uric acid concentration, which is predicted to increase
coronary risk by about 10% [79, 80]. However, again, Mendelian
randomization experiments have cast doubt about whether such
associations are causal, as once pleotropic pathways were taken
into account, no clear association was observed .
Heavy arterial calcification is a particular feature of advanced
CKD . Both intimal and medial calcifications are common
and associated with increased risk of cardiovascular disease, with
perhaps the volume of intimal atheromatous coronary plaque
calcification being more important than the density of
calcification [69, 82]. A key emerging risk factor for arterial calcification
is blood phosphate, the concentration of which increases as the
capacity for its urinary excretion falls. High blood phosphate
concentration can directly induce ossification of vascular smooth
muscle cells and is associated with increased arterial calcification
[83, 84]. For each 0.3 mmol/L increase in phosphate (which is
the approximate effect of each 10 mL/min/1.73m2 lower eGFR),
there is about a 30% increased risk of cardiovascular disease
. Phosphate lowering is achieved by dietary modification
and phosphate binding medication [70, 86]. However,
sufficiently large placebo-controlled trial have not been performed to
confirm cardiovascular benefit from this practice. Trials comparing
different binders are also complicated to interpret, as there are
possible adverse cardiovascular effects of calcium-containing
binders, and beneficial cardiovascular effects mediated through
lipid lowering with some of the non-calcium containing binders
. Nevertheless, lowering phosphate is deeply embedded in
Fibroblast growth factor-23 (FGF23) has recently emerged as
another potential mediator of cardiovascular risk in CKD. It has
particularly drawn interest as associations are consistently strong
and FGF23 concentrations rise early in CKD mirroring the early
rise in cardiovascular risk which is apparent with only modest
reductions in renal function [88, 89]. FGF23 serves to increase
phosphate excretion and does not appear to cause arterial
calcification, observations which both suggest FGF23 is a protective
homeostatic hormone (like natriuretic peptides) . However,
there is some mechanistic evidence that FGF23 may be directly
cardiotoxic [91, 92]. Randomized experiments are therefore
required to confirm whether consistently positive observational
associations between FGF23 and risk of coronary artery disease
represent confounding, or are causal.
Statin-based therapy is effective at lowering atherosclerotic
risk in CKD, [93, 94] but LDL cholesterol (with the exception
of nephrotic syndrome) is not generally raised in CKD [86,
87]. Instead, each 10 mL/min/1.73m2 lower eGFR is
associated with a modest reduction in HDL cholesterol,
perhaps as much as 0.1 mmol/L, which is associated with a
5–10% increased risk of coronary artery disease . As
discussed above, current evidence does not support HDL
cholesterol being causally related to coronary disease.
Perhaps more promisingly, reduced renal function is also
associated with increased concentration of Lp(a) particles
. Mendelian randomization experiments predict Lp(a) to
be causally associated with coronary artery disease,
particularly the small Lp(a) isoforms . Each 10 mL/min/
1.73m2 lower eGFR is associated with a 0.2–0.3 μmol/L
increase in Lp(a), which might increase coronary artery
disease risk by about 10% . Some uncertainty remains as
the raised Lp(a) in CKD is mainly of the large isoform type,
whose relevance to coronary artery disease risk is less well
understood, but emerging Mendelian randomization evidence
suggests that Lp(a) concentration may be associated with
coronary risk independent of Lp(a) particle size .
Future Directions for Randomized Trials
Early stage clinical trials of drugs which lower lipoprotein(a)
and triglycerides are in process, and the results to these
studies will be influential in determining future trials of
lipid-related factors [29, 33 ]. In addition, novel mechanisms
of reducing LDL cholesterol are being tested, including trials
of PCSK9 inhibitors (monoclonal antibodies which target
circulating PCSK9) [15, 16]. These antibodies have been
found to dramatically lower LDL levels and, according to
recently published results from the FOURIER trial, to
reduce cardiovascular events in patients with clinically evident
vascular disease . With respect to inflammatory factors,
there are a number of trials evaluating the effect of
antiinflammatory agents on cardiovascular outcomes, including
low-dose methotrexate (a generic drug used to treat
autoimmune conditions such as rheumatoid arthritis) and
canakinumab (a human monoclonal antibody targeting the
pro-inflammatory cytokine IL-1β) [39, 40, 50]. There is also
a need for future trials of anti-inflammatory agents targeting
specific cytokines for which there is strong evidence of
causality, such as IL-6.
Limitations of Review
This review focuses on selected blood-based biomarkers and
their relation to major vascular disease. There are other
important blood-based biomarkers that it was not possible to
cover in this review, some of which are listed in Table 1. In
addition, we did not address metabolomic approaches to the
simultaneous measurement of hundreds to thousands of
small molecules that may yet lead to the identification of
novel biomarkers. Furthermore, this review focuses on
associations with coronary heart disease and stroke and did not
address the relation of emerging risk factors with other
major manifestations of vascular disease, notably abdominal
aortic aneurysm and peripheral vascular disease. It was also
outside the scope of this review to discuss non-blood-based
emerging risk factors for vascular disease, such as radiation,
coronary artery calcification, carotid intima-media thickness,
carotid plaque and ankle-brachial index . For a recent
wide-ranging review of emerging risk factors for stroke see
Hopewell and Clarke [6 ].
This review has discussed a range of blood-based
cardiovascular risk factors that have emerged over the last few
decades, with a particular focus on their relation with major
vascular disease. For some risk factors, there is now strong
evidence that their association with coronary heart disease
and stroke is not causal. Non-causal risk factors may still
have value, however, when added to cardiovascular risk
scores and a number of cardiac-related biomarkers hold
particular promise in this regard. For other risk factors
(including triglyceride-rich lipoproteins, lipoprotein(a), IL-6 and
several coagulation factors), there is increasing evidence of
a causal role in the pathogenesis of major vascular disease.
Although much of the burden of vascular disease can be
explained by classic risk factors, studies of emerging risk
factors have contributed importantly to our understanding
of the pathophysiological mechanisms of vascular disease,
and new targets for potential therapies (for both primary and
secondary prevention) have been identified.
Compliance with Ethical Standards
Conflict of Interest All authors are research staff at the Clinical
Trial Service Unit and Epidemiological Studies Unit (‘CTSU’).
CTSU is funded by the UK Medical Research Council (which
supports an embedded MRC Unit [MRC Population Health Research
Unit]) as well as by grants from the British Heart Foundation and
from Cancer Research UK. The CTSU has a staff policy of not
accepting honoraria or other payments from the pharmaceutical
industry, except for reimbursement of costs to participate in scientific
Human and Animal Rights and Informed Consent All reported
studies/experiments with human or animal subjects performed by the
authors have been previously published and complied with all applicable
ethical standards (including the Helsinki declaration and its amendments,
institutional/national research committee standards and
Open Access This article is distributed under the terms of the Creative
C o m m o n s A t t r i b u t i o n 4 . 0 I n t e r n a t i o n a l L i c e n s e ( h t t p : / /
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
Papers of particular interest, published recently, have been
1. Herrington W , Lacey B , Sherliker P , Armitage J , Lewington S. Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease . Circ Res . 2016 ; 118 ( 4 ): 535 - 46 .
2. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies . Lancet . 2002 ; 360 ( 9349 ): 1903 - 13 .
3. Prospective Studies Collaboration. Body-mass index and causespecific mortality in 900 000 adults: collaborative analyses of 57 prospective studies . Lancet . 2009 ; 373 ( 9669 ): 1083 - 96 .
4. Emerging Risk Factors Collaboration . Major lipids, apolipoproteins, and risk of vascular disease . JAMA . 2009 ; 302 ( 18 ): 1993 - 2000 .
5. Emerging Risk Factors Collaboration . Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies . Lancet . 2010 ; 375 ( 9733 ): 2215 - 22 .
6. Hopewell JC , Clarke R. Emerging risk factors for stroke: what have we learned from Mendelian randomization studies? Stroke . 2016 ; 47 ( 6 ): 1673 - 8 . A recent wide-ranging review of emerging risk factors for stroke .
7. DeFilippis AP , Young R , Carrubba CJ , et al. An analysis of calibration and discrimination among multiple cardiovascular risk scores in a modern multiethnic cohort . Ann Intern Med . 2015 ; 162 ( 4 ): 266 - 75 .
8. Damen JA , Hooft L , Schuit E , et al. Prediction models for cardiovascular disease risk in the general population: systematic review . BMJ . 2016 ; 353 :i2416.
9. Hajifathalian K , Ueda P , Lu Y , et al. A novel risk score to predict cardiovascular disease risk in national populations (Globorisk): a pooled analysis of prospective cohorts and health examination surveys . Lancet Diabetes Endocrinol . 2015 ; 3 ( 5 ): 339 - 55 .
10. Helfand M , Buckley DI , Freeman M , et al. Emerging risk factors for coronary heart disease: a summary of systematic reviews conducted for the U .S. Preventive Services Task Force. Ann Intern Med . 2009 ; 151 ( 7 ): 496 - 507 .
11. Prospective Studies Collaboration . Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths . Lancet . 2007 ; 370 ( 9602 ): 1829 - 39 .
12. Jensen J , Blankenhorn DH , Kornerup V. Coronary disease in familial hypercholesterolemia . Circulation . 1967 ; 36 ( 1 ): 77 - 82 .
13. Cholesterol Treatment Trialists Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials . Lancet . 2010 ; 376 ( 9753 ): 1670 - 81 .
14. White J , Swerdlow DI , Preiss D , et al. Association of lipid fractions with risks for coronary artery disease and diabetes . JAMA Cardiol . 2016 ; 1 ( 6 ): 692 - 9 . A mendelian randomization analysis of the association of LDL cholesterol, HDL cholesterol and triglycerides with coronary heart disease and diabetes .
15. Sabatine MS , Giugliano RP , Keech A , et al. Rationale and design of the further cardiovascular OUtcomes research with PCSK9 inhibition in subjects with elevated risk trial . Am Heart J . 2016 ; 173 : 94 - 101 .
16. Schwartz GG , Bessac L , Berdan LG , et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial . Am Heart J . 2014 ; 168 ( 5 ): 682 - 9 .
17. Parish S , Peto R , Palmer A , et al. The joint effects of apolipoprotein B, apolipoprotein A1, LDL cholesterol, and HDL cholesterol on risk: 3510 cases of acute myocardial infarction and 9805 controls . Eur Heart J . 2009 ; 30 ( 17 ): 2137 - 46 .
18. Thompson A , Danesh J. Associations between apolipoprotein B, apolipoprotein AI, the apolipoprotein B/AI ratio and coronary heart disease: a literature-based meta-analysis of prospective studies . J Intern Med . 2006 ; 259 ( 5 ): 481 - 92 .
19. Keech A , Simes RJ , Barter P , et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial . Lancet . 2005 ; 366 ( 9500 ): 1849 - 61 .
20. HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients . N Engl J Med . 2014 ; 371 ( 3 ): 203 - 12 . A large randomized controlled trial which found that, among participants with atherosclerotic vascular disease, the addition of extended-release niacin-laropiprant (which lower LDL cholesterol and raises HDL cholesterol) to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events .
21. Johannsen TH , Frikke-Schmidt R , Schou J , Nordestgaard BG , Tybjaerg-Hansen A. Genetic inhibition of CETP, ischemic vascular disease and mortality, and possible adverse effects . J Am Coll Cardiol . 2012 ; 60 ( 20 ): 2041 - 8 .
22. Barter PJ , Caulfield M , Eriksson M , et al. Effects of torcetrapib in patients at high risk for coronary events . N Engl J Med . 2007 ; 357 ( 21 ): 2109 - 22 .
23. Schwartz GG , Olsson AG , Abt M , et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome . N Engl J Med . 2012 ; 367 ( 22 ): 2089 - 99 .
24. Voight BF , Peloso GM , Orho-Melander M , et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study . Lancet . 2012 ; 380 ( 9841 ): 572 - 80 .
25. Nicholls SJ , Nissen SE , Ballantyne C , et al. Impact of infusion of apoA-Milano HDL mimetic on regression of coronary atherosclerosis in acute coronary syndrome patients: MILANO-PILOT study . New Orleans: American Heart Association 2016 Scientific Sessions ; 2016 .
26. Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies . Lancet . 2010 ; 375 ( 9726 ): 1634 - 9 .
27. Jorgensen AB , Frikke-Schmidt R , Nordestgaard BG , TybjaergHansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease . N Engl J Med . 2014 ; 371 ( 1 ): 32 - 41 .
28. Do R , Willer CJ , Schmidt EM , et al. Common variants associated with plasma triglycerides and risk for coronary artery disease . Nat Genet . 2013 ; 45 ( 11 ): 1345 - 52 .
29. Gaudet D , Alexander VJ , Baker BF , et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia . N Engl J Med . 2015 ; 373 ( 5 ): 438 - 47 .
30. Boomsma DI , Kaptein A , Kempen HJ , Gevers Leuven JA , Princen HM . Lipoprotein(a): relation to other risk factors and genetic heritability. Results from a Dutch parent-twin study . Atherosclerosis . 1993 ; 99 ( 1 ): 23 - 33 .
31. Emerging Risk Factors Collaboration . Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality . JAMA . 2009 ; 302 ( 4 ): 412 - 23 .
32. Clarke R , Peden JF , Hopewell JC , et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease . N Engl J Med . 2009 ; 361 ( 26 ): 2518 - 28 .
33. Viney NJ , van Capelleveen JC , Geary RS , et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials . Lancet . 2016 ; 388 ( 10057 ): 2239 - 53 . An early phase clinical trial of an injectable antisense oligonucleotide to apolipoprotein(a). The drug was found to substantially reduce circulating levels of Lp(a).
34. Packard CJ , O'Reilly DS , Caslake MJ , et al. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease . West of Scotland Coronary Prevention Study Group. N Engl J Med . 2000 ; 343 ( 16 ): 1148 - 55 .
35. Lp-PLA2 Studies Collaboration. Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: coll a b o r a t i v e a n a l y s i s of 32 pr o s pe c t i v e st u d i e s . L a n c e t . 2010 ; 375 ( 9725 ): 1536 - 44 .
36. Casas JP , Ninio E , Panayiotou A , et al. PLA2G7 genotype, lipoprotein-associated phospholipase A2 activity, and coronary heart disease risk in 10 494 cases and 15 624 controls of European Ancestry . Circulation. 2010 ; 121 ( 21 ): 2284 - 93 .
37. Investigators STABILITY . Darapladib for preventing ischemic events in stable coronary heart disease . N Engl J Med . 2014 ; 370 ( 18 ): 1702 - 11 .
38. Libby P , Ridker PM , Hansson GK . Progress and challenges in t r a n s l a t i n g t h e b i o l o g y o f a t h e r o s c l e r o s i s . N a t u r e . 2011; 473 ( 7347 ): 317 - 25 .
39. Ridker PM , Thuren T , Zalewski A , Libby P. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) . Am Heart J . 2011 ; 162 ( 4 ): 597 - 605 .
40. Everett BM , Pradhan AD , Solomon DH , et al. Rationale and design of the cardiovascular inflammation reduction trial: a test of the inflammatory hypothesis of atherothrombosis . Am Heart J . 2013 ; 166 ( 2 ): 199 - 207 . e115
41. Emerging Risk Factors Collaboration. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis . Lancet . 2010 ; 375 ( 9709 ): 132 - 40 .
42. C Reactive Protein Coronary Heart Disease Genetics Collaboration . Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data . BMJ . 2011 ; 342 :d548.
43. Emerging Risk Factors Collaboration. C-reactive protein, fibrinogen, and cardiovascular disease prediction . N Engl J Med . 2012 ; 367 ( 14 ): 1310 - 20 .
44. Ridker PM . Targeting inflammatory pathways for the treatment of cardiovascular disease . Eur Heart J . 2014 ; 35 ( 9 ): 540 - 3 .
45. Danesh J , Kaptoge S , Mann AG , et al. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review . PLoS Med . 2008 ; 5 ( 4 ): e78 .
46. Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis . Lancet . 2012 ; 379 ( 9822 ): 1214 - 24 . A mendelian randomization analysis supporting the causal role of the IL-6 (a proinflammatory cytokine) pathway in coronary heart disease .
47. IL6R Genetics Consortium Emerging Risk Factors Collaboration. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies . Lancet . 2012 ; 379 ( 9822 ): 1205 - 1 3 . A m e n d e l i a n r a n d o m i z a t i o n a n a l y s i s , p u b l s h e d simultaneously to the previous reference, with findings that supporting the causal role of the IL-6 pathway in coronary heart disease .
48. Kaptoge S , Seshasai SR , Gao P , et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis . Eur Heart J . 2014 ; 35 ( 9 ): 578 - 89 .
49. Interleukin 1 Genetics Consortium . Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis . Lancet Diabetes Endocrinol . 2015 ; 3 ( 4 ): 243 - 53 .
50. Ridker PM , Howard CP , Walter V , et al. Effects of interleukin-1beta inhibition with canakinumab on hemoglobin A1c , lipids, C-reactive protein, interleukin- 6 , and fibrinogen: a phase IIb randomized, placebo-controlled trial . Circulation . 2012 ; 126 ( 23 ): 2739 - 48 .
51. Keavney B , Danesh J , Parish S , et al. Fibrinogen and coronary heart disease: test of causality by 'Mendelian randomization' . Int J Epidemiol . 2006 ; 35 ( 4 ): 935 - 43 .
52. Fibrinogen Studies Collaboration . Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis . JAMA . 2005 ; 294 ( 14 ): 1799 - 809 .
53. Lowe G , Rumley A. The relevance of coagulation in cardiovascular disease: what do the biomarkers tell us? Thromb Haemost . 2014 ; 112 ( 5 ): 860 - 7 .
54. Danesh J , Whincup P , Walker M , et al. Fibrin D-dimer and coronary heart disease: prospective study and meta-analysis . Circulation . 2001 ; 103 ( 19 ): 2323 - 7 .
55. Whincup PH , Danesh J , Walker M , et al. von Willebrand factor and coronary heart disease: prospective study and meta-analysis . Eur Heart J . 2002 ; 23 ( 22 ): 1764 - 70 .
56. Lowe GD , Danesh J , Lewington S , et al. Tissue plasminogen activator antigen and coronary heart disease . Prospective study and meta-analysis . Eur Heart J . 2004 ; 25 ( 3 ): 252 - 9 .
57. Wannamethee SG , Whincup PH , Shaper AG , Rumley A , Lennon L , Lowe GD . Circulating inflammatory and hemostatic biomarkers are associated with risk of myocardial infarction and coronary death, but not angina pectoris, in older men . J Thromb Haemost . 2009 ; 7 ( 10 ): 1605 - 11 .
58. Willeit P , Thompson A , Aspelund T , et al. Hemostatic factors and risk of coronary heart disease in general populations: new prospective study and updated meta-analyses . PLoS One . 2013 ; 8 ( 2 ): e55175 .
59. Ye Z , Liu EH , Higgins JP , et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91, 307 controls . Lancet . 2006 ; 367 ( 9511 ): 651 - 8 .
60. Natriuretic Peptides Studies Collaboration. Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individualparticipant-data meta-analysis . Lancet Diabetes Endocrinol . 2016 ; 4 ( 10 ): 840 - 9 . A meta-analysis of prospective studies which found N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration to be strongly associated with heart failure, coronary heart disease and stroke, and indicated that NT-proBNP concentration might usefully improve cardiovascular risk scores .
61. McMurray JJ , Packer M , Desai AS , et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure . N Engl J Med . 2014 ; 371 ( 11 ): 993 - 1004 .
62. Saunders JT , Nambi V , de Lemos JA , et al. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the atherosclerosis risk in communities study . Circulation . 2011 ; 123 ( 13 ): 1367 - 76 .
63. KDIGO CKD Working Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease . Kidney Int Suppl . 2013 ; 3 : 1 - 150 .
64. Levey AS , Coresh J. Chronic kidney disease . Lancet . 2012 ; 379 ( 9811 ): 165 - 80 .
65. Mafham M , Emberson J , Landray MJ , Wen CP , Baigent C. Estimated glomerular filtration rate and the risk of major vascular events and all-cause mortality: a meta-analysis . PLoS One.
2011 ; 6 ( 10 ): e25920 .
Tonelli M , Muntner P , Lloyd A , et al. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study . Lancet . 2012 ; 380 ( 9844 ): 807 - 14 .
Kono K , Fujii H , Nakai K , et al. Composition and plaque patterns of coronary culprit lesions and clinical characteristics of patients with chronic kidney disease . Kidney Int . 2012 ; 82 ( 3 ): 344 - 51 .
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association . 2000 ; 15 ( 2 ): 218 - 23 .
Wheeler DC , Haynes R , Landray MJ , Baigent C. Chapter 56: cardiovascular aspects of kidney disease . In: Taal MW, Chertow GM , Marsden P , Skorecki K , ASL Y , Brenner BM , editors. Brenner and Rector's the kidney . Philadelphia: Elsevier Saunders ; 2012 .
Park M , Hsu CY , Li Y , et al. Associations between kidney function and subclinical cardiac abnormalities in CKD . Journal of the American Society of Nephrology : JASN . 2012 ; 23 ( 10 ): 1725 - 34 .
Kidney Int . 1998 ; 54 ( 5 ): 1720 - 5 .
Blood Pressure Lowering Treatment Trialists Collaboration . Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials . BMJ . 2013 ; 347 :f5680.
Boudville N , Prasad GV , Knoll G , et al. Meta-analysis: risk for hypertension in living kidney donors . Ann Intern Med . 2006 ; 145 ( 3 ): 185 - 96 .
Clarke R , Bennett DA , Parish S , et al. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias . PLoS Med . 2012 ; 9 ( 2 ): e1001177 .
Clarke R , Halsey J , Lewington S , et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals . Arch Intern Med . 2010 ; 170 ( 18 ): 1622 - 31 .
Chen Z , Ding Z , Fu C , Yu C , Ma G . Correlation between serum uric acid and renal function in patients with stable coronary artery disease and type 2 diabetes . Journal of clinical medicine research.
Fang J , Alderman MH . Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study , 1971 - 1992 .
Lancet Diabetes Endocrinol . 2016 ; 4 ( 4 ): 327 - 36 .
82. Criqui MH , Denenberg JO , Ix JH , et al. Calcium density of coronary artery plaque and risk of incident cardiovascular events . JAMA . 2014 ; 311 ( 3 ): 271 - 8 .
83. Johnson RC , Leopold JA , Loscalzo J. Vascular calcification: pathobiological mechanisms and clinical implications . Circ Res . 2006 ; 99 ( 10 ): 1044 - 59 .
84. Ix JH , De Boer IH , Peralta CA , et al. Serum phosphorus concentrations and arterial stiffness among individuals with normal kidney function to moderate kidney disease in MESA . Clinical journal of the American Society of Nephrology : CJASN . 2009 ; 4 ( 3 ): 609 - 15 .
85. Palmer SC , Hayen A , Macaskill P , et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis . JAMA . 2011 ; 305 ( 11 ): 1119 - 27 .
86. Block GA , Wheeler DC , Persky MS , et al. Effects of phosphate binders in moderate CKD . Journal of the American Society of Nephrology : JASN . 2012 ; 23 ( 8 ): 1407 - 15 .
87. Navaneethan SD , Palmer SC , Craig JC , Elder GJ , Strippoli GF . Benefits and harms of phosphate binders in CKD: a systematic review of randomized controlled trials . American journal of kidney diseases : the official journal of the National Kidney Foundation . 2009 ; 54 ( 4 ): 619 - 37 .
88. Isakova T , Wahl P , Vargas GS , et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease . Kidney Int . 2011 ; 79 ( 12 ): 1370 - 8 .
89. Go AS , Chertow GM , Fan D , McCulloch CE , Hsu CY . Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization . N Engl J Med . 2004 ; 351 ( 13 ): 1296 - 305 .
90. Scialla JJ , Lau WL , Reilly MP , et al. Fibroblast growth factor 23 is not associated with and does not induce arterial calcification . Kidney Int . 2013 ; 83 ( 6 ): 1159 - 68 .
91. Leifheit-Nestler M , Grosse Siemer R , Flasbart K , et al. Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease . Nephrology , dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association . 2016 ; 31 ( 7 ): 1088 - 99 .
92. Gutierrez OM . Connecting the dots on fibroblast growth factor 23 and left ventricular hypertrophy . Nephrology , dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association . 2016 ; 31 ( 7 ): 1031 - 3 .
93. Baigent C , Landray MJ , Reith C , et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (study of heart and renal protection): a randomised placebo-controlled trial . Lancet . 2011 ; 377 ( 9784 ): 2181 - 92 .
94. Cholesterol Treatment Trialists Collaboration. Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials . Lancet Diabetes Endocrinol . 2016 ; 4 ( 10 ): 829 - 39
95. Kronenberg F. Causes and consequences of lipoprotein(a) abnormalities in kidney disease . Clin Exp Nephrol . 2014 ; 18 ( 2 ): 234 - 7 .
96. Saleheen D , Haycock PC , Zhao W , et al. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis . Lancet Diabetes Endocrinol . 2017 . doi:10.1056/NEJMoa1615664.
97. Sabatine MS , Giugliano RP , Keech AC , et al. FOURIER steering committee and investigators: evolocumab and clinical outcomes in patients with cardiovascular disease . N Engl J Med . 2017 . doi:10. 1016/S2213-8587(17)30088- 8 .