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Atherosclerosis

Atherosclerosis, also known as hardening of the arteries, is a chronic inflammatory process in which lipids and immune cells gradually accumulate in the vessel wall, forming atherosclerotic plaques. This condition arises from a complex interplay of genetic and lifestyle factors, which are well documented both clinically and epidemiologically.

For calculating the atherosclerosis score in Synapse, the standard SCORE-2 formula[1] (which uses age, sex, systolic blood pressure, total cholesterol, and smoking status) is extended with additional pro-atherogenic factors. These include insulin resistance, excess abdominal fat, chronic inflammation, cholesterol, chronic kidney insufficiency, physical activity, sedentary behaviour, and stress. By incorporating these additional variables, we can build a more holistic risk profile and implement interventions at an earlier stage.

Score2

SCORE2[1] (Systematic COronary Risk Evaluation 2) is a validated risk model that estimates the 10-year risk of fatal and non-fatal cardiovascular events in individuals aged 40 to 69 years. SCORE2-OP does the same for individuals aged 70 to 89 years. This model builds on the original SCORE table and takes into account age, sex, systolic blood pressure, non-HDL cholesterol, and smoking status.

At Synapse, we apply the following cut-offs[1]:

Risk <50 years 50-69 years >70 years
Low <2.5% <5% <7.5%
Moderate 2.5-7.5% 5-10% 7.5-15%
High >7.5% >10% >15%

An important limitation of SCORE2 is that the risk of atherosclerosis is estimated only over a 10-year period, whereas atherosclerosis is a process that develops over multiple decades and can begin in childhood. This means we often intervene too late and miss a significant opportunity for prevention. To compensate for this, Synapse also considers additional parameters that help estimate the risk of atherosclerosis more accurately.

30-year risk

To correct for the underestimation of cardiovascular risk in younger populations, Synapse uses the 30-year cardiovascular risk score[68], developed on the basis of the Framingham Heart Study. This model is applicable between ages 20 and 59 and provides a longer time horizon for risk stratification.

The clinical value of this approach lies in improved risk communication. For example, a young individual with a 10-year risk of 2% (1 in 50) may still have a 30-year risk of 12–15% (e.g. 1 in 8). This longer time horizon demonstrably increases motivation for lifestyle interventions.

At Synapse, we apply the following age-dependent model selection:

  • Under 20 years: no cardiovascular risk score
  • 20 to 59 years: 30-year cardiovascular risk
  • 60 years and older: SCORE2 / SCORE2-OP

The cut-offs we apply at Synapse are:

Risk 30-year CVR
Low risk <12%
Moderate risk 12-40%
High risk >40%

Kidney function

Chronic kidney disease (CKD) is widely recognised as an important risk factor for atherosclerosis[5], although the extent to which this relationship is direct or indirect is not yet fully understood. Indirectly, CKD contributes to two of the most prominent risk factors for atherosclerosis: dyslipidaemia and hypertension.

Through the accumulation of various substances that can irritate the vessel wall, CKD may also contribute directly to the development of atherosclerosis[5]. These metabolites inhibit nitric oxide synthase (NOS), reducing vasodilation and accelerating vascular wall damage.

Homocysteine

Elevated homocysteine[70, 71] is associated with increased all-cause mortality and with numerous conditions, particularly cardiovascular disease. An independent and partly causal relationship has been described for venous thrombosis, peripheral arterial disease, coronary atherosclerosis, and stroke. The underlying mechanisms include oxidative stress, inflammation, and endothelial dysfunction, with reduced nitric oxide availability.

At Synapse, we apply the following cut-offs[70, 71] :

Homocysteine (μmol/L)
Optimal ≤8
Normal 8-10
Mildly elevated 10-12
Elevated 12-16
Markedly elevated >16

Inflammation

Chronic inflammation[5] (CI) refers to a persistent, low-grade activation of the immune system present in the body without a clear infectious cause. This form of inflammation is characterised by increased production of pro-inflammatory cytokines such as interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), and C-reactive protein (CRP).

Research has shown that CI plays a crucial role in the development and progression of atherosclerosis[7]. Inflammatory mediators promote endothelial dysfunction, stimulate the accumulation of immune cells in the vessel wall, and contribute to the instability of atherosclerotic plaques. This increases the risk of cardiovascular complications such as myocardial infarction and stroke.

Insulin sensitivity

Insulin sensitivity[8] is a key determinant of glucose homeostasis and metabolic regulation. A decline in insulin sensitivity (insulin resistance) leads to compensatory hyperinsulinaemia by the pancreatic β-cells to maintain euglycaemia. This process lies on a continuum from insulin resistance to prediabetes and ultimately type 2 diabetes, where progressive β-cell dysfunction results in hyperglycaemia and increased cardiovascular risk.

Insulin resistance is a strongly associated risk factor for atherosclerosis and cardiovascular disease[9, 10, 11] , through the combination of metabolic dysregulation and secondary dyslipidaemia with endothelial dysfunction, pro-inflammatory activation, and accelerated arterial calcification.

Waist circumference

Excess abdominal fat is closely linked to an increased risk of atherosclerosis. Excessive fat accumulation affects multiple risk factors such as blood pressure, glucose levels, and lipid metabolism, and contributes to systemic inflammation. Adipocytes also secrete adipokines that can directly disrupt the functioning of endothelial cells, arterial smooth muscle cells, and macrophages in the vessel wall, further contributing to the development of atherosclerosis[18, 19] .

Exercise

Regular physical activity has a protective effect on the vasculature by reducing systemic inflammation, improving endothelial function, and thereby slowing atherosclerotic progression[12, 13] . Epidemiological studies demonstrate an inverse dose-response relationship between the amount of physical activity and cardiovascular risk[14].

Sedentary behaviour

Prolonged sitting is increasingly recognised as an independent risk factor for atherosclerosis. Physical inactivity leads to increased expression of vascular NADPH oxidase, resulting in greater production of reactive oxygen species (ROS)[15]. This additional oxidative stress worsens endothelial dysfunction and promotes atherosclerotic processes[13].

Stress

Chronic stress is an important lifestyle factor that contributes to both the onset and progression of atherosclerosis[13]. One plausible explanation is that stress damages the endothelium, leading to macrophage activation and foam cell formation, thereby initiating and advancing atherosclerotic plaques. Inflammation, cell signalling, lipid metabolism, and endothelial function all play a crucial role in this process[16, 17] .

Chronic inflammation

Inflammation is the body's natural defence response to injury or infection. In acute inflammation, we see a temporary increase in pro-inflammatory activity, briefly activating the immune system to neutralise the harmful stimulus. Once recovery occurs, the immune system returns to a resting state.

In chronic low-grade inflammation, however, the immune system remains persistently active below the surface. This can not only cause ongoing tissue damage but also lead to disruptions in metabolism and hormonal balance. Over time, this smouldering inflammatory response increases the risk of a broad range of conditions, including cardiovascular disease, diabetes, hepatic steatosis, neurodegenerative disease, and even certain forms of cancer.

How to measure chronic low-grade inflammation?

The best-known and most sensitive parameter for detecting an inflammatory response is C-reactive protein (CRP). Although this acute-phase protein provides a useful initial indication, the test alone is insufficiently specific to accurately determine the risk of chronic low-grade inflammation.

As a complement to CRP, Synapse also evaluates:

  • Aggregate scores that take into account the distribution of white blood cells, platelets, and other inflammatory markers
  • Individual biomarkers, such as ferritin and uric acid, to build a more complete picture of inflammatory status
  • Lifestyle factors such as poor diet, sedentary behaviour, and other environmental factors that underlie the onset and perpetuation of chronic inflammation

Aggregate scores

Because the literature lacks consensus on which aggregate biomarker has the highest validity for estimating chronic inflammation, Synapse uses the three most extensively described scores in its score calculation.

INFLA score

Chronic low-grade inflammation is an important risk factor for cardiometabolic disease and can be detected at an early stage using the Low-Grade Inflammation Score (INFLA score)[20, 21, 22] . In simple terms, a higher INFLA score means more inflammation in the body.

The INFLA score is a composite measure that integrates four components:

  • hs-CRP
  • leukocytes
  • platelets
  • granulocyte-to-lymphocyte ratio (sum of neutrophils, eosinophils, and basophils)

Each biomarker is categorised based on deciles:

  • Values in the highest deciles (7th–10th) receive a score of +1 to +4.
  • Values in the middle deciles (5th–6th) receive a score of 0.
  • Values in the lowest deciles (1st–4th) receive a score of -4 to -1.

By summing the scores of all four components, a total INFLA score is obtained that can range from -16 to +16. A higher score indicates greater low-grade inflammation and an elevated risk of future cardiometabolic problems. Routinely measuring the INFLA score in adults without existing cardiometabolic disease can contribute to timely intervention and prevention of cardiometabolic pathology[22].

The cut-offs we apply at Synapse are:

Risk Score
Low risk ≤-5
Moderate risk -5 to -1
High risk -1 to 3
Very high risk > 3

SII

The Systemic Inflammation Index (SII)[23, 24, 25] is another biomarker for chronic inflammation that is widely studied in the literature and also correlates with both total and cardiovascular mortality. This index is calculated using the following formula:

SII = P × N L

Here P represents the peripheral platelet count (103/μL), N the neutrophil concentration (%), and L the lymphocyte concentration (%). A lower SII score indicates a lower level of chronic inflammation, making the SII a useful biomarker for estimating subclinical cardiovascular risk.

There is no consensus on exact cut-off values for the SII. At Synapse, the following cut-offs have been adopted:

Risk Score
Low risk ≤350
Moderate risk 350 - 450
High risk 450 - 600
Very high risk > 600

SIRI

The Systemic Inflammation Response Index (SIRI)[24, 26] is a third aggregate score that can be used as a biomarker in screening for chronic inflammation. Like the INFLA score and the SII, it correlates with both total and cardiovascular mortality. The SIRI is calculated using the following formula:

SIRI = N × M L

Here N represents the neutrophil concentration, M the monocyte concentration, and L the lymphocyte concentration. To obtain the correct units, Synapse calculates:

SIRI = N (%) × M (%) × leukocytes (/μL) L (%) × 105

A higher SIRI score indicates higher levels of smouldering inflammatory activity and elevated cardiovascular risk. There is no consensus on exact cut-off values for the SIRI. Synapse has adopted the following cut-offs:

Risk Score
Low risk ≤0.7
Moderate risk 0.7 to 0.99
High risk 1 to 1.5
Very high risk >1.5

Individual biomarkers

Given the crucial importance of chronic low-grade inflammation (CLI) in the development of various chronic diseases and the lack of consensus on the most valid aggregate inflammation scores, Synapse has chosen to evaluate individual inflammatory biomarkers alongside the indices described above.

hsCRP

C-reactive protein (CRP)[27, 28, 29, 30, 31] is an acute-phase reactant produced in the liver in response to inflammation. The high-sensitivity variant (hs-CRP) is a well-characterised biomarker with high sensitivity for detecting chronic low-grade inflammation. "High sensitivity" refers to the much lower detection limit (<0.6 mg/L) compared to most standard CRP assays (<6 mg/L). Elevated hs-CRP values are associated in numerous studies with an increased risk of cardiovascular disease[32, 33, 34] . The following risk categories for chronic inflammation and cardiovascular disease are generally used:

Risk Score
Low risk ≤1.0 mg/L
Moderate risk 1.0 - 3.0 mg/L
High risk 3.0 - 5.0 mg/L
Very high risk >5.0 mg/L

Ferritin

Ferritin[35, 36, 37, 38] is a protein responsible for iron storage and also functions as an acute-phase reactant, as its concentration rises with inflammation. Several studies suggest that ferritin may play a role in detecting chronic low-grade inflammation and argue that it can serve as a prognostic biomarker.

The ferritin cut-off values applied at Synapse are:

Risk Score
Male Female
Low risk ≤400 µg/L ≤150 µg/L
Elevated risk >400 µg/L >150 µg/L

Uric acid

Uric acid is an end product of purine metabolism and a well-known risk factor for atherosclerosis and cardiometabolic disease[39]. Hyperuricaemia is also associated with chronic inflammation[40].

Elevated uric acid levels can promote oxidative stress and endothelial dysfunction, contributing to persistent inflammation and atherogenesis. Measuring uric acid can therefore help in estimating both cardiovascular risk and chronic low-grade inflammation.

Risk Score
Low risk ≤7.9 mg/dL
Elevated risk >7.9 mg/dL

Lifestyle factors

Synapse not only maps the current inflammatory status but also takes into account how lifestyle factors influence the future risk of chronic inflammation. Based on the literature, several well-documented determinants have been selected: smoking, poor diet, and alcohol use. These factors contribute significantly to both the onset and the perpetuation of low-grade inflammatory processes.

Smoking

Smoking[41, 42] is one of the most pronounced risk factors for chronic inflammation and cardiovascular disease. During smoking, toxic compounds including free radicals enter the bloodstream, leading to oxidative stress and activation of immune cells.

These processes stimulate the production of pro-inflammatory cytokines and cause a persistent inflammatory response that damages the vessel wall and accelerates atherosclerotic processes.

Inflammatory food

Diet[43, 44] plays a major role in chronic inflammation, particularly when too many refined carbohydrates and processed foods are consumed and fibre intake is insufficient. These patterns disrupt the gut microbiome, promote insulin resistance, and elevate pro-inflammatory cytokines.

Within Synapse, "inflammatory diet" refers to a dietary pattern high in unhealthy fats, refined sugars, and processed foods, and low in fibre.

Alcohol

Chronic or excessive alcohol use[45, 46] can cause liver damage and increase intestinal permeability, allowing bacterial endotoxins to enter the bloodstream more easily. This leads to sustained production of pro-inflammatory mediators and promotes oxidative stress in various organs, contributing to the onset and perpetuation of chronic inflammation.

Sleep

Disrupted sleep can lead to an increase in systemic inflammatory markers[47, 48] . During poor sleep, the normal resolution of inflammatory processes becomes imbalanced, as key molecules that promote recovery (including resolvins) remain suppressed for extended periods. This can give rise to smouldering inflammation that increases the risk of various immune-mediated conditions.


Blood pressure

Elevated blood pressure[49, 50] is one of the most important risk factors for cardiovascular disease. Even mildly elevated values can cause damage to the vessel wall, which over time leads to structural changes, endothelial dysfunction, and progressive atherosclerosis.

ACC / AHA HTN categories [51] SBP (mmHg) DBP (mmHg)
Normal ≤120 ≤80
Mildly elevated 120-130 80-85
Elevated 130-135 85-90
Stage 1 135-140 90-95
Stage 2 >140 >95

Kidney function

Reduced kidney function[52] is an important, often underestimated risk factor for cardiovascular disease. Kidney insufficiency is accompanied by accumulation of waste products, dysregulated fluid and electrolyte balance, and hormonal changes that can contribute to hypertension, chronic inflammation, and atherosclerosis. Synapse assesses kidney function using the CKD-EPI formula[53].

Stage eGFR (ml/min/1.73m2)
G1 ≥90
G2 60 - 89
G3a 45 - 59
G3b 30 - 44
G4 15 - 29
G5 <15

ACR

The albumin-to-creatinine ratio (ACR)[69] is a biomarker that corrects the amount of albumin for urine concentration via creatinine. The ACR detects early glomerular damage, often before a decline in eGFR becomes apparent. Albuminuria is also an independent predictor of cardiovascular morbidity and mortality, meaning the ACR refines not only kidney function assessment but also the overall vascular risk profile.

At Synapse, we apply the following ACR categories[69]:

Category ACR (mg/g) Description
A1 <30 Normal to mildly elevated
A2 30-300 Moderately elevated
A3 >300 Severely elevated

By combining eGFR and ACR, the KDIGO risk matrix[69] is obtained, providing more accurate risk stratification than eGFR alone. The table below shows the corresponding risk level for each combination of eGFR stage and ACR category.

eGFR / Risk A1 (<30) A2 (30-300) A3 (>300)
G1 (≥90) Low Moderate High
G2 (60-89) Low Moderate High
G3a (45-59) Moderate High Very high
G3b (30-44) High High Very high
G4 (15-29) High Very high Very high
G5 (<15) Very high Very high Very high

Cholesterol

Hypercholesterolaemia is a well-known and well-documented risk factor for cardiovascular disease, as it directly contributes to the development of atherosclerosis.

To make interpretation easier for patients, Synapse uses a single composite cholesterol score that integrates several relevant parameters, including non-HDL cholesterol, HDL cholesterol, apoB, and Lp(a).

Non-HDL cholesterol

Cholesterol is a fatty substance produced in the liver and transported in the blood via various lipoproteins. Because the atherogenic lipoproteins include not only LDL but also IDL and VLDL, non-HDL cholesterol provides a more accurate estimate of the atherogenic lipid profile than LDL alone[54].

Non-HDL = total cholesterol - HDL

In line with the 2025 focused update of the ESC/EAS guidelines[73], Synapse applies risk-dependent cut-offs for non-HDL cholesterol. A cardiovascular risk category is determined for each individual. One criterion is sufficient to place a person in a category; the highest category takes precedence:

Very high risk

  • SCORE2/SCORE2-OP >20%
  • Severe kidney insufficiency based on eGFR and ACR
  • Documented atherosclerotic vascular disease (coronary, cerebrovascular, or peripheral)
  • Diabetes mellitus with organ damage (based on eGFR and ACR)
  • Diabetes mellitus with ≥3 cardiovascular risk factors (smoking, hypertension, dyslipidaemia, obesity)
  • Type 1 diabetes with duration >20 years
  • Familial hypercholesterolaemia with an extremely elevated risk factor

High risk

  • SCORE2/SCORE2-OP 10-20%
  • Moderate kidney insufficiency based on eGFR and ACR
  • Diabetes mellitus without organ damage, with duration ≥10 years or an additional risk factor
  • Familial hypercholesterolaemia without extremely elevated risk factors
  • One extremely elevated risk factor: triglycerides >310 mg/dL, LDL >190 mg/dL, or blood pressure >180/110 mmHg

Moderate risk

  • SCORE2/SCORE2-OP above the age-dependent threshold but <10%
  • Other diabetes mellitus (short duration, no additional risk factors, no organ damage)

Low risk

None of the above criteria apply, or a SCORE2/SCORE2-OP[1] below the age-dependent threshold (<2.5% at <50 years, <5% at 50-69 years, <7.5% at ≥70 years).

The highest risk category across all criteria determines the final classification. Based on this, the following non-HDL cut-offs are applied[55, 73] :

Non-HDL Low Moderate High Very high
Low ≤146 ≤130 ≤100 ≤85
Moderate 146 - 160 130 - 146 100 - 130 85 - 100
High 160 - 180 146 - 160 130 - 146 100 - 130
Very high >180 >160 >146 >130

ApoB

ApoB is the structural protein on all atherogenic lipoproteins (LDL, VLDL, IDL, and Lp(a)); each particle carries exactly one ApoB molecule. The ApoB concentration therefore directly reflects the number of atherogenic particles in circulation, whereas (non-)HDL cholesterol primarily reflects the cholesterol mass within those particles. Recent research shows that ApoB is consequently a better predictor of atherosclerotic risk than non-HDL cholesterol[55].

Cholesterol levels say nothing about particle size or number: many small, cholesterol-poor LDL particles can yield a normal non-HDL-C value but a high ApoB and thus a greater atherogenic risk. ApoB captures this discordance and therefore correlates more strongly with clinical outcomes than non-HDL-C.

At Synapse, the following cut-offs[56] have been adopted:

Risk Apo B
Low ≤100
Intermediate 100-120
High 120-130
Very high >130

HDL cholesterol

High-density lipoprotein (HDL) is described in the literature as a protective factor against cardiovascular disease[55], as it plays a crucial role in the transport of cholesterol from peripheral tissues back to the liver. In general, higher HDL levels are associated with lower cardiovascular risk. Although exact cut-off values may vary between guidelines, the following generally apply[57]:

Risk HDL (mg/dL)
Male Female
Low ≥60 ≥60
Intermediate 50-60 55-60
High 40-50 50-55
Very high <40 <50

Lp(a)

Lipoprotein(a) [Lp(a)] is a lipoprotein particle containing both apoB100 and apolipoprotein(a) and is 70–90% genetically determined. Elevated Lp(a) levels are an independent and causal risk factor for atherosclerotic cardiovascular disease, primarily because they can promote atherogenesis, inflammation, and thrombosis. Unlike LDL cholesterol and apoB, a high Lp(a) concentration continues to increase the risk of cardiovascular disease even when LDL and apoB are lowered[60].

Although research from sources such as the UK Biobank[61] shows that an Lp(a) value above 30 nmol/L is already associated with increased cardiovascular risk, universally standardised measurement methods and guidelines for both diagnosis and treatment are currently lacking[62]. Synapse therefore incorporates Lp(a) separately in the cholesterol score, so that individuals with elevated Lp(a) can be identified and monitored at an early stage.

At Synapse, we apply the following cut-offs[61]:

Risk Lp(a) (nmol/l)
Low ≤75
Intermediate 75-125
High 125-188
Very high >188

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