Table 3.
Factors to consider in assessing risk of atherosclerosis and individualizing treatment.
| Factor | Details of increased risk |
|---|---|
| Presence of plaque in any vascular bed | Either non-calcified as seen on ultrasound or other modalities and/or calcified plaque seen in aorta, peripheral arteries or by CAC. Plaque is a sign of advanced atherosclerosis. Calcified plaque is an even later finding. Thickening Intimal-media is also of concern and is the earliest sign. |
| Insulin resistance, diabetes, metabolic syndrome* | Adiposopathy [261), insulin resistance, prediabetes, diabetes, metabolic syndrome [253], excess visceral fat. Hemoglobin A1C predicts subclinical atherosclerosis [254]. |
| Hypertension* | Essential, secondary, or primary aldosteronism [154] Blood pressure is safest at or below 120/70 mm Hg at any age [255], [256], [257], [258] |
| Elevated Lipoprotein (a) [259], [260], [261], [262], [263], [264]* | Levels > 75 Nmol/L [265], [266], [267], [268], [269] Elevated levels are likely as common as 20% of the population. A major contributor to ASCVD and calcific aortic stenosis. Also increases risk of stroke in children [263,270]. Measurement in nmol/L is preferable to mg/dl. |
| Familial Hypercholesterolemia [271]* | Heterozygous FH is the most common monogenic condition, affecting between 1 in 200–300 Americans, and as frequent as 1 in 24 of those with ASCVD [272]. |
| Elevated hsCRP [273] or GlycA [274], [275], [276]* | Indicators of active inflammation. However, hsCRP can be lower at times despite even advanced atherosclerosis with plaque (probably due to temporary inactivity of inflammation). A normal hsCRP does not negate the risks of other important factors, as inflammation activity can wax and wane. High Sensitivity CRP > 1.0 mg/dl denotes even higher risk. |
| LDL-C, non-HDL-C, ApoB* |
LDL-C of 20–40 mg/dl seems to be the healthy level for humans from birth on, but impractical to achieve in developed societies. Apolipoproteins are the primary cause of atherosclerosis [277]. ApoB and non-HDL-C can help refine atherogenic particle levels. |
| Triglycerides* | Shaik and Rosenson [278], [279], [280], [281] Risk begins to increase above 100 mg/dl [282] Post-prandial surge important as well. |
| Remnant Cholesterol | Remnant cholesterol (approximation) = Total cholesterol – HDL-C – LDL-C. Levels above 10 mg/dl indicate risk [283]. Apolipoprotein B levels and non-HDL Cholesterol also include atherogenic remnants and are likely more predictive than LDL-C alone. |
| Age⁎⁎ | Risk increases with age (age is the most determinative factor in risk calculators). Even over age 75 years, treatment is effective, safe and appropriate [284], [285], [286], [287], [288], [289] |
| Family history* | Early ASCVD, diabetes , hypertension [290] all increase risk for descendants [291], [292], [293], [294], [295], [296] |
| Obesity, visceral fat | Major cause of metabolic syndrome and atherosclerosis, even when at first ‘metabolically healthy’ [252,[297], [298], [299], [300], [301]]. |
| Chronic kidney disease* | CKD and atherosclerosis each increases risk and pathology of the other [302], [303], [304], [305] |
| Non-alcoholic fatty liver disease | Closely related to atherosclerosis and contributory to it [169]. |
| Other co-morbidities | Hypo- or hyperthyroidism [306], gout [307], sleep apnea [308], gut microbiome (theoretical) [309], Cushing's syndrome [310], many others. The microbiome is not currently actionable. |
| Some medications | Some increase LDL (Corticosteroids [311], Androgenic steroids [312], Progestogens, Thiazide diuretics, Beta-blockers, Retinoic acid derivatives, Oral estrogens [313]). Chronic corticosteroids increase risks even at low doses. Many others [314]. |
| Substance use* | Tobacco [315,316], marijuana [317], [318], [319], alcohol [320], cocaine [321] |
| Autoimmune disease* | Rheumatoid arthritis [322,323], Systemic Lupus Erythematosus [324], psoriasis and psoriatic arthritis [325,326], ankylosing spondylitis [327], scleroderma [328], inflammatory bowel disease [329], probably others |
| immunological disease and inflammation elsewhere in the body [82,159]; clonal hematopoiesis of indeterminate potential (CHIP) [160], [161], [162], [163]; neutrophil extracellular traps [164], [165], [166], [167] | These are not yet readily actionable and further research is needed. |
| Genetic factors and social determinants of health | Knowledge and applicability are developing rapidly, already useful for FH and some other genetic variants [330], [331], [332], [333], [334] |
| Race/ethnicity (All people are complex genetic mixtures, but some genetic factors are alerted by ethnicity in some cases. While of course not universal or definitive, Race/ethnicity can signal risk requiring deeper evaluation)* | South Asian (much higher risk of atherosclerosis, high Lipoprotein (a) and diabetes and at early ages) [280,[335], [336], [337], [338], [339], [340], [341]], African American (hypertension, renal disease); Non-white Hispanic (diabetes, obesity, CAD); many others. Some of Asian heritage have lower risk. Ethnicity affects incidence of biomarkers [342] |
| Other lab parameters | Elevated Microalbumin/creatine ratio [343,344], even in children [104]. High uric acid [345,346], low vitamin D [347], periodontitis [383], elevated ceramides [348] and others [384] are associated with increased risk of atherosclerosis, though causation remains to be fully determined and thus treatment not yet justified just to reduce risk of atherosclerosis. Their presence implies increased risk even if causation not proven. Thus, a high uric acid would raise concern but lowering uric acid just for that reason is not indicated. |
| Testosterone deficiency and treatment | Reasonable evidence that hypogonadism increases risk of atherosclerosis, less certain if treatment affects risk. Excess testosterone treatment probably increases risk. Must use replacement therapy carefully [349]. |
| Female reproductive* | Premature menopause, high cholesterol in pregnancy (cholesterol usually increases in pregnancy and in menopause), preeclampsia, eclampsia, gestational diabetes mellitus and polycystic ovary syndrome all increase risk [350], [351], [352] |
| Social factors* | Socioeconomic status [353]; discrimination [238,354] and financial barriers to access to healthcare [355]. Culture, beliefs, life views, etc. that affect use of medical science. Lack of belief in science. Desire for ‘natural’ approach. Poor compliance and long-term adherence [356,357]. Unjustified fear of LLT medications [36] |
| Mental health [358] | Depression (associated and possibly causal [359]), stress [360], anxiety or anger syndromes [361]. Some anti-psychotic medications increase atherosclerotic risk [314]. |
| Lifestyle [362]* | Atherogenic diet (highly processed food, high salt and simple carbohydrates, poorly balanced nutrition) [363], [364], [365], [366]; saturated fat [367], [368], [369], [370]; trimethylamine-N-oxide (TMAO) [371,372]. Inadequate aerobic and resistance exercise [373,374]. Excess sedentary time independent of exercise [375], [376], [377]. Mediterranean diet [378], vegan diet [379,380], DASH Diet [102] are proven much healthier and less atherogenic. Overweight, obesity and (most important) excess visceral fat. |
| Environment | Air pollution [86,381] contributes to atherosclerosis risk, as do excess noise [381], [382], [383], [384] and chemical pollution [87,168] |
| Acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) | This virus causes significant endothelial changes in many arteries. This causes immediate cardiac pathology in some patients, even in mild cases. Whether it will have long-term consequences remains to be seen, but all COVID patients should be carefully monitored for the development of cardiac problems over time and for accelerated atherosclerosis. |
(Some of these, designated with *, are partly or wholly addressed in the 2019 AHA guidelines, as contributors or risk enhancers, but often partially or at higher thresholds than recommended in this paper. Age (⁎⁎) is a major determinant of the AHA risk calculator).