Inflammation now predicts heart disease more strongly than cholesterol

Inflammation now predicts heart disease more strongly than cholesterol Brandon Ballinger Sep 29, 2025 Chronic inflammation has long been known to double your risk of heart disease, but prior to now, inflammation has never been a SMuRF: standard modifiable risk factor for heart disease. The American College of Cardiology just released recommendations that change that. The ACC is now recommending that everyone measure inflammation (specifically, hs-CRP) via a blood test: Because clinicians will not treat what they do not measure, universal screening of hsCRP in both primary and secondary prevention patients, in combination with cholesterol, represents a major clinical opportunity and is therefore recommended. American College of Cardiology There were a many interesting bits of evidence that led to this recommendation. The whole article, published in JACC, is worth a read, but this blog post extracts a few of the most interesting parts — or at least, the parts I thought were most interesting. Want to skip ahead and measure your inflammation? Empirical Health's advanced heart health panel includes hs-CRP, ApoB, Lp(a), and other critical heart health biomarkers. For decades, LDL cholesterol (or ApoB) has been the main focus of cardiovascular risk assessment. But this chart shows hs-CRP is actually a stronger predictor of heart disease than LDL. Why? In some ways, cholesterol has become a victim of its own success. We now screen the whole population for high cholesterol, give statins to those with high LDL (or ApoB), and so then the majority of people who end up having heart attacks have lower cholesterol than they would naturally have. This means most of the majority of residual risk for heart attacks will be found in biomarkers that aren’t SMuRFs. Inflammation (hs-CRP) is one such non-SMuRF, one perhaps one of the strongest. This is especially true in people already on statins or those without traditional risk factors (sometimes called “SMuRF-less” patients). In these groups, cholesterol may be well controlled, but inflammation remains a key driver of events. Of course, other traditional risk factors matter in addition to inflammation: blood pressure, HbA1c or insulin resistance, eGFR (kidney function), and so on. The ACC consensus reviews a range of clinical trials testing both drugs and lifestyle interventions for lowering inflammation and reducing cardiovascular risk. Here’s a summary of the clinical trials and their results: Trial Name Drug (Class) Sample Size (n) Population/NYHA Functional Class Follow-Up Primary Endpoint Treatment Outcome ATTACH Infliximab (TNF inhibitor) 150 NYHA III/IV HF 7 mo Clinical status (composite score) No improvement or worsening; deaths highest in high-dose infliximab ACCLAIM IVIG 2314 NYHA II-IV HF 10.2 mo Composite all-cause mortality and CV hospitalization No reduction in events; trend toward benefit in NYHA III and IV CANTOS Canakinumab (anti–IL-1β) 10,061 Prior MI; hsCRP ≥2 mg/L 3.7 y (median) Nonfatal MI, nonfatal stroke, or CV death (MACE); HF-related mortality Reduced MACE and HF events; no effect on all-cause mortality; primary endpoint events: 3.86% vs 4.50% CIRT Methotrexate 4,786 Stable MI plus CAD 2.3 y (median) CV event rates No effect on CV events, inflammation, or lipids CLEAR SYNERGY Colchicine 3,056 Acute MI plus PCI 22.6 mo Death from CV causes, recurrent MI, ischemic stroke No significant difference in primary endpoint COLCOT Colchicine 4,745 Acute MI patients 22.6 mo CV event rates CV events lower than placebo LoDoCo2 Colchicine 5,522 Stable CAD 28.6 mo Composite of CV death, nonfatal MI, ischemic stroke, or ischemia-driven revasc. CV events lower than placebo GISSI-HF Rosuvastatin (statin) 4,574 NYHA II-IV HF 3.9 y All-cause mortality and CV hospitalization No effect on primary endpoints JUPITER Rosuvastatin (statin) 17,802 No CVD / LDL <130 mg/dL; hsCRP ≥2 mg/L 1.9 y (median) MI, stroke, arterial revascularization, hospitalization for unstable angina, or CV death Reduced events (HR 0.56–0.69) CORONA Rosuvastatin (statin) 5,011 NYHA II-IV HF; ischemic etiology 32.8 mo CV death, nonfatal MI, nonfatal stroke No effect on primary endpoint OPT-CHF Etanercept (TNF inhibitor) 1,500 NYHA II-IV HF 6 mo Death, hospitalization, or worsening HF No effect on primary endpoint DCMP Prednisone (corticosteroid) 84 NYHA II-IV HF; biopsy-proven myocarditis 5.7 and 12.3 mo Improvement in LVEF, survival, or combined outcome of death or transplantation No significant benefit RENEWAL Etanercept (TNF inhibitor) 2,048 NYHA II-IV HF 6 mo Composite outcome of death or hospitalization No effect on primary endpoint What works to lower inflammation? Statins (especially in people with high hs-CRP): Substantial reduction in events, even when LDL is normal (JUPITER trial). (especially in people with high hs-CRP): Substantial reduction in events, even when LDL is normal (JUPITER trial). Colchicine : Reduces recurrent events in people with established heart disease (COLCOT, LoDoCo2). : Reduces recurrent events in people with established heart disease (COLCOT, LoDoCo2). Canakinumab : Reduces events but is expensive and increases infection risk (CANTOS). : Reduces events but is expensive and increases infection risk (CANTOS). Lifestyle: Anti-inflammatory diets (Mediterranean, DASH), regular exercise, smoking cessation, and maintaining a healthy weight all lower hs-CRP and reduce risk. What doesn’t work? Some anti-inflammatory drugs (methotrexate, TNF inhibitors, corticosteroids) have not shown benefit in major trials. If you’ve already measured your hs-CRP (great!), then it’s ideally below <1 mg/L. hs-CRP above 3 mg/L is high risk: (If you’re in moderate or high ranges, see the section above for what to do.) The ACC evaluated other markers: IL-6, fibrinogen, neutrophil-to-lymphocyte ratio, EPA/AA ratio, and serum amyloid A. These have also been shown to predict cardiovascular risk, but once hs-CRP is known, don’t add more signal. In other words, you’re best off simply measuring hs-CRP, and then spending money elsewhere on heart health. The JACC article is packed with other interesting insights. These ones were interesting: Imaging biomarkers (like CT, PET, MRI, and perivascular “fat attenuation index”) can detect vascular inflammation and may help predict coronary events, but are not yet ready for routine clinical use. (like CT, PET, MRI, and perivascular “fat attenuation index”) can detect vascular inflammation and may help predict coronary events, but are not yet ready for routine clinical use. Bempedoic acid is a newer cholesterol-lowering drug that also lowers hs-CRP, but its long-term outcomes are still being studied. is a newer cholesterol-lowering drug that also lowers hs-CRP, but its long-term outcomes are still being studied. Residual inflammatory risk : Even with well-controlled LDL on statins, many people still have elevated hs-CRP and ongoing risk—so inflammation should be addressed separately from cholesterol. : Even with well-controlled LDL on statins, many people still have elevated hs-CRP and ongoing risk—so inflammation should be addressed separately from cholesterol. Universal hs-CRP screening is now recommended by the ACC for both people with and without established heart disease. is now recommended by the ACC for both people with and without established heart disease. Colchicine (0.5 mg/d) is now FDA-approved as an adjunct for secondary prevention in stable ASCVD, but should be avoided in people with significant kidney or liver disease. is now FDA-approved as an adjunct for secondary prevention in stable ASCVD, but should be avoided in people with significant kidney or liver disease. Novel IL-6 inhibitors are being studied as future anti-inflammatory therapies for heart disease. A simple blood test for hs-CRP is widely available and inexpensive. The ACC now recommends routine hs-CRP testing for both people at risk (primary prevention) and those with established heart disease (secondary prevention).