Does Low LDL-C Promote Hemorrhagic Stroke?

There has long been concern that a low total cholesterol and low-density lipoprotein cholesterol (LDL-C) may cause an increased risk of a hemorrhagic stroke. This concern arose because epidemiological studies found a correlation between low serum cholesterol levels and a greater risk of experiencing a hemorrhagic stroke (1, 2).Another recent prospective study examined the association between LDL-C concentrations and hemorrhage stroke risk. This ongoing cohort study included 96,043 participants with a mean age of 51.3 years, who were free of stroke, myocardial infarction, and cancer at the baseline. Serum LDL-C concentrations were assessed in 2006, 2008, 2010, and 2012. Cumulative average LDL-C concentrations were calculated from all available LDL-C data during that period. Incident intracerebral hemorrhage (ICH) was then confirmed by review of medical records.During the ensuing 9 years, the researchers identified 753 incident ICH cases. ICH risk was similar among participants with LDL concentrations of 70 to 99 mg/dL and those with LDL-C concentrations ?100 mg/dL. However, for the subjects with lowest LDL-C concentrations (<70 mg/dL) researchers observed a significantly higher risk of developing ICH than those with LDL-C levels of 70 to 99 mg/dL. The elevated adjusted hazard ratios were 1.65 (95% confidence interval [CI] 1.32–2.05) for LDL-C concentrations of 50 to 69 mg/dL and 2.69 (95% CI 2.03–3.57) for LDL-C concentrations <50 mg/dL. Significant association between lower LDL-C and higher risk of ICH when LDL-C was <70 mg/dL, and the association became nonsignificant when LDL-C ?70 mg/dL. These data can help determination of the ideal LDL range in patients who are at increased risk of both atherosclerotic disease and hemorrhagic stroke and can guide planning of future lipid-lowering studies (3).Of course, correlation does not prove causation. There is no doubt lowering LDL-C with diet and/or drugs reduces the risk of ischemic strokes and heart attacks, but should we be concerned about pushing LDL-C levels so low that this might increase the risk of hemorrhagic strokes? That concern was addressed in a recent editorial by Dr. Erin Michos and Seth Martin. The more common ischemic strokes we know are promoted by higher LDL-C and apoB, and nonHDL-C levels. By contrast, hemorrhagic strokes have little or nothing to do with atherosclerosis. Hemorrhagic stroke risk factors include hypertension, cerebral aneurysms, other vascular malformations, systemic bleeding disorders, and/or the use of anticoagulation drugs including warfarin/coumadin, heparin, factor Xa inhibitors like Xarelto & Eliquis, and thrombin inhibitors. Over the long-term, elevated blood pressure (BP) is the single greatest promoter of both ischemic and hemorrhagic stroke.Drs. Michos and Martin argue that correlation does not equal causation because of confounding variables. For example, illness may tend to lower LDL-C and increase the risk of hemorrhagic stroke. Many ill people with chronic pain and/or other serious illnesses may be more likely to consume more alcohol, pain killers like NSAIDS, or other drugs that could impact hemorrhagic stroke risk via increasing BP, decreasing blood clotting, and/or increasing the risk of falls and head trauma that could lead to a heightened risk of hemorrhagic stroke. Overall, Drs. Michos and Martin found little reason to believe the correlations observed between very low LDL-C levels and increased hemorrhagic stroke are likely to be causal. They conclude: “… it is important to not be afraid to set aside old notions and embrace fresh ones in our efforts to ward off the devastating consequences of recurrent ASCVD, including stroke, with aggressive LDL-C lowering. This should be performed in conjunction with other lifestyle and pharmacologic preventive strategies, including BP control” (4).This reviewer is inclined to agree with the perspective of Drs. Michos & Martin. Looking at all the evidence, it is hard to argue a low LDL-C somehow leads to a greater risk of hemorrhagic stroke. While there is a correlation, it appears more likely that this correlation is due to confounding variables such as those mentioned in the editorial and above. People who are less healthy often have poor appetites and eat less than people who are healthier. Eating less often leads to lower LDL-C. Even worse, what sicker people do eat is more likely to be convenience foods high in added salt and low in potassium and magnesium. Low intake of potassium and magnesium are associated with increased risk of hemorrhagic stroke (5).Bottom Line: The proven benefits of a healthy diet low in added salt, refined carbohydrates, and with little animal foods high in saturated fat and cholesterol lowers LDL-C and reduces factors causally linked to a greater risk of heart disease and stroke. A diet composed of minimally-processed plant-based foods may be more challenging for those who are already quite ill but is likely to cut the risk of both ischemic and hemorrhagic stroke. For those concerned about ischemic and hemorrhagic stroke, it makes far more since to limit dietary salt/sodium and consume more whole plant foods rich in potassium and magnesium and naturally very low in salt than to worry about a very low LDL-C level.By James J. Kenney PhD, FACNReferences:

1. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med. 1989;320:904– 910. doi: 10.1056/NEJM198904063201405.
2. Rist PM, Buring JE, Ridker PM, Kase CS, Kurth T, Rexrode KM. Lipid levels and the risk of hemorrhagic stroke among women. Neurology. 2019;92:e2286–e2294. doi: 10.1212/WNL.0000000000007454.
3. https://n.neurology.org/content/93/5/e445
4. https://sci-hub.se/downloads/2019-11-12/04/10.1161@CIRCULATIONAHA.119.044275.pdf.
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441806/