Response to Letter Regarding Article, “Low-Density Lipoprotein Cholesterol Concentrations and Death Due to Intraparenchymal Hemorrhage: The Ibaraki Prefectural Health Study”

Abstract

We thank Dr Drinka for his interest in our study1 and the opportunity to clarify several issues. Dr Drinka presented one possible causal pathway that might link reduced low-density lipoprotein (LDL) cholesterol with the development of arteriolosclerosis and increased risk of intraparenchymal hemorrhage. This hypothesis asserts that distal lipohyalin degeneration (destruction: arteriolosclerosis) may be protected against by proximal atheromatous degeneration (plaque formation: atherosclerosis) through the flow restriction and consequent lower blood pressure in the distal penetrating artery. The lower risk of intraparenchymal hemorrhage associated with higher LDL cholesterol levels may be explained in part by his flow restriction hypothesis. Although we consider the proposed causal pathway to be plausible, we do not consider this explanation to be the major one involving low LDL cholesterol for the following reasons. First, if it were true that atheromatous degeneration prevents the development of arteriolosclerosis, increased risk of intraparenchymal hemorrhage should be observed at levels of LDL cholesterol at which the risk of coronary heart disease decreases. However, in our study the increased risk of death from intraparenchymal hemorrhage was observed at a level of LDL cholesterol 100 mg/dL, whereas death from coronary heart disease plateaued in this range. Second, low high-density lipoprotein cholesterol and high triglycerides, which may lead to atheromatous degeneration, were not associated with reduced death from intraparenchymal hemorrhage. Our finding supports Konishi’s osmotic fragility hypothesis2 that very low levels of serum cholesterol in the intimal cell membranes of intracerebral arteries contribute to plasma insudation into the intima because of reduced osmotic resistance, which leads to the destruction of smooth muscle cells in the media and increased risk of intraparenchymal hemorrhage.3 This hypothesis was also supported by a community-based pathology study.4 An in vivo study suggested the hypothesis, showing that low sarcolemmal cholesterol content in neonatal cardiomyocytes enhanced sarcolemmal fluidity and anoxial-induced cell damage.5 Moreover, other in vivo studies showed that cellular cholesterol depletion may induce apoptosis. 6 Further studies are necessary to explore pathological mechanisms.