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From hemorrhagic stroke to lipid paradox: a double-hit hypothesis underlying low low-density lipoprotein cholesterol related cardiovascular risk—a narrative review

Zhou, Xin; Yang, Qing

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doi: 10.1097/JBR.0000000000000067
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Abstract

Introduction

Mounting evidence from large randomized clinical trials (RCTs) has demonstrated a clear benefit of low density lipoprotein cholesterol (LDL-C) lowering therapy for the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD).[1,2] Additionally, the finding that long-term statin use and low LDL-C may potentially increase cancer incidence, has not been consistently observed in long-term follow-up studies.[3–5] On the contrary, statin use in patients with cancer is associated with reduced mortality.[6] It appears that low LDL-C, whether achieved by statin therapy or in statin-naïve patients, is associated with long-term cardiovascular health. However, there is a growing body of evidence from observational studies of an increased incidence of hemorrhagic stroke in patients with low LDL-C (<70 mg/dL).[7,8] Furthermore, in patients suffering acute coronary syndrome (ACS), recent reports from large registry studies have found a paradoxical phenomenon in which hypercholesterolemia (total cholesterol ≥240 mg/dL or LDL-C ≥160 mg/dL) is associated with better short-term outcomes,[9–12] which has been termed the “lipid paradox” or “cholesterol paradox.” The mechanisms underlying how low LDL-C is associated with hemorrhagic stroke and the lipid paradox are undefined. With the advent of inhibitors of proprotein convertase/subtilisin-kexin type 9, which are capable of lowering LDL-C to levels not previously achieved by statins,[13,14] the concept of “lower is better” is a hot topic in cardiovascular medicine. This review aimed to summarize the evolution and current status of these two low LDL-C related concepts. It is worth emphasizing that in the era of increasing use of high-intensity LDL-C lowering and antiplatelet strategies in ASCVD patients receiving percutaneous coronary intervention (PCI), balancing the risk of thrombosis with bleeding complication should be a priority.

Database search strategy

In this review, the authors used the PubMed database to search for observational studies and clinical trials evaluating the association between LDL-C and hemorrhagic stroke. The literature search was restricted to English-language and full-text articles published from 1946 to November 23, 2019. Relevant studies were retrieved using the following keywords (“cholesterol, ldl” [MeSH Terms] or “low density lipoprotein cholesterol” [Text word]) and (“cerebral hemorrhage” [MeSH Terms] or “hemorrhagic stroke” [Text word] or “intracerebral hemorrhage” [Text word] or “hemorrhagic transformation” [Text word]). The authors also searched the relevant reference lists from the identified publications.

Low low-density lipoprotein cholesterol-related hemorrhagic stroke

Hemorrhagic stroke is the second most common subtype of stroke and is associated with low survival rates and a high risk of disability, worldwide.[15] China has a higher percentage of hemorrhagic stroke than that in Western counties.[16] The pathological and epidemiological features of hemorrhagic stroke are distinct from ASCVD. An inverse or U-shaped association between total cholesterol was first reported in the Japanese population,[17] and this finding is consistently reported in East Asian patients,[8,18–20] and in women of European descent.[21]

Epidemiological studies evaluating the association between low LDL-C and hemorrhagic stroke

The first study to address the association between LDL-C levels and the risk of hemorrhagic stroke was reported in 2009, and was based on a large population-based cohort study involving 30,802 men and 60,417 women in Japan.[22] During a median follow-up of 10.3 years, 264 intraparenchymal-related hemorrhagic deaths were identified.[22] After adjusting for traditional cardiovascular risk factors, an inverse association between low LDL-C levels and increased risk of death secondary to hemorrhagic stroke was observed. This finding is very similar to the findings in a recent report from the China Kadoorie Biobank involving 489,762 individuals with no prior history of stroke and coronary heart disease at baseline.[23] During a median follow-up of 9 years, 8270 patients with intracerebral hemorrhage and 32,869 patients with ischemic stroke were identified. Using Mendelian randomization analysis, the authors found that LDL-C levels were positively associated with a risk of ischemic stroke and inversely associated with a risk of intracerebral hemorrhage. Specifically, 1 mM (38.6 mg/dL) increase in LDL-C was associated with a 17% higher risk of ischemic stroke, and a 14% lower risk of intracerebral hemorrhage. However, these associations between low LDL-C and an increased risk of hemorrhagic stroke were based on only one LDL-C measurement at baseline. A more recent report from the Kailuan Study in China used cumulative average LDL-C levels calculated from four measurements in 96,043 participants over a 6-year period, and examined the association between average LDL-C levels and hemorrhagic stroke during a 9-year follow-up.[8] Using restricted cubic spline, the authors of the study identified a threshold effect at an LDL-C level of 70 mg/dL, below which the incidence of hemorrhagic stroke increased significantly. According to these findings, to balance the benefit of LDL-C lowering on ASCVD and the risk of low LDL-C-associated hemorrhagic stroke, the authors recommended an LDL-C level of 70 to 99 mg/dL as the appropriate range for LDL-C. Similarly, another study in China with an extended follow-up of 20 years also confirmed higher risk of hemorrhagic stroke in patients with LDL-C <70 mg/dL, and proposed an LDL-C level of 70 to 99 mg/dL as the “optimal” level.[7] Notably, uncontrolled hypertension is an important contributor amplifying low LDL-C-associated hemorrhagic stroke.[7]

Low LDL-C and hemorrhagic transformation

Another important condition associated with cerebral bleeding is hemorrhagic transformation, which is seen at the infarction site during acute cerebral infarction with restoration of blood flow after ischemic stroke. According to the imaging features, hemorrhagic transformation is divided into patchy hemorrhagic infarction and space-occupying parenchymal hematoma. It is generally believed that patchy hemorrhagic infarction occurs at the ischemic capillary level through red blood cell exudation, whereas parenchymal hematoma results from vascular rupture in the ischemic area induced by perfusion pressure.[24] Previous studies have identified lower LDL-C as an independent predictor for hemorrhagic transformation in patients with acute ischemic stroke in a US population[25] and in a Korean population.[26] These two studies were criticized for their small sample sizes and limited cases of hemorrhagic stroke, and their findings were not replicated in a US-based registry study.[27] However, two recent studies from Chinese mainland (a single-center case-control study) and Taiwan region (a multicenter cohort study), consistently reported an independent association between low LDL-C and risk of hemorrhagic transformation.[28,29] For every 1 mM reduction in LDL-C levels, the risk of hemorrhagic transformation increased by 46.2%.[28] The study from China systematically evaluated the performance of current predictive models for post-stroke hemorrhagic transformation, and found a significantly additive value of an LDL-C level of <130 mg/dL on model performance,[29] providing the first evidence that lipid profile is an important component of bleeding risk prediction models. Therefore, ethnic differences in lipid profile,[30] that is, East Asians vs people of European or African descent, might explain the discrepancy between findings from Western countries vs East Asians countries.

High-intensity LDL-C lowering trials and hemorrhagic stroke

In large high-intensity LDL-C lowering RCTs, a trend towards an increased risk of hemorrhagic stroke was also observed in ischemic stroke patients[31] and in ACS patients.[32] The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial randomized 4731 patients who had had a stroke or transient ischemic attack within 1 to 6 months, to high-dose (80 mg) atorvastatin or placebo. During a median follow-up of 4.9 years, high-dose atorvastatin led to a 66% increase in hemorrhagic stroke (55 vs 33; hazard ratio (HR) = 1.66, 95% confidence interval (CI): 1.08–2.55).[31] The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study tested the hypothesis that ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events when added to statins.[32] During a median follow-up of 7 years, the rate of hemorrhagic stroke was numerically higher in the ezetimibe-statin group (59 vs 43; HR = 1.38, 95% CI: 0.93–2.04, P = 0.11). In the Cholesterol Treatment Trialists Collaboration second meta-analysis, hemorrhagic stroke was also numerically (not statistically) more frequent in patients on high-intensity LDL-C lowering therapy.[33] A recent meta-analysis, including 7 RCTs involving 31,099 participants receiving high-dose statins (defined as atorvastatin 80 mg, simvastatin 80 mg, pravastatin 40 mg, or rosuvastatin 20 mg per day), found that high-dose statin therapy was associated with a 53% increased risk of hemorrhagic stroke (relative risk 1.53, 95% CI: 1.16–2.01, P = 0.002).[34] However, the net benefit of high-intensity LDL-C lowering on ASCVD prevention should not be over-interpreted. For example, in the IMPROVE-IT study, the primary composite endpoint during follow-up was cardiovascular death, myocardial infarction, stroke, unstable angina, and coronary revascularization, with a hazard ratio of 0.94 (95% CI: 0.89–0.99). The study provided some evidence of a treatment benefit, but only as a 2.0% absolute treatment difference, indicating a modest benefit.[35] Notably, a multicenter study addressing the effect of high-intensity LDL-C lowering therapy with 80 mg atorvastatin in ACS patients yielded negative findings.[36] Another study among statin-naïve patients with non-ST elevation acute coronary syndrome (NSTE-ACS) before PCI in Korean and Chinese population yielded similar negative results.[37] These studies showed that there is no evidence to support a clinical benefit of high-intensity LDL-C treatment in the Chinese population.

Overall, the findings from epidemiological studies, clinical observations and large RCTs provide ample evidence indicating an inverse association between LDL-C levels and hemorrhagic stroke, and the association is stronger in East Asians. Therefore, an optimal LDL-C level based on the trade-off between a lower ASCVD risk and a higher hemorrhagic stroke risk should be systematically evaluated. In the absence of evidence supporting high-intensity LDL-C lowering in the Chinese population, the potential risk of low LDL-C-related hemorrhagic bleeding warrants caution in clinical practice.

Lipid paradox: definitions, evolution, and implications

Clinical evidence supporting the lipid paradox

Reports discussing dynamic plasma cholesterol changes in ACS patients date to the 1970s.[38] In one study involving 50 patients with myocardial infarction, the authors observed a slight but statistically significant decrease in total cholesterol during hospitalization, which was not significantly different from levels those measured 3 months later. In a more recent study, Pitt and coworkers found that LDL-C levels decreased 24 hours after admission (from 136.2 mg/dL to 133.5 mg/dL), followed by an increase over the subsequent 2 days (to 141.8 mg/dL).[39] Therefore, the slight decrease in the first 24 hours of ACS onset was not clinically meaningful.

In early observational analyses in patients with ACS, hypercholesterolemia was associated with a lower incidence of adverse events.[40,41] This observation has been termed the “hypercholesterolemia/lipid/cholesterol paradox,” and has been confirmed in patients with ST-elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction in different countries/ethnic populations.[9,11,42] Interestingly, one US study found that patients with previously (but no newly) diagnosed hypercholesterolemia, had lower in-hospital mortality, indicating prior medical contact may be a confounding factor to explain this paradoxical finding.[42] However, a later analysis using a large US nationwide registry for myocardial infarction involving 115,492 patients, found that when admission LDL-C levels were stratified by quartiles, compared with patients in the lowest quartile (LDL-C <77 mg/dL), the risk of in-hospital mortality in the second to the fourth quartiles decreased by 21%, 20%, and 15%, respectively.[10] This finding supports an inversely J-shaped relationship between LDL-C levels and in-hospital mortality in MI patients, with the nadir risk observed at an LDL-C level of 77 to 99 mg/dL.[10] It should be noted that the confounders for adjustment were inadequate in the study because several important clinical variables that were closely related to outcomes in MI patients were not captured in the registry. Additionally, patient enrollment occurred mainly through the end of 2006, which may not be representative of contemporary practice for MI patients. More recent studies from Japan and the US extended the association between admission LDL-C and ACS outcome from in-hospital mortality to long-term consequences.[43,44] The Japanese study found that among 942 consecutive ACS patients, those with lower LDL-C (<100 mg/dL) on admission were less likely to receive statin prescriptions, and had a 61% increase in all-cause mortality during a median follow-up of 4.2 years.[43] A similar finding was reported in the US study.[44] It should be noted that by strict definition, lipid paradox regarding ACS refers to short-term outcomes in the acute phase of symptom onset, which may reflect the unique changes in lipid profile during this period. Practically, these findings may facilitate awareness of statin prescriptions and thus, enhance patients’ adherence in these high-risk populations. Moreover, when considering the temporal and spontaneous decline in LDL-C levels during the first week after STEMI, the current dyslipidemia guidelines of the by European Society of Cardiology recommend performing a lipid profile as early as possible in ACS patients.[45] Scientifically, the exact mechanism underlying the inverse association between admission LDL-C levels and adverse events during the acute phase of MI should be thoroughly investigated.

Traditional cardiovascular risk factors and lipid paradox

Regarding the lipid paradox in STEMI patients, serial findings from an Australian group provide insight into the potential mechanisms underlying this phenomenon.[46,47] Standard modifiable cardiovascular risk factors (SMuRFs), which are composed of diabetes, hyperlipidemia, hypertension and cigarette smoking, are fundamental elements for predicting long-term cardiovascular events. In a single-center cohort involving 695 consecutive STEMI patients, a study reported that 25% (132/692) of first-presentation STEMI cases secondary to atherosclerosis had no known SMuRFs at the time of symptom onset, and this trend increased during the study period from 2006 to 2014.[46] In a more recent work from this group, by analyzing a combined database from two registries involving 3081 STEMI patients, the authors found that 19% of first STEMI patients with no history of SMuRFs, had higher in-hospital mortality compared with individuals with one or more SMuRFs.[47] Notably, the authors did not find significant differences in major adverse cardiovascular events at 6 months during the post-discharge follow-up. These findings support the interpretation that current in-hospital management strategies for STEMI, which are based mainly on interventions targeting SMuRFs, may be less effective to improve SMuRF-negative/less patients, for example those with low LDL-C levels on admission. Therefore, for STEMI patients without clustering of traditional cardiovascular risk factors, identifying potential biomarkers/mechanisms underlying this phenotype could facilitate the development of novel preventive strategies.

An important and as yet-unresolved issue is whether there is a difference between treatment-induced low LDL-C and spontaneous low LDL-C (statin-naïve) to explain the lipid paradox. In a Turkish study, 1808 STEMI patients receiving primary angioplasty, were divided into four categories according to admission LDL-C (low: <70 mg/dL; high, ≥70 mg/dL) and pre-hospital statin use (yes or no).[48] Compared with the other three categories, the key features of STEMI patients presenting with spontaneous low LDL-C were advanced age, low body mass index, worsened Killip class, low blood pressure, compromised renal function, and low hemoglobin level. Importantly, this category was also characterized by an enhanced inflammatory response on admission: compared with the statin-naïve/high LDL group, spontaneous low LDL-C patients had higher levels of C-reactive peptide (CRP), white blood cell counts and neutrophil/lymphocyte ratio. Consequently, the statin-naïve/low LDL group had the worst in-hospital and long-term (median follow-up duration: 40 months) outcomes among the four categories, whereas the pre-hospital statin/low LDL-C group had - significantly improved short and long term outcomes.[48] These findings have two important messages: (1) regarding patients’ clinical features and outcomes, STEMI patients with spontaneous low LDL-C were very similar to SMuRF-negative/less STEMI patients; and (2) patients with spontaneous low LDL-C presented with an exaggerated/uncontrolled inflammatory response following STEMI (or chronic inflammation before STEMI onset). Theoretically, patients with statin pretreatment-induced low LDL-C may have improved outcomes because of the well-known anti-inflammatory properties of statins. However, statin use may reflect differences between characteristics; patients treated with statins may have a high-risk profile and hence, potentially poor outcomes. For example, one study showed that in statin-pretreated STEMI, despite a lower 30-day mortality, the improvement was blunted at 6 months, driven mainly by an increased risk of target vessel revascularization.[49] In a recent analysis derived from a large US-based registry of NSTE-ACS, the authors analyzed the clinical profiles of statin-naïve patients with a mean age of >60 years, according to baseline LDL-C levels (<70, 70–99, 100–129, ≥130 mg/dL).[50] The authors found that patients in the lowest LDL-C group had their first NSTE-ACS event at a significantly older age and were less likely to have a family history of coronary heart disease, despite a higher prevalence of hypertension and diabetes. Regarding hemorrhagic stroke, the lipid paradox appears be independent of pretreatment with statins,[51] and could be seen in statin-naïve ischemic stroke but not in hemorrhagic stroke.[52] Therefore, the clinical outcomes between statin induced- and spontaneous low LDL-C remains to be addressed in well-designed analyses with sufficient power.

Chronic inflammation and lipid paradox

Interestingly, the concept of the lipid paradox has also been used in rheumatology to describe the phenomenon in which patients with low LDL-C in active rheumatoid arthritis have worsened cardiovascular outcomes.[53,54] Dyslipidemia is common in active rheumatoid arthritis patients, and is characterized by lower LDL-C and high-density lipoprotein cholesterol (HDL-C). In this population, although the data are limited, epidemiological studies have shown an increased risk of cardiovascular disease compared with individuals without rheumatoid arthritis.[53] Additionally, suppressing inflammation with disease-modifying anti-rheumatic drugs (such as hydroxychloroquine, methotrexate, sulfasalazine and leflunomide) appears to raise LDL-C levels, and contributes to a contradictory reduction in cardiovascular risk.[55] To delineate the relationship between intravascular inflammation and blood lipid levels, Johnsson et al[56] analyzed the association between CRP levels and blood total cholesterol and HDL-C in 11,437 samples from a population of with both acute and chronic conditions. The authors demonstrated a biphasic change between total cholesterol and CRP: total cholesterol increased within the healthy CRP range of <5 mg/L, whereas a decreasing trend was observed when CRP levels exceeded 10 mg/L. The study also found an inverse relationship between HDL-C and CRP. These studies provide further evidence supporting uncontrolled inflammation as a potential contributor to the lipid paradox.

Results from these studies also suggest that chronic inflammation or uncontrolled inflammation in response to stress may serve as an important phenotype underlying the mechanism of the lipid paradox.

Microbial translocation following STEMI: potential impact and association with the lipid Paradox

In an effort to identify non-traditional risk factors associated with poor outcomes in STEMI patients, we recently identified a potential link between microbial translocation and innate immunity activation after myocardial infarction.[57] Patients with heart failure more frequently have reduced blood flow to the gastrointestinal system, which contributes to intestinal wall edema, thickening and gut epithelial barrier dysfunction.[58] These changes result in gut-derived microbial translocation into the systemic circulation, which is common in patients with impaired intestinal barrier function, that is, inflammatory bowel disease.[59] With these considerations, we were the first to report higher microbial numbers and diversity in the systemic microbiome of STEMI patients, which was correlated with systemic inflammation and predicted adverse cardiovascular events.[57] Following experimental myocardial infarction in mice, compromised left ventricular function and intestinal hypo-perfusion drove a transient intestinal barrier dysfunction and increased gut permeability through tight junction protein suppression and intestinal mucosal injury. Consequently, antibiotic therapy using polymyxin B to target lipopolysaccharide, a circulating biomarker for microbial translocation, alleviates systemic inflammation and left ventricular dysfunction in mice. These data support the interpretation of microbial translocation as a potential driver of post-myocardial infarction-related inflammation. In chronic heart failure patients, one study found that lower total cholesterol and LDL-C levels are independently associated with a worse prognosis. Mechanistically, this finding, as well as findings in previous studies, suggests that circulating LDL-C can bind to and inactivate a broad range of microorganisms and their toxic products, such as lipopolysaccharide.[60] Therefore, it is possible that after STEMI, LDL-C particles may exert their protective role by neutralizing microbial translocation, whereas a reduction in LDL-C levels may predispose to uncontrolled inflammation and adverse outcomes.

A double-hit hypothesis and its implications

Despite solid evidence linking low LDL-C and hemorrhagic stroke among East Asians, the mechanisms underlying an association is far from clear. Current hypotheses are based mainly on the fact that an adequate lipid level is essential for maintaining normal membrane fluidity and vessel integrity, according to early studies, and hypotheses included low LDL-C-induced blood-brain barrier permeability derangement,[61] increased vessel wall smooth muscle necrosis,[17] increased fragility of red blood cell membranes and suppression of LDL-induced platelet activation.[20] As mentioned earlier, the lipid paradox in patients with ACS, and in chronic inflammation conditions, such as rheumatoid arthritis, is not limited to the bleeding risk. Therefore, we hypothesized a “double-hit” model for low LDL-C-related cardiovascular risk (Fig. 1), which is described as follows: after low LDL-C exposure (the first hit, spontaneous or treatment-induced), there are functional and structural changes in endothelial cells and smooth muscle cells in the vessel wall, as well as changes in red blood cells and platelet function. The second hit may be iatrogenic or secondary to exposure to stressful environmental factors, such as initiation of high-intensity antiplatelet therapy after PCI, aggressive LDL-C-lowering therapy, anticoagulation (perioperative/oral), high blood pressure, infection and possibly intestinal microbial translocation. These factors increase stress in these vulnerable patients and contribute to bleeding events and an uncontrolled inflammatory response leading to increased cardiovascular risk. Notably, concerning the effect of the interaction of antiplatelet therapy and low LDL-C on bleeding risk, one study from China and another report from Japan found that low LDL-C level was an independent risk factor for discharge bleeding risk following PCI in patients receiving dual-antiplatelet therapy.[12,62] Therefore, East Asians seem more vulnerable to low LDL-C exposure-related bleeding risk.

Figure 1
Figure 1:
The “double-hit” hypothesis of low LDL-C-related cardiovascular risk. With exposure to very low LDL-C levels (the first hit, whether spontaneous or treatment-induced), there are functional and structural changes in endothelial cells and smooth muscle cells in the vessel wall, as well as changes in red blood cells and platelets. The second hit may be iatrogenic or secondary to exposure to stressful environmental factors, such as initiation of high-intensity antiplatelet therapy after percutaneous coronary intervention, aggressive LDL-C-lowering therapy, anticoagulation (perioperative/oral), hypertension, infection, and possibly intestinal microbial translocation. These factors work synergistically in vulnerable patients to trigger bleeding events and an uncontrolled inflammatory response, and consequently lead to increased cardiovascular risk. BBB = blood-brain barrier, LDL-C = low-density lipoprotein cholesterol, RBC = red blood cell.

Conclusion and Perspective

With emerging evidence supporting the role of proprotein convertase subtilisin/kexin type 9 inhibitors in preventing ASCVD, and the current paradigm of “lower is better” for LDL-C-lowering treatment, caution should be exercised in patients with low LDL-C levels (<70 mg/dL), especially in older patients,[60] and East Asian patients. Our hypothesis concerning the underlying pathogenesis of low LDL-C and cardiovascular risk may help explain the lipid paradox, and more importantly, may raise clinicians’ awareness to identify potential high-risk patients with the aim of balancing the risk of thrombosis with bleeding complication.

Acknowledgments

None.

Author contributions

XZ wrote the manuscript. XZ and QY contributed to the manuscript conception, revised the manuscript and approved the final version of the manuscript.

Financial support

This work was supported by the National Natural Science Foundation of China (Nos. 81570335, 81970304) and a grant from Tianjin Municipal Science and Technology Commission, China (No. 18ZXZNSY00290).

Conflicts of interest

The authors declare that they have no conflicts of interest.

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Keywords:

acute coronary syndrome; bleeding; hemorrhagic stroke; lipid paradox; risk factor

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