Dr. Tolga Daniel Dittrich

Considering the trend toward simpler imaging approaches for patient selection for endovascular treatment in acute ischemic stroke, COMBINE ASPECTS seeks to improve our current understanding of ASPECTS-based stroke acute imaging to further optimize treatment selection strategies and make meaningful contributions to stroke care.

Within five subprojects, we aim to systematically assess and refine the diagnostic and prognostic capabilities of ASPECTS. The subprojects will explore a spectrum of critical areas:

1. the accuracy of native CT in estimating ischemic core
2. the impact of discordant baseline imaging findings on treatment decisions
3. the utility of ASPECTS in evaluating ischemic core reversibility
4. the potential of hypodensity mapping to predict functional outcomes, and
5. the reliability of ASPECTS assessment amidst moderate to severe small vessel disease

Background: Atherogenic lipoproteins, also called ApoB lipoproteins, circulate in the blood and can be trapped into the arterial wall, where they initiate and drive atherosclerosis. All atherogenic lipoproteins are coated by apolipoprotein (apo) B. ApoB lipoproteins include:

1. the cholesterol-rich low-density lipoprotein (“bad cholesterol”)
2. lipoprotein(a) (Lp(a)) and
3. the triglyceride-rich very-low density lipoprotein.

There are pharmacological treatments to lower ApoB blood levels. Statins lower apoB levels by lowering low-density lipoprotein cholesterol (LDL-C) and reduce the risk of ischemic stroke caused by atherosclerosis. However, even among patients achieving very low LDL-C blood levels, there is a relevant residual risk of stroke. Factors who can contribute to the residual risk include:

1. atherogenic Lp(a) - whose blood levels are genetically determined and are increased by statins - and
2. a hemorrhage within the carotid atherosclerotic plaque - a marker of plaque vulnerability - as seen on Magnetic Resonance (MR) Plaque Imaging.

Recently, we completed a prospective cohort study with 1759 participants showing that increased Lp(a) levels were associated with an increased risk of ischemic stroke linked to carotid atherosclerosis independent of LDL-C (manuscript submitted). In a separate cohort study, carotid intraplaque hemorrhage was associated with an increased risk of ischemic stroke. However, so far, no study assessed - within the same cohort of patients - the link between apoB, Lp(a) and carotid intraplaque hemorrhage with ischemic stroke. Important questions remain yet unanswered, for instance - are patients suffering no ischemic stroke despite carotid intraplaque hemorrhage protected by low apoB and Lp(a) levels? Do patients who suffer ischemic stroke despite low apoB and Lp(a) levels have more frequently carotid intraplaque hemorrhage?

Specific Aims: AGELESS has 3 specific aims - they all refer to patients with carotid atherosclerosis:

1. to compare patients with and without carotid intraplaque hemorrhage, as assessed with MR-Plaque Imaging, in terms of apoB, Lp(a) levels and traditional cardiovascular risk factors.
2. to assess the risk of first-ever ischemic stroke in relation to apoB, Lp(a) levels, and presence of intraplaque hemorrhage, after adjusting for traditional cardiovascular factors.
3. to assess the risk of recurrent ischemic stroke in relation to apoB, Lp(a) levels, and presence of intraplaque hemorrhage, after adjusting for traditional cardiovascular factors.

Methods: We plan a cohort study over four years - the AGELESS study. AGELESS will recruit patients with carotid atherosclerosis (stenosis 30-99%) with (n=250) and without (n=250) ischemic stroke at the Stroke Center of the University Hospital Basel (primary center and central MR reading) and Zurich (partner center), Switzerland. Aims 1 & 2 will be assessed through a cross-sectional, case-control design; aim 3 through a prospective longitudinal design. Patients with and without an ischemic stroke will be mainly included in the Stroke Unit and outpatient neurovascular unit, respectively. All patients will undergo carotid MR-Plaque Imaging. For aim 3, the duration of follow-up for recurrent ischemic stroke will span between 3 months and 45 months of the index stroke, depending on when along the study course patient are recruited.

Relevance: AGELESS aims to build a bridge of knowledge linking the type and concentration of atherogenic lipoproteins via in-vivo MR-Plaque Imaging to clinically relevant endpoints such as ischemic stroke. Understanding the contributions of the different lipoproteins on ischemic stroke becomes even more important in view of the growing number of lipid-lowering therapies - each one with differential effects on the subtypes of atherogenic lipoproteins. Moreover, owing to the high natural risk of stroke recurrence in the first 3 months, sponsors of pharmaceutical trials traditionally exclude patients with an acute ischemic stroke. In AGELESS, we deem right this vulnerable phase of utmost interest to better understand stroke risk conditional on lipoproteins levels and novel, strong imaging marker of stroke risk such as intraplaque hemorrhage.