Thread by @Lpa_Doc

1/23 Saturday Morning Class #14 Lp(a) and stroke @stsimikas @OxPL_apoB

Happy Saturday to all. Today, we will review evidence of Lp(a) as a risk factor for stroke in children, middle aged adults and elderly.

First, a graphic, note increase in papers in Medline since 1986

2/23 Useful fact: on Medline, searches for “Lp(a)”, “Lp (a)”, “lipoprotein(a)” or “lipoprotein (a)” don’t work. You need to use “lipoprotein a”. Medline has 8,759 citations on “lipoprotein a”. There are 611 citations on “lipoprotein a and stroke”, so 6.9% of citations

3/23 I have probably read only 25% of these (hopefully the key ones). If each takes 30 minutes on average to get the gist, it will take ~4400 hours to get through all of them, or 547, 8-hour days of just reading papers… so about 2 full years not including weekends. Daunting.

4/23 Background: Assigning associations/causality to risk factors for stroke or transient ischemic attack (TIA) is more complex vs other CV phenotypes, due to the fact that stroke can be due to multiple etiologies, from small or large vessel ischemia, hemorrhage, and embolism

5/23 These varied etiologies not only have different pathophysiological bases, but they also need to be carefully adjudicated. Since Lp(a) is an atherothrombotic risk factor, its association with stroke or TIA attack would be most likely be present in ischemic etiologies.

6/23 What is evidence: a meta-analysis in 2015 encompassing comprising 90,904 subjects and 5029 stroke events, and several other recent studies from China, US, and EU ihave all shown an association.

sciencedirect.com/science/articl…
sciencedirect.com/science/articl…

7/23 Some key methodological issues:

1-Blood samples need to be collected within 24 hours of admission, which is an important methodological issue as Lp(a) is known to rise during severe illness due to its role as an acute phase reactant.

8/23 2-The LPA gene has an IL-6 response element and increases in IL-6 may upregulate apo(a) synthesis. This minimizes confounding by mostly excluding a causal association of elevated Lp(a) to the size of the infarction, rather than the pre-event level as the etiology

9/23 3-Lack of Lp(a) assay standardization make it difficult, but nit impossible, to compare data
4-need to make sure only “ischemic” stroke is counted and not lacun]nar stroke (i.e high blood pressure), hemorrhage (anuerysms) or embolic stroke (i.e from afib, aortic arch)

10/23 In most studies, odds ratios are ~1.5 in highest vs lowest categories (usually quartiles). This is fairly robust, but often a bit lower than risk of MI. Lets look at 3 categories of pts- children, young adults and elderly

11/23 Children-
1-Reports continue to be published on children with stroke of unclear etiology, and in particular recurrent stroke. However, causally is difficult to assign since stroke in children is a very rare event (<<1% of children) but elevated Lp(a) is quite common

12/23 2-20% of children expected to have Lp(a) >50 mg/dL since levels are genetically determined, similar to adults.
3-Children frequently have a “second hit” that may include congenital/structural heart disease, coagulation disorders or chronic pro-inflammatory conditions.

13/23 4-In addition, children with elevated Lp(a) rarely have atherosclerosis, unless they have concomitant severe familial hypercholesterolemia, so Lp(a) as a causal agent may be more due to disruption of fibrinolytic pathways.

14/23 Young adults:
1-ORs are up to 4.0. Many have negative w/u for other etiologies, like occult paroxysmal atrial fibrillation, aortic arch atheroma, patent foramen ovale with paradoxical emboli, and hypercoagulable state. Often, many of these evaluations have a low yield

15/23 2-Adding Lp(a) to such a work-up is expected to be cost-effective as it is an inexpensive test and only has to be measured once and may identify unsuspected cases in an otherwise negative work-up, and should be now considered as part of the routine work-up.

16/23 3- elevated Lp(a) from birth with superimposed pro-inflammatory effects of OxPL and anti-fibrinolytic properties of apo(a) may predispose to non-obstructive plaque inflammation and ischemic events.
4-In pt <65 yo with no obvious other etiology, its worth checking Lp(a)

17/23 Elderly
1- elderly subjects accumulate multiple risk factors which may be additive or synergistic to Lp(a) that can manifest as carotid and intracranial disease, leading to distal embolization of plaque/platelet emboli as well as acute thrombotic occlusion.

18/23 Pathophysiology
1-It is to be emphasized that Lp(a) is not ‘pro-thrombotic” per se and would only be involved pathophysiologically in mediating thrombus growth/extension if a thrombus was already forming due to another etiology.

19/23 2- In contrast, young adults, traditional cardiovascular risk factors may not have fully accumulated, but may have early atherosclerosis where plaque burden cannot wholly account for events.

20/23 Therapy:
1-Prompt restoration of flow. It is to be emphasized that thrombolytic agents act by activating plasminogen to plasmin that then acts to degrade on fibrinogen and fibrin clots, leading to thrombus resolution.

21/23 2-Tissue plasminogen activators have no have direct fibrinolytic effects. Both plasminogen/plasmin and apolipoprotein(a) contain a lysine binding pocket and can attach tightly to thrombi and damaged endothelium.

22/23 3-Since Lp(a) at high local concentrations can prevent activation of plasminogen, it is possible that subjects with elevated Lp(a) may have lower rates of reperfusion and/or higher rates of re-occlusion following thrombolytic therapy or mechanical thrombectomy.

23/23 Right now, ASOs @ionispharma, @Novartis remain most promising approach if this is the etiology. Will be assessed in Lp(a) HORIZON trial - clinicaltrials.gov/ct2/show/NCT04…