“Reports have demonstrated that the minuscule JAK2V617F clones with low VAF have a clinically biological impact on the cardiovascular system.
In patients with vascular diseases with mean JAK2V617F of 0.45% ranging from 0.06% to 1.73%, mRNA expressions of IL-1β in JAK2V617F-expressing peripheral leukocytes were significantly increased compared to JAK2V617F-negatives .
In the experimental CH models using GFP, mice with JAK2V617F chimerism of 1–19% as well as 20–49% and 50–100% showed similar pulmonary hypertension phenotypes, and mice with JAK2V617F chimerism even with lower chimerism of <1% tended to display exacerbated pulmonary hypertension.
Clones carrying JAK2V617F potentially proliferated and matured from the precursors in the tissues such as the lungs.
Patients with JAK2V617F VAF <2% showed similar survival and thrombotic incidence as those with VAF 2-10%. Participants with JAK2V617F VAF ≥1% who showed the majority of 1-10% VAF represented a significantly increased prevalence of venous thrombosis ]. A small clone with JAK2V617F mutation remains stable as a subpopulation for many years ].
Thus, the persistent exposure to JAK2V617F even with low VAF and the vicious cycle between CH and cardiovascular diseases [[52]] may contribute to the process of disease progression. Further studies are required to elucidate the link between VAF levels of JAK2V617F and its clinical relevance for cardiovascular disease.”
Fresh look at non-MPN risks of Jak2 allele. It appears to be from a translation.
I made some misc comments here:
My take is low VAF of Jak2 v617f (allele) is a risk for cardio for both MPNs and non-MPNs, while zero Jak2 allele does not have these risks. If so most of us will hold these risks since getting to zero is rare even on IFN.
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Jak2 allele is also a cardio risk: "JAK2V617F (is) causally associated with cardiovascular diseases independently of the presence of hematological disorders (MPN etc)."
MPNs are Dx when Jak2 allele is more than 1%: "this VAF level is generally accepted as a cut-off for routine MPN diagnostic purposes"
But Jak2 cut-offs are uncertain because tests they are based on have improved, currently less than 1%. "current next-generation sequencing platforms are capable of detecting a low level of somatic mutations <1% VAF, the cut-off values of JAK2V617F VAF were set with 1-5%" Suggests our discussions of MPN effects at the lower alleles are muddied since it goes as high as 5%.
Non MPNs with Jak2 allele varied from 0.10% to 5.32%. Among these "the presence of JAK2V617F-mediated CH was associated with 12.1 times the risk of incidence of coronary heart disease. CH is clonal hematopoiesis which seems to be Jak2+ healthy individuals who do not show any hematologic disorders (this is one place the translation is not clear to me)
Jak2 is uniquely risky for cardio: This risk (with Jak2 allele) was much higher than other CH-related genes such as DNMT3A, TET2, and ASXL1
Regular cardio Dr appointments are a good idea: "A recent clinical study revealed that JAK2 somatic mutations of ... were strongly associated with an increased risk of heart failure" "management for cardiovascular diseases in persons with JAK2V617F-CH and MPN patients is critical for improving their prognosis." I see a cardio Dr regularly.
Jak2 increases hi BP and there may be a target for treatment: "The inhibition of ALK1 completely prevented the development of pulmonary hypertension in mice with JAK2V617F"
Large risk of aortic aneurysms: "23% of the patients with JAK2V617F-positive MPN exhibited aortic aneurysms, suggesting a much higher prevalence of aortic aneurysms in MPN patients in comparison to the general population."
For cardio disease even very small (<1%) VAF adds risk over long times: "A small clone with JAK2V617F mutation remains stable as a subpopulation for many years. Thus, the persistent exposure to JAK2V617F even with low VAF and the vicious cycle between CH and cardiovascular diseases [[52] may contribute to the process of disease progression"
Cardio Risk Prognosis: "identifying JAK2V617F-positive carriers may be an innovative strategy as precision medicine to stratify cardiovascular events."
Rux may reduce cardio risk, but is own risks are a concern. They suggest already available therapies which go after IL-1β for heart failure and other therapy to address ALK1 for blood pressure. (would IL-1β therapies help MPNs?)
Could cholesterol control reduce risk of mutations? "a recent study revealed that atherosclerosis (plaque effects) accelerated hematopoietic stem cell division and proliferation and expedited clonal evolution (eg Jak2 allele)"
Thank you for your in depth comments, although not having a medical background a lot of it is a bit over my head but what I take from this is that those of us with the JAK2V617F mutation are at increased risk of heart disease. I note you see a see a cardio Dr regularly. Can I ask, do you get him/her to carry out specific tests and if so what are they?
I've had abnormal EKGs for years, it's from, in non medical terms, a mildly squished chest. So heart is mounted funny and room is tight.
Cardio is different from MPN that it's a mature field that is changing but at normal rates. So the tests and implications are better understood which is a nice change.
I've had the usual, UltraSound (2 of them) to look for valve function and heart structure, stress on the treadmill, EKG, Lipids blood, and a CAT scan for calcium in the heart and hands-on from cardio Dr. They found minor backwash in the valve.
I just did a heart monitor for two weeks to finally resolve thumps and bumps in the heart. It's Supraventricular Tachycardia where "there’s an extra pathway in your heart that causes an electrical signal to circle around and around instead of moving down to the ventricles." Dr is not concerned, but there are such electrical malfunctions that are more serious, I think AFib is one.
I am at risk for the aortic aneurysms since my mother had one, so MPN + mother = extra risk for this.
So far no MPN sort of complications in cardio. But we see here it can show up any time so I'll keep up the appts.
Many thanks for your detailed reply. It is a good point that Cardio is a mature field and it is also good that you have been able to have your heart thoroughly checked out.
I had some atrial fibrillation in the past that seems to have settled down but my GP used to get an EKG annually, checking for a long QT interval but that hasn't happened for 3 years now. Maybe I will ask for that to be run again or invest in a Fitbit to see if it shows up still.
That's good that so far you don't have any MPN related cardio issues. Keep up the appointments.
I was diagnosed as having PV by my regular hematologist 2 years ago. due to being Jak2 +. I have high cholesterol but since my calcium cardiac scan was 0, my cardiologist said I do not need to go on a statin as I am very low risk for having a cardiac event. My allele burden is 3.5%. My bone marrow looked normal on biopsy. I am being classified as MPN-U. My MPN doc says it is puzzling but will probably change to PV (or possibly ET) in the future & am still at risk for a thrombotic event. The article is way over my head. Am I understanding it to say that if you are Jak2+ and have a low allele burden that you are high risk for a cardiac event?
I agree the article is not easy reading. Your condition may match what they called JAK2V617F-mediated CH which "which seems to be Jak2+ healthy individuals who do not show any hematologic disorders" If so it shares our 12x risk increase.
Some Drs would advocate you start IFN to reduce odds of that progression your Dr predicts, and maybe take your allele burden even lower. This is discussed in some prior posts with the idea of treating MPNs like other cancers, start early.
I first noticed Shortness of Breath a few months after my 2013 ET diagnosis and starting HU. Long story short: SOB never went away and gradually worsened, 2019 it was found to be angina, 2022 diagnosis of Coronary Artery Spasm. My heart and it’s vessels are otherwise healthy.
My understanding of the published papers is limited but have wondered for a long time if my MPN and SOB evolving to CAS (vasospasm) are linked.
Thanks for posting. It’s encouraging to read that Jak2 is being investigated outside the hematology/oncology department to expand our treatment options in the future.
This is very interesting to me because I just had a CAT scan of my abdomen yesterday because of pain in my left side. I thought it was my spleen but it was not. I was told I have arterial atherosclerosis. I don’t have high cholesterol and I have been slenderer my entire life and try to eat well. I am post Et Mf and I do you have a Jak2 VC17F mutation. I wonder now, if that’s the reason.
Ultimately I think this speaks to the issue that the JAK2 mutation does more than upregulate hematopoiesis. The JAK-STAT pathway is responsible for more than that. The body's kinase systems are complex with many different functions.
I'm reading through this all now. As I posted a few days ago, I had an Afib event on Dec 1st out of nowhere. I ride a Peloton bike 2x a week focusing on HIT and endurance, do other cardio work and strength train 3x a week. I do stress tests maybe every two years and also take blood work to test for precursors.
I have never had heart issues other than infrequent tachycardia in my 40's due to stress. . During stress test this week I went into Afib again and my heart then stayed up at 138 for over 50 minutes while I was trying to relax. I was admitted and given Flecainide and metoprolol. I'm on flecainide twice a day and Eliquos for 30 days to prevent blood clots.
I simply can't believe this turn of events.
My cardiologist was also stunned as she said I have no risk factors then then age--65 next year. My heart has nothing wrong with it structurally.
The initial thinking was that it was Besremi so I was told to not give myself my dose this week. Now, the doctors think Besremi probably didn't cause it and the benefits of the drug out way any small risk.
Stress? I am taking care of my husband after his open heart surgery. Been a rough year.
Recently, I often had unstable blood pressure, mostly high. About three weeks ago I started taking hawthorn capsules regularly. My blood pressure has stabilized and is now within normal limits. I have long known about the benefits of hawthorn and now I tried it. I am very pleased with the result and the fact that this is a natural supplement.
Thanks so much for posting, this explains an awful lot for me! I had a heart attack in March 2021, and at that time my blood counts in the hospital were normal, however I had been suffering from pruritus for many months, and not knowing the cause (ultimately discovered to be PV), I'd seen a dermatologist and then a gynecologist (itching being a menopause symptom, but I was really mostly past the menopause). It was a couple of months AFTER my heart attack that blood tests (initiated by the gynecologist) revealed very high levels of RBC, hemoglobin, hematocrit, platelets etc.) which then took me to my current hematologist who diagnosed the JAK2V617F and started me on treatment. I never really understood why I had a heart attack (blocked artery) when my blood counts weren't high at the time, but my hematologist said it was presence of JAK2V617F and he was obviously right. I am extremely lucky that I see a cardiologist and hematologist in the same medical group, and they can access each other's notes. My heart attack was a complete shock and mystery to me: I was an active 57-year old, slim, worked out, didn't smoke, ate a healthy pescatarian diet. As I say, this explains everything! Thanks again, Helen
That is in line with what my hematologist told me when I asked if I really needed aspirin therapy, given my healthy lifestyle. Regardless of platelet counts, harboring the Jak2 mutation increases our risks of blood clots.
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Kidney disease and ET, HU
Chronic kidney disease
Pegasys and elevated ALT and Ferritin
ET and Autoimmune disease
