CardioNerds join Dr. Tony Li Yi Wei, Dr. Rodney Soh Yu Hang, and Dr. Zan Ng Zhe Yan from the National University Heart Centre Singapore for a cocktail drink on the top of marina bay sands. They discuss the following case featuring a young woman with recurrent ACS ultimately found to have Takayasu Arteritis. The ECPR for this episode is provided by Dr. Teng Gim Gee and Professor Tan Huay Cheem. Episode audio was edited by student Dr. Shivani Reddy.

A 37-year-old woman presents with chest pain. She has a background history of Hashimoto thyroiditis, gestational diabetes, and anemia of chronic disease and possible iron deficiency. Her significant medical history includes ischemic heart disease with prior coronary angiogram showing triple vessel coronary artery disease for which she underwent coronary artery bypass graft surgery (CABG) with LIMA-LAD, SVG-OM, SVG-RCA. After CABG, she had recurrent admissions in the subsequent year with acute coronary syndromes where she underwent percutaneous coronary intervention (PCI) to SVG-OM, RI, proximal LAD, and distal LAD. She was a non-smoker and had been compliant with her medications. For her current presentation, she underwent myocardial perfusion imaging which showed a large sized area of inducible ischemia in the LCx territory.  Repeat coronary evaluation showed occluded SVG-OM, occluded LIMA-LAD where she underwent PCI. Clinically, she was noted to have weak brachial and radial pulses on the left side with systolic blood pressure difference between both arms. CT Thoracic Angiogram demonstrated concern for underlying large vessel vasculitis such as Takayasu arteritis. ESR was elevated at 34. Rheumatology was consulted and she was diagnosed with Takayasu arteritis and started on prednisolone and azathioprine. Given her young age, absence of traditional atherosclerotic risk factors, and progressive coronary disease, Takayasu arteritis was deemed the underlying etiology of her coronary disease.

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1. Approach to accelerated CAD and/or CAD in the young: Causes of MI in young patients can be divided into four groups, although a considerable overlap exists between all groups. (1) atheromatous CAD, (2) non-atheromatous process such as spontaneous coronary artery dissection, vasculitides such as Takayasu disease, (3) hypercoagulable states leading to recurrent arterial and venous thrombosis and/or thromboembolism, and (4) recreational drug use.
   
2. Clinical Presentation of Takayasu and prevalence of cardiac involvement: Takayasu’s arteritis is classified as a large-vessel vasculitis because it primarily affects the aorta and its primary branches. It has a worldwide distribution; however, the greatest prevalence is seen in Asia. Women are affected in 80 to 90 percent of cases, with an age of onset that is usually between 10 and 40 years.
   
3. Management of Takayasu arteritis: As for systemic anti-inflammatory therapy, the mainstay of treatment would be systemic glucocorticoids guided by the care of a rheumatologist. A steroid sparing agent may be given in conjunction for long term suppressive therapy to achieve longer-term disease control. The choice of additional agents depends on several factors including considerations regarding comorbidities, a patient’s plans for conceiving a child, cost of treatments, and availability of specific agents. Options include methotrexate, azathioprine as well as mycophenolate. There are also growing studies into anti-TNF-alpha agents such as etanercept or infliximab.
   

Focusing on young patients presenting with myocardial infarction (MI), the definition is often arbitrary, with most studies using an age cut off of around 40-45 years. As we know, the risk factor profile of the younger population is different with lower prevalence of traditional cardiovascular risk factors, and women of this age group are generally premenopausal.

Causes of MI among such patients can be divided into four groups, although a considerable overlap exists between all groups.

The first etiology is that of atheromatous CAD, which is linked to conventional risk factors in older patients that we are familiar with. This includes smoking, lipid abnormalities including familial hyperlipidemia, insulin resistance, hypertension, and obesity. Other more novel risk factors include hyperhomocysteinemia and elevated lipoprotein (a).

Secondly, there are non-atheromatous coronary pathologies. These include conditions such as spontaneous coronary artery dissection especially prevalent in peripartum females. Other considerations include vasculitides with coronary artery involvement such as Kawasaki disease with coronary artery aneurysms as well as Takayasu disease, coronary vasospasm, and microvascular dysfunction

The third etiology is that of hypercoagulable states leading to recurrent arterial and venous thrombosis. Examples include antiphospholipid syndrome and Factor V Leiden mutations. Acquired hypercoagulable states like nephrotic syndrome, thrombotic thrombocytopenic purpura, solid organ malignancy, and myeloproliferative disorders have possible associations with arterial disease in the form of MI (REF). Embolic phenomenon may also cause coronary obstruction (from thrombi, infective vegetations, cardiac masses, etc).

Finally, recreational drug use must be considered, although it is the least common etiology in Singapore because of strict laws prohibiting it. Cocaine use is associated with MI by inducing coronary vasospasm as well as hypercoagulability, and long term cocaine use also leads to accelerated atherosclerosis as well as nonischemic cardiomyopathy.

Takayasu’s arteritis is classified as a large-vessel vasculitis because it primarily affects the aorta and its primary branches. It has a worldwide distribution; however the greatest prevalence is seen in Asia. Women are affected in 80-90% of cases, with an age of onset that is usually between 10 and 40 years.

The onset of symptoms in Takayasu arteritis (TAK) tends to be subacute and diagnosis is often only made at the point where there is significant vascular disease leading to symptoms due to resultant ischemia in the affected vascular territory.

Physical examination is what led to the clinical suspicion of a large vessel vasculitis in our patient.

Measurement of BP should be done in all four extremities to evaluate for arterial stenoses. Many patients with TAK will have partial or complete occlusion of one or both subclavian, axillary, or brachial arteries, or the brachiocephalic artery, leading to low-pressure readings in the ipsilateral arm. Similarly, femoral or more distal arterial stenoses will lower leg blood pressures and stenosis of the aorta may lead to bilateral low blood pressure readings.

Bruits may be heard over the bilateral carotid, subclavian, axillary, renal, and femoral arteries, as well as the abdominal aorta. Cardiac auscultation may reveal signs of aortic valvular disease, pulmonary hypertension, or heart failure. Pulses should be felt for and evaluated at bilateral temporal, carotid, brachial, femoral, and dorsal pedal arteries, and any arterial tenderness should also be noted. Signs of limb ischemia should be sought.

In most cases, a clinical diagnosis of Takayasu arteritis can be made in a patient with both suggestive clinical findings (eg, constitutional symptoms, hypertension, diminished or absent pulses, and/or arterial bruits) and imaging showing narrowing of the aorta and/or its primary branches.

There are no specific diagnostic laboratory tests for TAK. As a disease with systemic inflammatory process, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be elevated but normal values do not exclude Takayasu arteritis.

Patients with suspected TAK should undergo imaging of the arterial tree by MR or CT angiogram to evaluate the arterial lumen, looking out for smoothly tapered luminal narrowing or occlusion that is sometimes accompanied by thickening of the wall of the vessel. 18 F-FDG – Positron emission tomography (PET), often in combination with CT (PET-CT) or MR (PET-MR) is an increasingly utilized test to evaluate for possible large-vessel vasculitis. The finding of “hot” segments (ie, those with increased standardized uptake values of fludeoxyglucose-F18) in the right clinical setting may be suggestive of large-vessel vasculitis. There is increasing use of PET to aid in the diagnosis of TAK.

Although definitive, getting a histological diagnosis via biopsy of the large arteries is impractical and rarely done. However, occasionally arterial tissue may become available after a revascularization procedure or aneurysm repair

American College of Rheumatology classification criteria were developed to help distinguish one form of vasculitis from another, however they are limited in terms of their use in clinical practice. The criteria are

• Age at disease onset ≤ 40 years
  
• Claudication of the extremities
  
• Decreased pulsation of one or both brachial arteries
  
• Difference of at least 10 mmHg in systolic blood pressure between the arms
  
• Bruit over one or both subclavian arteries or the abdominal aorta
  
• Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities, not due to arteriosclerosis, fibromuscular dysplasia, or other causes
  

Patients are said to have TAK if at least three of the six criteria are present. Although these criteria have been widely used by clinical researchers and clinicians to help diagnose patients, accurate diagnostic criteria have yet to be developed.

Management is targeted at tackling the inflammation in the various vascular territories and also endovascular or surgical procedures for critical areas of stenosis that have contributed to irreversible ischemia or aneurysm.

For example, as in this case, significant coronary artery disease leading to myocardial infarctions were addressed with surgical and/or percutaneous revascularization as per usual care for atherosclerotic CAD. Significant peripheral arterial disease can be treated in a similar fashion.

As for systemic anti-inflammatory therapy, the mainstay of treatment would be systemic glucocorticoids guided by the care of a rheumatologist.

• The initial dose of steroids would depend on the nature and severity of disease activity. The typical initial dose for prednisone is 1 mg/kg per day, up to a maximum daily dose of 60 to 80 mg, and should be continued for two to four weeks, at which time tapering of the dose should begin if patients demonstrate clinical improvement.
  
• In patients with more critical diseases such as aortitis or carotidynia, pulsed intravenous glucocorticoids can be considered as well.
  
• However, given the chronic, relapsing nature of the disease and the imperative to avoid glucocorticoid-related toxicities, patients are often prescribed a steroid sparing agent in conjunction for long term suppressive therapy to achieve longer-term disease control.
  
• No specific agent has been well-proven to be effective in trials, and it is common that patients are prescribed a series of medications, sometimes in combination.
  
• The choice of an additional agent depends on several factors including considerations regarding comorbidities, a patient’s plans for conceiving a child, cost of treatments, and availability of specific agents. Options include methotrexate, azathioprine as well as mycophenolate. There are also growing studies looking into anti-TNF-alpha agents such as etanercept or infliximab.
  
• Again, a rheumatologist with experience in treating Takayasu arteritis should be involved in multidisciplinary care.
  

In terms of long-term follow-up, monitoring disease activity and response to therapy may be challenging for clinicians, given the absence of specific laboratory tests or validated assessment criteria for disease activity.

• Expert consensus is that we can monitor for a decrease and eventual disappearance of constitutional symptoms, arthralgias, and claudication symptoms, accompanied by a decrease in acute phase reactants such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels.
  
• CT or MR angiography can also be repeated at regular intervals to evaluate for progressive disease.
  
• Given the regularity at which repeat imaging may be needed, serial MR angiography is preferred whenever possible to avoid the additive exposure to radiation and iodinated contrast dye.
  

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3. Kim H, Barra L. Ischemic complications in Takayasu’s arteritis: A meta-analysis. Semin Arthritis Rheum. 2018;47(6):900-906. doi:10.1016/j.semarthrit.2017.11.001
   
4. Maz M, Chung SA, Abril A, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis. Arthritis Rheumatol. 2021;73(8):1349-1365. doi:10.1002/art.41774
   
5. Esatoglu SN, Hatemi G. Takayasu arteritis. Curr Opin Rheumatol. 2022;34(1):18-24. doi:10.1097/BOR.0000000000000852