(PAPP)-A in sera from type 2 diabetic patients with hypercholesterolemia: Associations with carotid atherosclerosis and Toe-Brachial Index (TBI)
There are many risk factors for cardiovascular diseases (CVDs), some more insidious and complex than others, as are symptoms and indicators. The former is often identical for several diseases, not just of cardiovascular nature, and the same could be said for symptoms, while the indicators are usually or at least should be unique to enable accurate diagnosis. However, various comorbidities can alter the diagnostic value of some indicators, necessitating a more holistic diagnostic approach.
In this blog you will learn:
Significance of (PAPP)-A in incidence of CVD.
Diabetes mellitus as a risk factor for CVD.
Associations of (PAPP)-A sera levels with IMT and TBI.
Superiority of TBI for diagnosis of PAD in diabetic patients.
Are elevated levels of (PAPP)-A associated with an increased risk for CVD?
Pregnancy-associated plasma protein A (PAPP)-A is a serum marker that is most used for prenatal diagnosis of Down syndrome during pregnancy [1, 2]. However, several studies have found that (PAPP)-A is also expressed in a variety of other tissues besides the placenta . They include the ovaries, endometrium, testes, kidneys, and colon and even in unstable atherosclerotic plaques [4, 5].
Elevated serum levels of (PAPP)-A were noted in patients with acute coronary syndromes (ACS) and researchers have even demonstrated that elevated serum (PAPP)-A is a strong independent predictor of ischemic cardiac events and the need of revascularization in those with suspected myocardial infarction (MI) . It should therefore come as no surprise that many are advocating for serum (PAPP)-A to be used as a marker of ACS. However, more research is still needed before modifying existing diagnostic guidelines for ACS. Same cannot be said for a variety of risk factors for CVD, mainly modifiable ones like smoking or diabetes mellitus.
Is diabetes mellitus a risk factor for CVD?
Harmful effects of diabetes mellitus on the cardiovascular system are well-known and extensively researched with growing emphasis on synergetic contribution of other risk factors and comorbid conditions [7-10]. Examples include obesity and hypertension; prevalence between 10 % and 30 % for those with type 1 and up to 60 % for type 2 diabetes [11-14]. Consequently, morbidity and mortality rates due to CVDs are greater in diabetics than in non-diabetics.
Diabetic patients have higher rates of mortality, morbidity and re-infarction following a myocardial infarction (MI), with rates between 10 % to 20 % in diabetics in comparison to only 1 % to 4 % in non-diabetics [15-18]. Diabetes likewise increases the likelihood of diabetic neuropathy, diabetic nephropathy, and peripheral arterial disease (PAD) and a variety of other medical conditions [19-22].
Of those mentioned, PAD is particularly worth emphasising, especially due to harmful effects of diabetes on its incidence, severity, and diagnosis. Prevalence of symptomatic PAD in diabetic patients is estimated to be roughly 20 %, but this number is generally recognized as being an underestimation since far more cases of the disease are asymptomatic [23-25].
Regarding diagnosing PAD in diabetic patients; they are more likely to have non-compressible arteries (Mönckeberg’s sclerosis), in addition to those with rheumatoid arthritis and renal insufficiency, which preclude the use of common diagnostic methods [26-29]. More specifically, the essential ABI (ankle-brachial index) screening method, leaving TBI (toe-brachial index) as the only comparable method [30, 31].
Are elevated levels (PAPP)-A in sera associated with increased IMT and TBI?
A Japanese study involving 103 patients with type 2 diabetes aimed to determine the relationship between (PAPP)-A sera levels and carotid intima-media wall thickness (IMT), a recognized early marker of atherosclerosis, and ABI and TBI scores . Researchers found that examined patients had significantly higher serum (PAPP)-A levels than the control group (32 individuals, 16 males and 16 females) and greater carotid IMT . Interestingly, there was no significant correlation between ABI and serum (PAPP)-A levels while the opposite was true for TBI, which exhibited significant negative correlation .
Is TBI superior to ABI in diagnosis of PAD in diabetic patients?
Researchers’ findings of low TBI should of course come as no surprise since diabetics are more likely to have non-compressible arteries than non-diabetics and patients with incompressible arteries may even have normal ABI despite having PAD . They demonstrated better suitability of TBI in diagnosing PAD in diabetic patients in another study that highlighted the correlation between TBI and vascular inflammation markers in patients with type 2 diabetes . Given these findings and many other, the TBI is indeed superior to ABI in diagnosing PAD in patients with diabetes but is unfortunately still underutilized.
Elevated serum (PAPP)-A levels in patients with type 2 diabetes are associated with high IMT, indicating carotid atherosclerosis, and low TBI scores, but not ABI – demonstrating questionable usability of the latter in diabetics and other patients with high likelihood of having incompressible arteries.
 Substrate specificity of the metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) assessed by mutagenesis and analysis of synthetic peptides: substrate residues distant from the scissile bond are critical for proteolysis > https://pubmed.ncbi.nlm.nih.gov/12241545/
 Messenger ribonucleic acid levels of pregnancy-associated plasma protein-A and the proform of eosinophil major basic protein: expression in human reproductive and nonreproductive tissues > https://pubmed.ncbi.nlm.nih.gov/10491647/