Posts Tagged ‘hypercoagulability state’

Biomarkers and risk factors for cardiovascular events, endothelial dysfunction, and thromboembolic complications

Curator: Larry H Bernstein, MD, FCAP



Acute Coronary Syndrome

Predictive Cardiovascular and Circulation Biomarkers

Biomarkers are chemistry analytes measured in plasma, serum or whole blood that potentially identify injury or risk for injury.  They may be measured in the laboratory or at the bedside (point of care technology).  They may be measured as an enzyme (CK isoenzyme MB), a protein (troponins I & T), or as a micro RNA (miRNA).  In the last decade the discovery and use of cardiac biomarkers has moved toward very small quantities, even 100 times below the picogram range using Quanterix Simoa, compared with an enzyme immunoassay.

The time of sampling was based on time to appearance from time of damage, and the release of the biomarker is a stochastic process. The earliest studies of CK-MB appearance, peak height, and disappearance was by Burton Sobel and associates related to measuring the extent of damage, and determined that reperfusion had an effect.

There has been a nonlinear introduction of new biomarkers in that period, with an explosion of methods discovery and large studies to validate them in concert with clinical trials. The improvement of interventional methods, imaging methods, and the unraveling of patient characteristics associated with emerging cardiovascular disease is both cause for alarm (technology costs) and for raised expectations for both prevention, risk reduction, and treatment. What is strikingly missing is the kind of data analyses on the population database that could alleviate the burden of physician overload. It is an urgent requirement for the EHR, and it needs to be put in place to facilitate patient care.


Biomarkers: Diagnosis and Management, Present and Future

Curator: Larry H Bernstein, MD, FCAP
Biomarkers of Cardiovascular Disease : Molecular Basis and Practical Considerations.
RS Vasan .
Circulation. 2006;113:2335-2362.

sCD40L indicates soluble CD40 ligand; Fbg, fibrinogen; FFA, free fatty acid; ICAM, intercellular adhesion molecule; IL, interleukin; IMA, ischemia modified albumin; MMP, matrix metalloproteinases; MPO, myeloperoxidase; Myg, myoglobin; NT-proBNP, N-terminal proBNP; Ox-LDL, oxidized low-density lipoprotein; PAI-1, plasminogen activator inhibitor; PAPP-A, pregnancy-associated plasma protein-A; PlGF, placental growth factor; TF, tissue factor; TNF, tumor necrosis factor; TNI, troponin I; TNT, troponin T; VCAM, vascular cell adhesion molecule; and VWF, von Willebrand factor.


Accurate Identification and Treatment of Emergent Cardiac Events  

Author: Larry H Bernstein, MD, FCAP

The main issue that we have a consensus agreement that PLAQUE RUPTURE is not the only basis for a cardiac ischemic event. The introduction of  high sensitivity troponin tests has made it no less difficult after throwing out the receiver-operator characteristic curve (ROC) and assuming that any amount of cardiac troponin released from the heart is pathognomonic of an acute ischemic event.  This has resulted in a consensus agreement that

  • ctn measurement at a coefficient of variant (CV) measurement in excess of 2 Std dev of the upper limit of normal is a “red flag” signaling AMI? or other cardiomyopathic disorder

This is the catch.  The ROC curve established AMI in ctn(s) that were accurate for NSTEMI – (and probably not needed with STEMI or new Q-wave, not previously seen) –

  1. ST-depression
  2. T-wave inversion
  3. in the presence of other findings
  • suspicious for AMI

Wouldn’t it be nice if it was like seeing a robin on your lawn after a harsh winter?  Life isn’t like that.  When acute illness hits the patient may well present with ambiguous findings.   We are accustomed to relying on

  • clinical history
  • family history
  • co-morbidities, eg., diabetes, obesity, limited activity?, diet?
  • stroke and/or peripheral vascular disease
  • hypertension and/or renal vascular disease
  • aortic atherosclerosis or valvular heart disease

these are evidence, and they make up syndromic classes

  • Electrocardiogram – 12 lead EKG (as above)
  • Laboratory tests
  • isoenzyme MB of creatine kinase (CK)… which declines after 12-18 hours
  • isoenzyme-1 of LD if the time of appearance is > day-1 after initial symptoms (no longer used)
  1. cardiac troponin cTnI or cTnT
  • genome testing
  • advanced analysis of EKG

This may result in more consults for cardiologists, but it lays the ground for better evaluation of the patient, in the long run.

Perspectives on the Value of Biomarkers in Acute Cardiac Care and Implications for Strategic Management
Antoine Kossaify, … STAR-P Consortium
Biomarker Insights 2013:8 115–126.

In addition to the conventional use of natriuretic peptides, cardiac troponin, and C-reactive protein, other biomarkers are outlined in variable critical conditions that may be related to acute cardiac illness. These include ST2 and chromogranin A in acute dyspnea and acute heart failure, matrix metalloproteinase in acute chest pain, heart-type fatty acid binding protein in acute coronary syndrome, CD40 ligand and interleukin-6 in acute myocardial infarction, blood ammonia and lactate in cardiac arrest, as well as tumor necrosis factor-alpha in atrial fibrillation. Endothelial dysfunction, oxidative stress and inflammation are involved in the physiopathology of most cardiac diseases, whether acute or chronic. In summary, natriuretic peptides, cardiac troponin, C-reactive protein are currently the most relevant biomarkers in acute cardiac care.

 Inverse Association between Cardiac Troponin-I and Soluble Receptor for Advanced Glycation End Products in Patients with Non-ST-Segment Elevation Myocardial Infarction

ED. McNair, CR. Wells, A.M. Qureshi, C Pearce, G Caspar-Bell, and K Prasad
Int J Angiol 2011;20:49–54

Interaction of advanced glycation end products (AGEs) with the receptor for advanced AGEs (RAGE) results in activation of nuclear factor kappa-B, release of cytokines, expression of adhesion molecules, and induction of oxidative stress. Oxygen radicals are involved in plaque rupture contributing to thromboembolism, resulting in acute coronary syndrome (ACS). Thromboembolism and the direct effect of oxygen radicals on myocardial cells cause cardiac damage that results in the release of cardiac troponin-I (cTnI) and other biochemical markers. The soluble RAGE (sRAGE) compete with RAGE for binding with AGE, thus functioning as a decoy and exerting a cytoprotective effect. Low levels of serum sRAGE would allow unopposed serum AGE availability for binding with RAGE, resulting in the generation of oxygen radicals and proinflammatory molecules that have deleterious consequences and promote myocardial damage. sRAGE may stabilize atherosclerotic plaques. It is hypothesized that low levels of sRAGE are associated with high levels of serum cTnI in patients with ACS.
The levels of cTnI were higher in NSTEMI patients (2.180.33 mg/mL) as compared with control subjects (0.0120.001 mg/mL). Serum sRAGE levels were negatively correlated with the levels of cTnI. In conclusion, the data suggest that low levels of serum sRAGE are associated with high serum levels of cTnI and that there is a negative correlation between sRAGE and cTnI.

Correlation of soluble receptor for advanced glycation end products (sRAGE) with cardiac troponin-I

Correlation of soluble receptor for advanced glycation end products (sRAGE) with cardiac troponin-I


Figure 1 Serum levels of soluble receptor for advanced glycation end products (sRAGE) in control subjects and in patients with non-ST-elevation myocardial infarction (NSTEMI). Results are expressed as meanstandard error. *p<0.05, control versus NSTEMI.


Serum levels of soluble receptor for advanced glycation end products

Serum levels of soluble receptor for advanced glycation end products

Figure 3 Correlation of soluble receptor for advanced glycation end products (sRAGE) with cardiac troponin-I (cTnI) in patients with non-ST-segment elevation myocardial infarction.


Heart Failure Complicating Non–ST-Segment Elevation Acute Coronary Syndrome

MC Bahit, RD. Lopes, RM. Clare, et al.
JACC: HtFail 2013; 1(3):223–9 .

This study sought to describe the occurrence and timing of heart failure (HF), associated clinical factors, and 30-day outcomes in patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS). Of 46,519 NSTE-ACS patients, 4,910 (10.6%) had HF at presentation. Of the 41,609 with no HF at presentation, 1,194 (2.9%) developed HF during hospitalization. A total of 40,415 (86.9%) had no HF at any time. Patients presenting with or developing HF during hospitalization were older, more often female, and had a higher risk of death at 30 days than patients without HF (adjusted odds ratio [OR]: 1.74; 95% confidence interval: 1.35 to 2.26). Older age, higher presenting heart rate, diabetes, prior myocardial infarction (MI), and enrolling MI were significantly associated with HF during hospitalization.

Other risk factors

Additive influence of genetic predisposition and conventional risk factors in the incidence of coronary heart disease: a population-based study in Greece
N Yiannakouris, M Katsoulis, A Trichopoulou, JM Ordovas, DTrichopoulos
BMJ Open 2014;4:e004387.

Genetic predisposition to CHD, operationalised through a multilocus GRS, and ConvRFs have essentially additive effects on CHD risk.

PTX3, A Prototypical Long Pentraxin, Is an Early Indicator of Acute Myocardial Infarction

G Peri, M Introna, D Corradi, G Iacuitti, S Signorini, et al.
Circulation. 2000;102:636-641

PTX3 is a long pentraxin whose expression is induced by cytokines in endothelial cells, mononuclear phagocytes, and myocardium. PTX3 is present in the intact myocardium, increases in the blood of patients with AMI, and disappears from damaged myocytes. We suggest that PTX3 is an early indicator of myocyte irreversible injury in ischemic cardiomyopathy.

Early release of glycogen phosphorylase inpatients with unstable angina and transient ST-T alterations

J Mair, B Puschendorf, J Smidt, P Lechleitner, F Dienstl, et al.
BrHeartJ 1994;72:125-127.

Glycogen phosphorylase BB (molecular weight 96000 kDa as a monomer) is the predominant isotype in human myocardium where it occurs alongside the MM subtype. The release of glycogen phosphorylase from injured myocardium may reflect the burst in glycogenolysis initiated during acute myocardial ischaemia. This is supported by a rapid increase in serum concentrations of glycogen phosphorylase BB in patients with acute myocardial infarction before concentrations of creatine kinase, creatine kinase MB, myoglobin, and cardiac troponin T increase. Unstable angina, however, ranges from no myocardial cell damage to non-Q wave myocardial infarction.
All variables except for creatine kinase and creatine kinase MB activities were significantly higher on admission in patients with unstable angina and transient ST-T alterations than in patients without. However, glycogen phosphorylase BB concentration was the only marker that was significantly (p = 0-0001) increased above its discriminator value in most patients.

Endothelium and Vascular

Endothelial Dysfunction: An Early Cardiovascular Risk Marker in Asymptomatic Obese Individuals with Prediabetes
AK. Gupta, E Ravussin, DL. Johannsen, AJ. Stull, WT. Cefalu and WD. Johnson
Br J Med Med Res 2012; 2(3): 413-423.

Adults with desirable weight [n=12] and overweight [n=8] state, had normal fasting plasma glucose [Mean(SD)]: FPG [91.1(4.5), 94.8(5.8) mg/dL], insulin [INS, 2.3(4.4), 3.1(4.8) μU/ml], insulin sensitivity by homeostasis model assessment [HOMA-IR, 0.62(1.2), 0.80(1.2)] and desirable resting clinic blood pressure [SBP/DBP, 118(12)/74(5), 118(13)/76(8) mmHg]. Obese adults [n=22] had prediabetes [FPG, 106.5(3.5) mg/dL], hyperinsulinemia [INS 18.0(5.2) μU/ml], insulin resistance [HOMA-IR 4.59(2.3)], prehypertension [PreHTN; SBP/DBP 127(13)/81(7) mmHg] and endothelial dysfunction [ED; reduced RHI 1.7(0.3) vs. 2.4(0.3); all p<0.05]. Age-adjusted RHI correlated with BMI [r=-0.53; p<0.001]; however, BMI-adjusted RHI was not correlated with age [r=-0.01; p=0.89].

Association of digital vascular function with cardiovascular risk factors: a population study.
T Kuznetsova, E Van Vlierberghe, J Knez, G Szczesny, L Thijs, et al.
BMJ Open 2014; 4:e004399.

Our study is the first to implement the new photoplethysmography (PPG) technique to measure digital pulse amplitude hyperemic in a sample of a general population. The correlates of hyperaemic response were as expected and constitute an internal validation of the PPG technique in assessment of digital vascular function.

Thrombotic/Embolic Events

Risk marker associations with venous thrombotic events: a cross-sectional analysis 
BA Golomb, VT Chan, JO Denenberg, S Koperski,  & MH Criqui.
BMJ Open 2014;4:e003208.

To examine the interrelations among, and risk marker associations for, superficial and deep venous events—superficial venous thrombosis (SVT), deep venous thrombosis (DVT) and pulmonary embolism (PE). Significant correlates on multivariable analysis were, for SVT: female sex, ethnicity (African-American=protective), lower educational attainment, immobility and family history of varicose veins. For DVT and DVE, significant correlates included: heavy smoking, immobility and family history of DVEs (borderline for DVE). For PE, significant predictors included immobility and, in contrast to DVT, blood pressure (BP, systolic or diastolic). In women, estrogen use duration for hormone replacement therapy, in all and among estrogen users, predicted PE and DVE, respectively.

Endothelium and hemorheology
T Gori, S Dragoni, G Di Stolfo and S Forconi
Ann Ist Super Sanità 2007 | Vol. 43, No. 2: 124-129

The mechanisms underlying the regulation of its function are extremely complex, and are principally determined by physical forces imposed on the endothelium by the flowing blood. In the present paper, we describe the interactions between the rheological properties of blood and the vascular endothelium.The role of shear stress, viscosity, cell-cell interactions, as well as the molecular mechanisms that are important for the transduction of these signals are discussed both in physiology and in pathology, with a particular attention to the role of reactive oxygen species. In the final conclusions, we propose an hypothesis regarding the implications of changes in blood viscosity, and particularly on the significance of secondary hyperviscosity syndromes..

Fig. 1 | Endothelial “function” (i.e.,the production of protective autacoids by the vascular endothelium) and “dysfunction” (i.e., the involvement of the endothelium in vascular pathology). EDHF: En d o t h e l i um-De r i v e d Hyperpolarizing Factor; LDL:Low-Density Lipoprotein

Fig. 2 | Endothelial production of nitric oxide (NO) is stimulated by oscillatory shear stress, transmitted by the endothelial surface layer to the endothelial cells. NO: Nitric Oxide; NOS: Nitrous Oxide Systems; ESL: Endothelial Surface Layer






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