12. rational diagnosis of cardiovascular disease

12. RATION AL DIAGN OSIS OF CARDIOVASCU LAR DISEASE

For the follow-up, diagnosis and risk stratific ation of patients the diagnostic laboratory in c ombination with radiology tec hniques plays a major role. The aim of this review is to desc ribe the diagnostic usefulness of established and new analytes related to c ardiac func tion, c oagulation, endothelial dysfunc tion and risk fac tors. Some of the strategies mentioned are based on experimental bioc hemic al findings.

Prof. Mathias M. Müller, M.D. and Andrea Griesmacher, M.D. Institute for Laboratory Diagnostics, Kaiser-Franz-Josef-H ospital, Vienna, Austria,

Male Subjects Country

12.1 Introduction Cardiovasc ular diseases ( CVD) or diseases of the c irc ulatory system represent various c linic al c onditions due to atherosc lerotic impairment of c oronary, c erebral or peripheral arteries. The Americ an Heart Assoc iation uses the ICD 1 0 c odes I0 0 -I9 9 inc luding diseases of veins and lymphatic s. CVD are c onsidered nowadays as the major c auses of death in developed c ountries for men and women. Detailed epidemiologic al data for CVD are available from the Americ an Heart Assoc iation’s “2 0 0 2 Heart and Statistic al Update” summarizing the risk fac tors. 6 1 ,8 0 0 ,0 0 0 Americ ans suffer from one or more types of CVD ( 2 9 ,7 0 0 ,0 0 0 males and 3 2 ,1 0 0 ,0 0 0 females, 2 4 ,7 5 0 ,0 0 0 older than age 6 5 , details in Table 1 ) [ 2 1 ] .

Australia

253

172

38

113

61

27

Austria

369

205

59

168

70

38

Canada

380

284

36

122

65

25

France

213

85

41

78

21

22

Germany

347

190

53

149

64

32

Hungary

842

420

207

380

161

111

Italy

293

140

58

116

37

33

Japan

186

57

79

85

20

41

Russia

1167

639

361

540

230

229

Spain

252

121

51

99

32

28

United States 360

230

41

183

95

33

Table 2 . Deat h r at es for car diovascular diseases. Rat es p er 1 0 0 . 0 0 0

Cardiovascular disease All High blood pressure

Number of patients 61,800,000 50,000,000

Coronary heart disease

12,600,000

Female Subjects

CVD CHD Stroke CVD CHD Stroke

p op u la t i on

CVD=Cardiovascular Disease; CHD = Coronary Heart Disease. Referenc e: 2 0 0 2 Heart and Stroke Statistic al Update, Americ an Heart Assoc iation, http:// www.americanheart.org/presenter.jhtml?identifier= 1 9 2 8

Myocardial infarction 7,500,000 Angina pectoris Stroke Congenital heart failure Congestive heart failure

6,400,000 4,600,000 1,000,000 4,790,000

12.2 Markers for cardiac function 12.2.1 Acute myocardial infarction

Table 1. Prevalence for cardiovascular diseases in t he U SA.

Referenc e: 2 0 0 2 Heart and Stroke Statistic al Update, Americ an Heart Assoc iation http:// www.americanheart.org/presenter.jhtml?identifier= 1 9 2 8

From these data it was c alc ulated that 1 in 5 c itizens have some form of CVD. Comparison of the death rates of various c ountries ( Table 2 ) shows that there is a relationship between soc io-ec onomic situations and a kind of east-west and north-south dec line [ 2 2 ]

Sinc e 1 9 9 0 several new markers have been introduc ed in the diagnostic laboratory for ac ute myoc ardial infarc tion ( MI) . These analytes are spec ific c ardiac proteins exhibiting a better diagnostic validity than ac tivity of total CK l and CK-MB previously used. There is now c onsensus among IFCC experts that the most rational way to diagnose MI is the use of a so-c alled “early” and a “late” marker released from c ardiac myoc ytes under isc haemic c onditions. Myoglobin is c onsidered the optimal “early” marker starting to rise 2 to 3 hours and peaking 8 to 1 2 hours after onset of the c linic al symptoms. Normal c onc entrations are reac hed again after 2 4 hours. The c ardiac troponins peak at 1 2 to 4 8 hours, and remain elevated for 4 to 1 0 days. Ac c ording IFCC guidelines, spec imen

Page 95 eJIFCC2003Vol14No2pp095-103

2500 2000

300

1500 200 1000 100

Myoglobin, CK total

CK-MB, Troponin T + I

400

500

0 2

4

6

8

12

18

24

32

48

72

0 144

Hours after Onset CK total Activity

CK-MB Activity

CK-MB Mass

Myoglobin

Troponin T

Troponin I

Figure 1. Time course of markers for myocardial infarct ion

Marker

2h

4h

6h

10 h 14h

18h 22h

Myoglobin Sensitivity (%) 26.30 42.90 78.70 86.50 62.30 57.50 42.90 Specificity (%) 87.30 89.40 89.40 90.20 88.30 88.80 91.30 Youden-Index 0.14

0.32

0.68

0.77 0.51 0.46 0.34

Troponin T Sensitivity (%) 10.50 35.70 61.70 86.50 84.90 78.70 85.70 Specificity (%) 98.40 98.30 96.10 96.40 96.10 95.70 94.60 Youden-Index 0.09

0.34

0.58

c ollec tion should be done at admission, 4 , 8 , and 1 2 h ( or next morning) . In Figure 1 [ 1 ] a typic al time-c ourse in a patient with MI is shown. Ac c ording to the diagnostic validities published for CK total, CK-MB, the troponins and myoglobin ( Table 3 ) [ 2 ] it is antic ipated that after the present transition period c linic ians will ac c ept in the future myoglobin and troponin measurements as the gold standards for the diagnosis of MI.

0.83 0.81 0.74 0.80

With regard to unstable angina the IFCC and the National Ac ademy of Clinic al Chemistry ( NACB) have stated that patients with small inc reases of troponin ( the 9 7 .5 th perc entile of the normal healthy population) should be used as the c ut-off point for risk-stratific ation and further angiographic examinations.

Troponin I Sensitivity (%) 15.80 35.70 57.50 92.30 90.60 95.70 89.80 Specificity (%) 96.80 94.20 94.30 94.60 92.20 93.40 94.20 Youden-Index 0.13

0.30

0.52

0.87 0.83 0.89 0.84

Total CK-MB activity Sensitivity (%) 21.10 40.70 74.50 96.20 98.10 97.90 89.80 Specificity (%) 100.00 98.80 97.50 97.50 96.10 96.90 96.20 Youden-Index 0.21

0.40

0.72

0.94 0.94 0.95 0.86

Total CK-MB mass Sensitivity (%) 15.80 39.30 66.00 90.40 90.50 95.70 95.70

12.2.2 Ventricular dysfunction For more than 1 0 years a lot of researc h foc used on the func tion of the natriuretic peptides whic h affec t systemic blood pressure by several mec hanisms, inc luding modific ation of renal func tion and vasc ular tone, c ounterac ting of the renin-angiotensin-aldosterone system and ac tion on brain regulatory sites. These systems maintain a balanc e that ensures relative c onstanc y of body elec trolyte and water c ontent and c irc ulatory homeostasis. The natriuretic peptides ( B NP and ANP) investigated sinc e more than 1 0 years are potential diagnostic tools in the assessment of patients’ ventric ular func tion.

Specificity (%) 99.20 98.80 100.00 99.60 98.90 99.60 99.10 Youden-Index 0.15

0.38

0.66

0.90 0.89 0.95 0.95

Table 3. Diagnost ic validit ies of markers for myocardial infarct ion based on t im e from onset of chest pain

Brain natriuretic peptide ( BNP) , also known as ventric ular natriuretic peptide, is a c ardiac hormone sec reted predominantly from the ventric le. Its biologic ally ac tive, low molec ular form with 3 2 amino ac ids ( B NP-3 2 , proBNP ( 7 7 -1 0 8 ) , half-life time: 2 0 min) with vasodilator and natriuretic properties, is c leaved from the proBNP, stored in human c ardiac tissue and released from the c ardiac ventric les in response to stretc hing of the c hamber.

Referenc e: Zimmerman J. et al. [ 2 ]


Group

Sensitivity (%)

General population aged over 45 (n=307)

Specificity (%)

Positive predictive value (%)

Negative predictive value (%)

100

70

7

100

(65 – 100)

(65 – 75)

(3 – 14)

(99 – 100)

Patients with existing diagnosis of heart failure (n=103)

100 (92 - 100)

18 (10 – 29)

39 (28 – 49)

100 (78 – 100)

Patients at high risk for heart failure (n=133)

100 (72 – 100)

44 (35 – 54)

12 (5 – 21)

100 (96 – 100)

Table 4. Diagnost ic validit ies of NT- proBNP in t he general populat ions and in pat ient s wit h or at risk for heart failures.

Values in parentheses are 9 5 % c onfidenc e intervals Referenc e: Hobbs F. D. et al [ 5 ]

The sec ond remnant after c leavage, N-terminal proBNP ( NT-proBNP, proB NP ( 1 -7 6 ) , half-life time: 6 0 – 1 2 0 min) , is a 7 6 amino ac id peptide with no known biologic al func tion. Plasma levels of NT-proBNP and BNP-3 2 are similar in normal subjec ts. In NYHA Class I, II and III subjec ts, the levels of NT-proBNP are 4 -fold higher than c onc omitant BNP-3 2 levels. It was shown, that left ventric ular ejec tion frac tion ( LVEF) , exerc ise-test time and c reatinine c learanc e were independent predic tors of NTproBNP plasma c onc entrations. The levels of NT-proBNP and BNP-3 2 were highly c orrelated. Nevertheless, sinc e the inc rement above normal levels of NT-proBNP exc eeds that for BNP-3 2 in c ardiac impairment it is now agreed that NT-proBNP is a more useful marker of early c ardiac dysfunc tion than BNP-3 2 and may represent c ardiac status over longer periods [ 3 ] . NT-proBNP seems to be helpful in the diagnosis of heart failure in the overall population. NT-proBNP is reported to be a very useful tool [ 4 ] espec ially for the detec tion of left ventric ular systolic dysfunc tion. The diagnostic validities for NT-proBNP in the general population, in patients with existing heart failures and with risks for heart failure are shown in Table 4 [ 5 ] . Bec ause of its high negative

Statistics

The atrial natriuretic peptides ( ANP) exhibit similar physiologic al func tions than B NP. ProANP ( 1 -1 2 6 ) is stored in membrane-bound granules in artrial c ardioc ytes. Upon stimulation, these granules move to the c ell surfac e, releasing the stored proANP ( half-life time 6 0 min) . This prohormone is c leaved into the ac tive 2 8 amino ac id peptide ANP ( pro ANP ( 9 9 -1 2 6 ) , a-ANP, half-life time: 2 .5 min) , and an Nterminal ANP fragment ( NT-proANP, proANP ( 1 -9 8 ) whic h is further proc essed within the c irc ulation to form proANP ( 1 3 0 ) , proANP ( 3 1 -6 7 ) and proANP ( 7 9 -9 8 ) . Due to muc h longer biologic al half proANP moieties exhibit up to 5 0 times higher plasma c onc entration than a-ANP. Several studies reported that plasma-levels of a-ANP and NTproANP were signific antly elevated even in asymptomatic patients with left ventric ular dysfunc tion. A c omparison of the new c ardiac markers NT-proANP, BNP and NT-proBNP demonstrate the effic ienc y for diagnosis of patients with impaired left ventric ular ejec tion frac tion ( LVEF) ( Table 5 , Fig. 2 ) [ 7 , 8 ] .

BNP NT-proBNP NT-proANP Cut-off: 41 pmol/l Cut-off: 488 pmol/l Cut-off: 2150 pmol/l

Sensitivity (%)

73

70

59

Specificity (%)

77

73

61 48

Pos. Predictive Value (%)

70

61

Neg. Predictive Value (%)

79

80

71

Efficiency (%)

75

72

60

Table 5. Diagnost ic performance of BNP, NT- proBNP and NT- proANP at opt im al cut - off for discrim inat ing t wo groups of pat ient s wit h left vent r icular eject ion fr act ion ( LVEF) values

40%

Referenc e: Maeda K. et al. [ 7 ]

predic tive values patients with a positive result should be sent to the c linic ians for c ardiac imaging. Distinguishing dyspnoea due to c ongestive heart failure is also disc ussed as a potential applic ation of BNP measurements [ 6 ] .

This c linic al study shows on basis of the ROC c urves that NTproANP might be the most useful non-invasive marker. Based on the c linic al investigations, measurement of natriuretic peptides is useful for those c linic al c onditions summarized in Table 6 . Even in c linic ally asymptomatic patients the peptides were reported to be of value.


B: Resting LVEF < 40 % based on RNV.

A: LVEF < 48 % based on 3D-echocardiography and < 55 % based on RNV

Figure 2. ROC curves for BNP, NT- proBNP and NT- proANT in pat ient s wit h im paired left vent ricular eject ion fract ion. Refer ence: Ham m erer- Lercher A. et al. [ 8 ]

Cardiac disease / condition

NT-proANP NT-proBNP

Assessment of cardiac condition (symptomatic, asymptomatic)

++

++

Screening for NYHAN I patients

+

+

Diagnosis of left ventricular dysfunction

+

+

Diagnosis of heart failure

+

+

+

+

Diagnosis of ventricular hypertrophy

+

Prognosis of myocardial infarction Diagnosis of pre-eclampsia

+

+

Diagnosis of essential hypertension

+

+

Monitoring of ACE-inhibitors therapy

Table 6. Nat r iur et ic pept ides in hear t funct ion assessm ent

12.3 Markers for thrombophilia Thrombophilia c an be defined as an inc reased tendenc y for venous and arterial thrombo-embolic events. Thrombophilia oc c urs from very different bioc hemic al, genetic and immunologic al abnormalities and is induc ed by mec hanic al or rheologic al adverse events. Thromboembolic episodes due to plasmatic hyperc oagulation and hypofibrinolysis are often assoc iated with surgery, immobilization, autoimmune disease, impaired gluc ose toleranc e or type 2 diabetes mellitus resulting in reduc ed endothe-

lial thrombotic resistanc e and hyper-reac tivity of thromboc ytes. The various c onditions assoc iated with thromboembolic events are summarized in Table 7 . Defining the c ause of hyperc oagulability may determine the type and duration of treatment for the assoc iated thromboembolic events. In addition, finding a genetic defec t in c oagulation allows for testing at least the firstdegree asymptomatic family members.


Congenital deficiencies / mutations

Acquired factors / secondary

Antithrombin III

Anti-phospholipid antibodies (Autoimmune)

APC Resistance (Factor V Leiden)

APC Resistance

Hyperhomocysteinemia

Hyperhomocysteinemia (vitamin deficiency)

Cystationine-ß-synthetase Methionine synthetase Methylene-tetrahydrofolate reductase Protein C

Pregnancy or other conditions Deficiencies: Protein C, S

Protein S

Increased coagulation factors: Fibrinogen Factors VIII, IX, XI

Prothrombin G 20210A mutation

Table 7. Congenit al and acquir ed fact or s associat ed wit h t hr om boem bolic event s

12.3.1 Rational screening

12.4 Markers of endothelial function

Several c linic al investigations have been c onduc ted to determine the prevalenc e of the various c oagulation fac tor defec ts in the general population. All these c hanges in the plasmatic c oagulation lead to a several fold inc rease in the risk for developing thromboembolic events. In Table 8 [ 9 , 1 0 , 1 1 ] the c linic al knowledge gathered so far is summarized. It is obvious that the risk for thrombosis in families showing one or even more defec ts is usually 4 - to 8 -fold higher c ompared to the general population.

Over the last twenty years, researc hers have found an extraordinary variety of endothelial func tions, inc luding c ontrol over c oagulation, fibrinolysis, vasc ular tone and growth as well as immune responses [ 1 2 ] . With regard to its c entral loc ation, its integrating and transduc ing c apability, and the large repertoire of its biologic ally ac tive produc ts, the endothelium plays a main role in a series of pathophysiologic al balanc es ( Figure 4 ) . It is well ac c epted that the repeated injury or lac k of the endothelium is responsible for loc al ac tivation of platelets, ac tivation of c oagulation and release of growth fac tors whic h lead to intimal hyperplasia, lipid ac c umulation and formation of atherosc lerotic lesions. The well-known c onsequenc es of theses lesions are the development of c ardiovasc ular diseases.

Based on these fac ts and figures the diagnostic laboratory is requested to perform a kind of rationale step-by-step diagnosis in patients with c linic al symptoms and or a family history of thromboembolic diseases ( deep venous thrombosis, stroke, pulmonary embolism) . Investigation of a patient always starts with the global ( routine) c oagulation tests, followed by sc reening for the protein C pathway ( Figure 3 ) and homoc ysteine plasma levels, finally ending-up with the determination of the single c oagulation fac tors and antiphospholipid antibodies. Usually a prolonged ac tivated prothrombin time due to c onsumption of c oagulation fac tors or defic ienc ies is one of the first hints of a disturbanc e. It is stressed that hyperc oagulability disorders c an be diagnosed in approximately 8 0 % of patients suffering from thrombotic events.

1 2 .4 .1 Endothelium and c oagulation In an antagonistic manner dependent on the environment the endothelial monolayer influenc es platelet func tion, plasmatic c oagulation and fibrinolysis by a variety of antiand proc oagulant produc ts and metabolites released being normally in a balanc e ( table 9 ) . A c ruc ial physiologic al func tion of the endothelium is to fac ilitate blood flow by providing an antithrombotic surfac e that inhibits platelet

Deficiencies /mutations Incidence in the population % Relative risk of thromboembolism Table 8. Incidence of

Antithrombin III

0.02 – 0.17

8

fact ors in t he general

APC Resistance Factor V Leiden

Heterozygote: > 20 Homozygote: 3.6 – 6.0

2–8 100

popula t i on a nd t he

Hyperhomocysteinemia

incr eased r elat ive r isk s

(MTHF reductase)

congeni t a l defect s a nd i n cr ea sed coa gu la t i on

for t hr om boem bolism

Heterozygote: 5- 10 Homozygous: 40

Protein C

0.14 – 0.5

Protein S

< 1.0

8 8

Prothrombin 20210A

1- 3

2–4

11

2-4

Conditions Factor VIIIc > 1500 U/L Factor IX > 1280 U/L

2.5

Factor XI > 1200 U/L

2.2

Fibrinogen > 5 g/L

4.0


signific antly higher in those patients developing late restenosis [ 1 4 ] . From these results inc reased plasma thrombomodulin levels seem to be a hint for hypercoagulability.

12.4.2 Endothelium and vascular tone

Figure 3. The prot ein C pat hway

adhesion and c lotting [ 1 2 ] . This is due to the negative c harged layer of proteoglyc ans, by inhibition of platelet aggregation by prostac yc lin ( PGI 2 ) and endothelium derived relaxing fac tor ( EDRF) and by inhibition of plasmatic c oagulation. However, when the endothelium is perturbed by physiologic al forc es or by spec ific c hemic al fac tors, the c ells undergo programmatic bioc hemic al c hanges that c ulminate in their transformation to a prothrombotic surfac e ( Table 9 ) . Fac tor VIII-vWF as well as thrombomodulin c an serve as a marker of endothelial dysfunc tion in several diseases demonstrating probably imbalanc e. For example in patients suffering from peripheral vasc ular disease signific antly elevated plasma levels in c omparison to healthy c ontrols are reported ( Table 1 0 ) [ 1 3 ] . In patients with a peripheral arterial oc c lusive disease thrombomodulin measured at entry is reported to be

Endothelial c ells sec rete mediators that influenc e the vasc ular tonus and hemodynamic s ( Table 1 1 ) [ 1 2 ] . The switc h from a normally predominant release of relaxing fac tors to that of c ontrac ting fac tors is suggested to play a key role in atherosc lerosis. Release of NO from endothelial c ells is enhanc ed by physic al and c hemic al stimuli suc h as pulsatile blood flow, hypoxia, free radic als, ac etylc holine, thrombin, serotonin, histamine, substanc e P and bradykinin [ 1 2 ] . NO ac ts as a kind of anti-vasoc onstric tor to stimuli suc h as free radic als during oxidative stress and inflammation responsible for release of endothelin I and ACE, the most potent to vasoc onstric tors. The latter are inc reased under various c linic al c onditions and most probably triggered by immunologic al and inflammatory stimuli; inc reased blood levels of ET-1 are seen in patients with c ongestive heart failure ( CHF) and after heart transplantation [ 1 5 ] The systemic hypotension observed in septic patients is related to an inc rease in NO produc tion. The imbalanc e of the vasc ular tonus by exc essive endothelin I and NO produc tions due to endothelial dysfunc tion is c learly demonstrated in patients suffering from bac terial septic infec tions ( Figure 5 ) [ 1 6 ] . NO measured as NO2 - /NO3 - is a good predic tor of all shoc k c onditions [ 1 7 ] .

12.4.3 Endothelium and immune response Vasc ular endothelial c ells play an important part in c ombination with blood c ells during the ac tivation of the immune system. There exists a c omplex system: c ytokines exc reted from lymphoc ytes and monoc ytes stimulate

Figure 4. Pat hological m echanism for endot helial act ivat ion and dysfunct ion


endothelial c ells to release c ytokines too, eic osanoids, and adhesion molec ules. The up-regulation and expression of adhesion molec ules result in c hemo attrac tion of mononuc lear c ells and fac ilitate their penetration through the endothelial monolayer to the intimae, a proc ess important for parthenogenesis ( 1 2 ) . Marked inc reases in c irc ulating levels of adhesion molec ules were observed in hyperlipidaemia, hypertension, diabetes mellitus, under oxidative stress, and c igarette smoking ( 1 2 ,1 8 ,1 9 ) . Inc reased plasma levels of the adhesion molec ule P-selec tin in patients with hypertension demonstrate the progressive vasc ular damage due to inc reased sheer stress ( Figure 6 ) ( 1 9 ) and most probably c onc omitant with adhesion of leukoc ytes on the endothelial surfac e.

Inhibitor of coagulation

Promoters of coagulation

Prostacycline

Thromboxane A 2

Thrombomodulin

Platelet activating factor

Heparin-Proteoglycans

Tissue factor

Relaxors

Constrictors

Prostacyclin

Endothelin 1

Nitric oxide (EDRF)

Angiotensin II (formed by ACE)

EDRF like substances Platelet derived growth factor

Table 11. Endot helial cells and vascular t onus

Tissue plasminogen activator Plasminogen activator inhibitor Urokinase

Factor VIII von Willebrand Figure 5. Dist urbance of endot helial t onus signaling in sept ic pat ient s: NO and endot helin- 1 plasm a levels.

Referenc e: Avontuur JA et al [ 1 6 ]

Table 9. Endot helial cells and coagulat ion

The physiologic al func tion of the endothelium is rather c omplex and the various func tions desc ribed oc c ur simultaneously in order to keep a homeostatic c ondition. Several molec ules mentioned as markers of ac ute and c hronic endothelial ac tivation with subsequent dysfunc tion of the endothelium are c onsidered to play a role in atherosc lerosis. They may furthermore serve as a tool to monitor the impac t of prevention and intervention on vascular damage.

Marker

Controls

Patients

Factor VIII von Willebrand (U/L) 1020 ± 300 1330 ± 340 * Thrombomodulin (ng/ml)

46 ± 14

55 ± 15 **

Figure 6. Plasm a levels of t he adhesion m olecule Pselect i n i n pa t i ent s wi t h hyper t ensi on.

Referenc e: Verhaar MC et al [ 1 9 ] Table 10. Markers of endothelial dysfunction in patients suffering peripheral vascular disease

12.5 Risk factors Oxidative stress as a result of the enhanc ed formation of reac tive oxygen spec ies ( ROS) due to infec tions or immune response plays a c entral role in the pathogenesis of arteriosclerosis associated diseases. Hypercholesterolaemia, hyperlipidaemia, hypertension, c igarette smoking, diabetes mellitus, and the c hronic ac tivation of the immune system are c lassic al c onditions where enhanc ed ROS c onc entrations are observed. The measurements of thiobarbituric ac id reac tive substanc es ( TBARS) are serving sinc e several years as measure for these pathologic al c onditions, sinc e oxidative spec ies are essential for the

modific ation of lipoproteins and their atherogenic effec ts. In diabetic s with peripheral vasc ular diseases and/or c oronary artery diseases plasma TBARS were signific antly elevated ( Table 1 2 ) ( 2 0 ) . Their inc rease was more pronounc ed than the lipids investigated and c orrelated with the patients’ c linic al c onditions.

12.6 Conclusion It was the aim of this review to highlight established markers of c ardiovasc ular diseases used for the diagnosis of myoc ardial infarc tion and for the diagnosis of thromboembolic events. In addition some new molec ules were desc ribed as potential new markers of dysfunc tion of the endothelium and thus being relevant for atherogenesis.


Parameter

Healthy persons (n=62)

Type I controls (n=62)

Type I with PVD or CAD (n=15)

Type II controls (n=42)

Type II with PVD or CAD (n=39)

8.0*# (6.9 – 8.8) 6.2 (4.9 – 6.7) 1.2 (1.0 – 1.6) 9.2* (6.7 – 10.6) 1.3* (1.1 – 1.5)

9.2* (7.6 – 10.5) 5.4+ (4.4 – 6.3) 1.2+ (1.0 – 1.9) 10.1*+ (7.9 – 13.0) 1.4* (1.1 – 1.9)

8.9* (7.7 – 9.6) 6.4+ (5.4 – 7.3) 2.1*+ (1.5 – 3.1) 13.9*+ (11.4 – 17.2) 1.6* (1.2-1.9)

HbA1c 3.8 9.4*# (%) (2.8 – 5.5) (8.0 – 10.2) Total cholesterol (mmol/L) 5.7 5.0 (5.5 – 6.3) (4.1 – 6.0) Triglycerides 1.2 1.1 (mmol/L) (1.1 – 1.7) (0.9 – 1.6) TBARS 5.4 9.1* (µmol/L) (4.0 – 6.9) 7.5 . 11.9 ∑TBARS/(CHOL+TG) 0.7 1.4* (0.6 – 0.9) (1.2 – 1.8)

Table 12. Biochem ical dat a for diabet ics wit h and wit hout peripheral vascular diseases ( PVD) or coronary art ery diseases ( CAD )

medians ( interquartile ranges Q1 – Q3 ) * p < 0 .0 0 5 c ompared to healthy individuals # p < 0 .0 0 5 between type I patients with and without PVD/CAD + p < 0 .0 0 5 between type I patients with and without PVD/CAD Referenc e: Griesmac her A et al [ 2 0 ]

For many of them, however, the mec hanisms underlying the genesis of c irc ulating forms, as well as their pathophysiologic al signific anc e, remain unc lear so far. Further studies are nec essary to establish the diagnostic relevanc e of these serum markers of endothelial func tion in large sc ale c linic al investigations. They may be additional tools in the risk stratific ation of c ardiovasc ular diseases.

5

Hobbs FD, Davis RC, Roalfe AK, Hare R, Davies MK, Kenkre JE. Reliability of N-terminal pro-brain natriuretic peptide assay in diagnosis of heart failure: c ohort study in representative and high risk c ommunity populations. B MJ 2 0 0 2 ; 3 2 4 : 1 4 9 8 – 5 0 3 .

6

Dao Q, Krishnaswamy P, Kazanegra R, Harrison A, Amirnovin R, Lenert L, Clopton P, Alberto J, Hlavin P, Maisel AS. Utility of B-type natriuretic peptide in the diagnosis of c ongestive heart failure in an urgent-c are setting. J Am Coll Cardiol 2 0 0 1 ; 3 7 : 3 7 9 - 8 5 .

7

Maeda K, Tsutamoto T, Wada A, Mabuc hi N, Hayashi M, Tsutsui T, Ohnishi M, Sawaki M, Fujii M, Matsumoto T, Kinoshita M. High levels of plasma brain natriuretic peptide and interleukin-6 after optimized treatment for heart failure are independent risk fac tors for morbidity and mortality in patients with c ongestive heart failure. J Am Coll Cardiol 2 0 0 0 ; 3 6 : 1 5 8 7 – 9 3 .

8

Hammerer-Lerc her A, Neubauer E, Muller S, Pac hinger O, Pusc hendorf B , Mair J. Head-to-head c omparison of N-terminal pro-brain natriuretic peptide, brain natriuretic peptide and N-terminal pro-atrial natriuretic peptide in diagnosing left ventric ular dysfunc tion. Clin Chim Ac ta 2 0 0 1 ; 3 1 0 : 1 9 3 - 7 .

9

De Stefano V, Finazzi G, Mannuc c i PM. Inherited thrombophilia: pathogenesis, c linic al syndromes, and management. B lood 1 9 9 6 ; 8 7 : 3 5 3 1 – 4 4 .

Recommended literature: 1

Katz IA, Irwig L, Vinen JD, Marc h L, Wyndham LE, Luu T, Nelson GI. Bioc hemic al markers of ac ute myoc ardial infarc tion: strategies for improving their c linic al usefulness. Ann Clin B ioc hem 1 9 9 8 ; 3 5 : 3 9 3 -9 .

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Zimmerman J, Fromm R, Meyer D, B oudreaux A, Wun CC, Smalling R, Davis B, Habib G, Roberts R Diagnostic marker c ooperative study for the Diagnosis of myoc ardial infarc tion. Circ ulation 1 9 9 9 ; 9 9 : 1 6 7 1 – 7 .

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Hunt PJ, Ric hards AM, Nic holls MG, Yandle TG, Doughty RN, Espiner EA. Immunoreac tive aminoterminal pro-brain natriuretic peptide ( NT-PROBNP) : a new marker of c ardiac impairment. Clin Endoc rinol 1997; 47: 287 - 96.

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Talwar S, Siebenhofer A, Williams B, Ng L. Influenc e of hypertension, left ventric ular hypertrophy, and left ventric ular systolic dysfunc tion on plasma N terminal proB NP. Heart 2 0 0 0 ; 8 3 : 2 7 8 -8 2 .

1 0 Rosendaal FR. High levels of fac tor VIII and venous thrombosis. Thromb Haemost 2 0 0 0 ; 8 3 : 1 -2 .


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