change of editor-in-chief of heart and metabolism · biomarkers: past, present, and future graham...

To our readers

Change of Editor-in-Chief ofHeart and Metabolism

Dear Readers,

Heart Metab. 2009; 43:1

I have been serving as theEditor-in-Chief of the journalHeart and Metabolism since1999 and I have enjoyedhaving had the opportunityto contribute to its develop-ment. Being Editor-in-Chiefof Heart and Metabolismhas been a very rewardingexperience. During thisperiod, the journal has con-tinuously provided you with

the newest findings about the role of metabolism incardiac disease and its clinical and therapeuticalimplications. I also believe that we have made con-siderable progress over these past few years in improv-ing the quality of the journal.

The growing interest and understanding of the roleof cardiac metabolism has greatly boosted our read-ership. Today, the journal is distributed in over30 countries worldwide, and its website has alsobecome increasingly popular. However, due to newhorizons in my professional career that require all myattention, I will not have the necessary time to devoteto the journal and, as a result, shall be standing down.

Finally, I would like to express my sincere bestwishes to the new Editor-in-Chief, Professor M.Marzilli, an experienced, dynamic and talented pro-fessional who I am certain will bring vision, passionand energy to the further development of the journal. Iwish Heart and Metabolism and all its readers con-tinuing success in the future.

Frans VisserFormer Editor-in-Chief

I am honoured to accept theposition as Editor-in-Chief ofHeart and Metabolism.

I was a founding BoardMember and have been dee-ply involved in the growth ofHeart and Metabolism fromthe beginning.

In assuming this positionand on behalf of all themembers of the Editorial

Board, I pledge that the journal will stay, true to itsname, and will continue to give you the very latestevidence on all aspects of fundamental and clinicalresearch on cardiac metabolism, as well as its thera-peutical implications.

I will do my best to maintain and further enhancethe scientific quality of the journal, so that it becomesrecognized as a reference in this field.

At the same time I wish to make it even moreattractive and useful for our readers.

A special thank you must go to Frans Visser for theincredible job he has done as Editor-in-Chief of Heartand Metabolism and for the kind words. It will not beeasy to match the progress the journal has made underhis direction, but, with the support of the EditorialBoard and of the Editorial staff, we can maintain thepace!

Mario MarzilliEditor-in-Chief

1

Contents

EDITORIAL

Biomarkers: past, present, and futureGraham Jackson 3

BASIC ARTICLE

The biological basis of troponin in heart disease: possible uses for troponin fragmentologyVlad C. Vasile and Allan S. Jaffe 5

MAIN CLINICAL ARTICLE

The role of biomarkers in clinical practiceAnthony S. Wierzbicki and Adie Viljoen 9

METABOLIC IMAGING

Troponin compared with late enhancement in the assessment of myocardial injuryEvangelos Giannitsis and Hugo A. Katus 13

NEW THERAPEUTIC APPROACHES

Trends in genomic biomarkersBruce McManus 19

FOCUS ON TRIMETAZIDINE (VASTAREL MR)Effects of Vastarel MR on brain natriuretic peptide and cardiac troponin concentrationsPericle Di Napoli 23

CASE REPORT

Serial determination of troponin concentrations in the diagnosis of acute myocardial infarctionVlad C. Vasile, Lori A. Blauwet and Allan S. Jaffe 27

REFRESHER CORNER

Temporal profi le of protein release in myocardial infarctionPiero Montorsi, Marco Villa and Maria Antonietta Dessanai 31

FEATURED RESEARCH

Abstracts and commentaries 36

GLOSSARY

Gary D. Lopaschuk 40

Editorial

Biomarkers: past, present and futureGraham Jackson

Department of Cardiology, Guy’s and St Thomas’ Hospitals NHS Trust, London, UK

Correspondence: Graham Jackson, Cardiology Department, Guy’s & St Thomas’ Hospital NHS Trust,Lambeth Palace Road, London SE1 7EH, UK.

e-mail: [email protected]

Coronary artery disease (CAD) continues to be a majorcause of morbidity and mortality in both men andwomen in developed and developing countries. Theextent of myocardial damage after an acute myo-cardial infarction (AMI) determines prognosis. Thediagnosis of an AMI is based on a combination ofsymptoms, electrocardiographic changes, and bio-markers. In this issue of Heart and Metabolism, wefocus on established and novel biomarkers and theirrole in diagnosis, risk stratification, and prognosis.

Drs Wierzbicki and Viljoen provide us with a com-prehensive clinical overview, pointing out that, inaddition to a diagnostic role in AMI, biomarkers arealso used to monitor drug treatments and their poten-tial toxicity. We tend to think in terms of C-reactiveprotein, troponin (T, I, or C), and brain natriureticpeptide (BNP), but a wider panel of markers is avail-able to aid both diagnosis and risk evaluation.

In the Basic Article, Drs Vasile and Jaffe describe indetail the molecular biology of troponin in cardiacdisease, and the potential for using troponin fragmentsto delineate differing pathological processes, leadingto distinct diagnostic and therapeutic potential.

The time course of biomarker release is important,and differences that may occur, and their clinical


relevance, are the subject of the Refresher Corner.We know that the release of protein at the time ofAMI provides both diagnostic and prognostic infor-mation, so it is helpful to have a review of the timecourses of individual biomarkers, which in turn pro-vides a framework for evaluating therapeutic inter-vention (whether mechanical or pharmacological).The Case Report shows how these time coursesor increasing trends are a valuable adjunct tomanagement.

In the drug focus article, importantly we arereminded of the role of trimetazidine in reducing leftventricular remodeling and potentially improvingprognosis. The significant reductions in troponin Tand BNP concentrations after 6 months of treatment(60 mg daily) compared with no trimetazidine treat-ment are associated with preservation of left ventri-cular -function. This signals the need for a large-scalestudy to evaluate the symptomatic and prognostic roleof trimetazidine in patients with reduced left ventri-cular function.

In the future, genetic biomarkers may transformour understanding and management of patients withCAD, so the New Therapeutic Approaches article byProfessor McManus is both timely and enlightening.

3

mailto:[email protected]

Basic article

The biological basis of troponin inheart disease: possible uses for

troponin fragmentologyVlad C. Vasile and Allan S. Jaffe

Department of Internal Medicine, Division of Cardiovascular Diseases and Department of LaboratoryMedicine and Pathology, Mayo Clinic and Mayo Medical School, Rochester, Minnesota, USA

Correspondence: Dr Allan S. Jaffe, Mayo Clinic, 200 First St SW, Division of Cardiovascular Diseases,Gonda 5, Rochester, Minnesota 55905, USA.

Tel: +1 507 284 3680; fax: +1 507 266 0228; e-mail: [email protected]

Conflict of interest: Dr Vasile, None; Dr Jaffe is a consultant and has received research supportfrom Siemens and Beckman-Coulter. He is currently a consultant, or has consulted over time,

for most of the major diagnostic companies.

Abstract

This article describes the molecular biology of troponin in heart disease. Prospective uses for thisbiomarker are mentioned, with a particular emphasis on cardiac troponin fragments that could beassociated with distinct clinical entities. The article explores the topic of specific cardiac troponinfragments resulting from modification or degradation, linked with different pathological processes, asindications of novel potential uses for this biomarker in heart disease. In addition, it addresses someimplications that could have an impact on several circumstances that confront physicians within clinicalpractice.

Heart Metab. 2009;43:5–8.

Keywords: Troponin fragments, phosphorylation, dephosphorylation

Introduction detection in the blood is synonymous with myocardial

Detection of myocardial injury relies on the highlysensitive and specific determination of cardiac tropo-nin (cTn). Thus increased cTn is essential for thediagnosis of acute myocardial infarction (AMI) [1].However, there may be other specific applications forcTn fragments, and increases in cTn concentrationsare observed in conditions other than AMI.

The troponin complex consists of three subunits:troponin C (cTnC), troponin I (cTnI) and troponin T(cTnT); it interacts with components of the thin tro-pomyosin and actin filament to ensure correct con-traction coupling [2]. Several isoforms of cTns C, I,and T assist in this task [3].

Troponin C (TnC) lacks cardiac specificity. Incontrast, it is believed that all isoforms of cTnI areexpressed exclusively in cardiomyocytes, thus its

Heart Metab. 2009; 43:5–8

injury. The cTnI isoforms are characterized by a32 amino acid posttranslational tail at the N-terminus[4]. The junction between this sequence and thestable central part of the molecule is the target formonoclonal antibodies that recognize cTnI [5].Expression of troponin T or I is controlled by threegenes [6]. By alternative splicing, several isoforms ofcTnT are generated, with sequence variability regionslocated at the C- or the N-terminus, or both [6,7].

Conditions other than AMI in which cTnconcentrations are increased

Physical exerciseTransient increases in cTnT occur after severe physicalexercise, early during exertion [8]. Initially, it was

5


Basic articleVlad C. Vasile and Allan S. Jaffe

believedthat these increasesresolvedin24 h,but recentdata from sensitive assays do not support this [9]. It isdifficult todistinguishwhethercTnis releasedbyrevers-ible or irreversible injury. Similarly, whether there arereparative processes is unclear. Either way, differentfragments might be elaborated in this situation.

Chronic renal failure

Concentrations of cTnT are often abnormal in patientswith chronic renal failure [10]. The etiology of theseincreases is obscure, but probably includes any of:endothelial dysfunction, acute cardiac stretch, intra-dialysis hypotension and hypertension, left ventricularhypertrophy, and coronary artery disease, occult orovert. Some authors report small cTn fragments [11]but others dispute that [12].

Myocardial stunning

Myocardial stunning is a reversible myocardial dys-function seen after ischemia. It also can be inducedby arrhythmias or open heart surgery [13]. A specificdegradation product occurs in this circumstance fromthe loss of 17 residues at the C-terminus of cTnI[14]. Transgenic animals overexpressing this trun-cated form, cTnI1–193, exhibit myocardial dysfunctionwith properties similar to those of myocyte stunning. Acomparable fragment was found after bypass surgery[15]. In in-vitro experiments, transfection of truncatedcTnI1–193 produces a diastolic impairment in healthyhuman cardiomyocytes [16]. This suggests that thedegradation of cTnI contributes to diastolic dysfunc-tion in vivo. If these cTn fragments were causative,they could be monitored to identify which patientswith impaired function might improve.

Transient left ventricular apical ballooningsyndrome

This syndrome can mimic AMI clinically [17]. It ischaracterized by more extensive ventricular dys-function than would be expected from the modestincreases observed in cTn values, which are goodsurrogates for infarct size [18,19]. Phosphorylated ortruncated cTn may be the basis for this dysfunction.

Reperfusion in acute myocardial infarction

Reperfusion in AMI can be induced by thrombolytictherapy or percutaneous coronary angioplasty. It mayincrease the extent of cardiac injury [20]. Underhypoxia, modifications of cTn may be specificallyassociated with this ‘‘ischemia-reperfusion’’ process[21]. Patients with larger myocardial infarctions dis-play greater amounts of degraded cTn fragments. It ispossible that the proteases involved in clot dissolution

6

or those implicated in induction of inflammationin response to injury could degrade cTns. The bio-chemical environment of the myocardium might bedifferent than that of blood, leading to different cTnchanges. Detectable changes might be useful in dis-tinguishing more from less robust recanalization.

Acute myocarditis

Acute myocarditis can present similarly to AMI [22].Increases in cTnI occur in mouse models of auto-immune myocarditis [23] and in patients with heartfailure secondary to chronic myocarditis. Presumably,inflammation leads to myocardial injury. It may bethat fragments produced secondary to inflammationare different from those triggered by ischemia. Recog-nition of dissimilarities might permit differentiation ofdistinct disease states in clinical practice. Moreover,cTn may play a part in inflammation itself [24].

Basic molecular biology on whichfragmentology is based

The regulation of contraction physiology is com-plex and includes abundant phosphorylation anddephosphorylation steps within troponin and actin-tropomyosin. cTnI is phosphorylated at specific ser-ine/threonine residues by protein kinase A (PKA) [25].The extent of phosphorylation of cTnI and cTnTdepends on these kinases and phosphatases, but alsoon their spatial conformation, which confers accessi-bility to phosphorylation sites. Posttranslational phos-phorylation of cTnI/cTnT by processes that block orreveal specific sites may also change the status of cTn.Physiologic degradation occurs at the N-terminus;residues 27, 28 or 31 seem to possess key significance.

During ischemia, protein kinase C (PKC) and p21-activated kinase induce cTn phosphorylation [26].Proteolysis occurs initially at the C-terminus, at aminoacid 192, followed by additional cleavages. Trunca-tion of cTnI at amino acid residue 192 is associatedwith human disease [13,14]. The alteration of cTnT/cTnI by proteolysis, phosphorylation, or both, gener-ates an assortment of fragments (Table I).

The majority of cTnI interacts with TnC, and cTnsubunits or serum proteins [27]. In patients with AMI,a proportion of the cTnI circulates bound to cTnCalong with complexes of cTnsT, I and C. Duringischemia, truncation of the N-terminus eliminatesPKA phosphorylation sites and sites involved incTnI–TnC interaction. Thus degradation and phos-phorylation also influence circulating fragments.The detection of these isoforms could elucidatespecific etiologies for cardiac disease.

One pool of cTn corresponds to a ‘‘cytosolic’’localization. Such localization is based on solubility


Basic articleThe biology and potential of troponin fragments

Table I. Modified forms of cTnI.

Condition Type of modification Amino-acid position Enzyme

Physiological Phosphorylation N-terminus Increased concentrations ofprotein kinase A

Physiological Proteolysis N-terminus (starting atposition 27, 28, or 31)

Proteases

Pathological Phosphorylation C-terminus Reduced concentrations ofprotein kinase A

Pathological Phosphorylation C-terminus Protein kinase C

Pathological Phosphorylation C-terminus P21-activated kinase

Pathological Proteolysis C-terminus (ends at 192) Proteases

Pathological Proteolysis N-terminus (ends at 63) Proteases

Pathological Proteolysis N-terminus (ends at 73) Proteases

studies; thus a better term might be ‘‘early-releasablepool.’’ The other pool is believed to be structurallybound. Only 4% of cTnI and 5% of cTnT are found inthe cytosolic compartment [28]. Presumably, the initialrelease of troponin derives from the cytosolic pool,whereas the persistent increases are from degradationof the structural compartment. Patients with renal fail-ure demonstrate the same cTn clearance curves [29],suggesting that the persistence of cTn is not as a result ofdelayed elimination. During reperfusion, the earlypeak in cTnT occurs at 14 h after the onset of pain[22], probably from the cytosolic pool. This peak isabsent in patients reperfused later than 5.5 h after theonset of pain and in patients with AMI who do notundergo reperfusion [28]. The cytosolic compartmentof the unbound cTnT and cTnI is responsible for thisinitial peak in patients with early reperfused AMI, andseems to be composed mostly of free chains [30].Persistent increases in cTn concentration are attributedto lysosomal degradation of the ‘‘structural’’ pool ofcTn during infarct remodeling and collagen deposition[31]. Increases in cTn in pulmonary embolism resolveby 40 h in the absence of current emboli. The shortduration of cTn in the bloodstream after acute exertionand pulmonary embolism might be explained by thecTn released from the cytosolic compartment ratherthan from the structural pool; the latter would beaffected only if necrosis occurs, if it is extensive enoughfor detection, or by changes in the fragments released.

Conclusion

The complex biology of cTns should allow for thedevelopment of novel assays able to discriminatevarious fragments that may be elaborated selectivelywithin distinct pathological processes. These frag-


ments resulting from metabolism or phosphorylationhave the potential for both diagnostic and therapeuticimportance.

REFERENCES

1. Thygesen K, Alpert JS, White HD. Universal definition ofmyocardial infarction. J Am Coll Cardiol. 2007;50:2173–2195.

2. Takeda S, Yamashita A, Maeda K, Maeda Y. Structure ofthe core domain of human cardiac troponin in the Ca(2R)-saturated form. Nature. 2003;424:35–41.

3. Dhoot GK, Perry SV. Distribution of polymorphic forms oftroponin components and tropomyosin in skeletal muscle.Nature. 1979;278:714–718.

4. Perry SV. Troponin I: inhibitor or facilitator. Mol Cell Biochem.1999;190:9–32.

5. Katrukha A. Antibody selection strategies in cardiac troponinassay. In: Cardiac Markers, 2nd ed. Edited by Wu H. Totowa,NJ: Humana Press; 2003. pp. 173–185.

6. Perry SV. Troponin T: genetics, properties and function.J Muscle Res Cell Motil. 1998;19:575–602.

7. Gahlmann R, Troutt AB, Wade RP, Gunning P, Kedes L.Alternative splicing generates variants in important functionaldomains of human slow skeletal troponin T. J Biol Chem.1987;262:16122–16126.

8. Middleton N, George K, Whyte G, Gaze D, Collinson P, ShaveR. Cardiac troponin T release is stimulated by enduranceexercise in healthy humans. J Am Coll Cardiol. 2008;52:1813–1814.

9. Mingels A, Jacobs L, Michielsen E, Swaanenburg J, Wodzig W,van Dieijen-Visser M. Reference population and marathonrunner sera assessed by highly sensitive cardiac troponin T andcommercial cardiac troponin T and I assays. Clin Chem. 2009;55:101–108.

10. Freda BJ, Tang WH, Van Lente F, Peacock WF, Francis GS.Cardiac troponins in renal insufficiency: review and clinicalimplications. J Am Coll Cardiol. 2002;40:2065–2071.

11. Diris JH, Hackeng CM, Kooman JP, Pinto YM, Hermens WT,van Dieijen-Visser MP. Impaired renal clearance explainselevated troponin T fragments in hemodialysis patients.Circulation. 2004;109:23–25.

12. Fahie-Wilson MN, Carmichael DJ, Delaney MP, Stevens PE,Hall EM, Lamb EJ. Cardiac troponin T circulates in the free,intact form in patients with kidney failure. Clin Chem. 2006;52:414–420.

13. Bolli R, Marban E. Molecular and cellular mechanisms ofmyocardial stunning. Physiol Rev. 1999;79:609–634.

7

Basic articleVlad C. Vasile and Allan S. Jaffe

14. Van Eyk JE, Powers F, Law W, Larue C, Hodges RS, Solaro RJ.Breakdown and release of myofilament proteins during ische-mia and ischemia/reperfusion in rat hearts: identification ofdegradation products and effects on the pCa-force relation.Circ Res. 1998;82:261–271.

15. McDonough JL, Labugger R, Pickett W, et al. Cardiac troponinI is modified in the myocardium of bypass patients. Circula-tion. 2001;103:58–64.

16. Narolska NA, Piroddi N, Belus A, et al. Impaired diastolicfunction after exchange of endogenous troponin I withC-terminal truncated troponin I in human cardiac muscle.Circ Res. 2006;99:1012–1020.

17. Tsuchihashi K, Ueshima K, Uchida T, et al. Transient leftventricular apical ballooning without coronary artery stenosis:a novel heart syndrome mimicking acute myocardial infarc-tion. Angina Pectoris-Myocardial Infarction Investigations inJapan. J Am Coll Cardiol. 2001;38:11–18.

18. Steen H, Giannitsis E, Futterer S, Merten C, Juenger C, KatusHA. Cardiac troponin T at 96 hours after acute myocardialinfarction correlates with infarct size and cardiac function.J Am Coll Cardiol. 2006;48:2192–2194.

19. Vasile VC, Babuin L, Giannitsis E, Katus HA, Jaffe AS. Rela-tionship of MRI-determined infarct size and cTnI measure-ments in patients with ST-elevation myocardial infarction. ClinChem. 2008;54:617–619.

20. Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? J Clin Invest. 1985;76:1713–1719.

21. Li G, Martin AF, Solaro JR. Localization of regions of troponin Iimportant in deactivation of cardiac myofilaments by acidicpH. J Mol Cell Cardiol. 2001;33:1309–1320.

22. Assomull RG, Lyne JC, Keenan N, et al. The role of cardio-vascular magnetic resonance in patients presenting with chestpain, raised troponin, and unobstructed coronary arteries. EurHeart J. 2007;28:1242–1249.

8

23. Smith SC, Ladenson JH, Mason JW, Jaffe AS. Elevations ofcardiac troponin I associated with myocarditis. Experimentaland clinical correlates. Circulation. 1997;95:163–168.

24. Goser S, Andrassy M, Buss SJ, et al. Cardiac troponin I but notcardiac troponin T induces severe autoimmune inflammationin the myocardium. Circulation. 2006;114:1693–1702.

25. Mittmann K, Jaquet K, Heilmeyer LM Jr. Ordered phos-phorylation of a duplicated minimal recognition motif forcAMP-dependent protein kinase present in cardiac troponinI. FEBS Lett. 1992;302:133–137.

26. Buscemi N, Foster DB, Neverova I, Van Eyk JE. p21-activatedkinase increases the calcium sensitivity of rat triton-skinnedcardiac muscle fiber bundles via a mechanism potentiallyinvolving novel phosphorylation of troponin I. Circ Res.2002;91:509–516.

27. Wu AH, Feng YJ, Moore R, et al. Characterization of cardiactroponin subunit release into serum after acute myocardialinfarction and comparison of assays for troponin T and I.American Association for Clinical Chemistry Subcommitteeon cTnI Standardization. Clin Chem. 1998;44:1198–1208.

28. Katus HA, Remppis A, Scheffold T, Diederich KW, Kuebler W.Intracellular compartmentation of cardiac troponin T and itsrelease kinetics in patients with reperfused and nonreperfusedmyocardial infarction. Am J Cardiol. 1991;67:1360–1367.

29. Ellis K, Dreisbach AW, Lertora JL. Plasma elimination ofcardiac troponin I in end-stage renal disease. South Med J.2001;94:993–996.

30. Atar D, Madsen LH, Labugger R, VanEyk JE. Molecular modi-fications of troponin I and T detected in serum from patientswith acute myocardial infarction. Ugeskr Laeger. 2003;165:116–120.

31. Jugdutt BI. Ventricular remodeling after infarction and theextracellular collagen matrix: when is enough enough? Cir-culation. 2003;108:1395–1403.


Main clinical article

The role of biomarkers inclinical practice

Anthony S. Wierzbickia and Adie Viljoenb

aGuy’s & St Thomas Hospitals, London, UK, and bLister Hospital, Stevenage, Hertfordshire, UK

Correspondence: Dr A. S. Wierzbicki, Guy’s & St Thomas Hospitals, London SE1 7EH, UK.Tel: 00 44 207 1881256; e-mail: [email protected]

Conflicts of interest: None.

Abstract

Atherosclerosis is a process that begins intra-arterially and then becomes intraluminal. Imaging isthe best method with which to identify and monitor the progression of atherosclerosis; however, untilrecently, methods have been neither available or practical. Epidemiological studies have shown thatbiochemical markers, including lipids, glycemia, and renal function, contributed to the risk ofcardiovascular events. Later measures of inflammatory processes involved in atherosclerosis andneurohormones (eg, natriuretic peptides) have been added to risk stratification. Biochemicalmarkers are well established, in addition to electrophysiology, for the definition of various grades ofmyocardial infarction, and biomarker panels now form the core of the diagnostic criteria for definition ofacute coronary syndromes. Biomarkers are also used in the development, validation, and safetymonitoring of drugs used in the management of atherosclerotic disease. Thus use of biochemicalmarkers is essential to the diagnosis, prognosis, and safety assessment of atherosclerosis.

Heart Metab. 2009;43:9–11.

Keywords: Biomarker, asymmetric dimethylarginine, C-reactive protein, troponin, B-type natriureticpeptide, lipoprotein-associated phospholipase A2, cardiovascular risk, myocardial infarction, statin,safety

Introduction diagnosis and staging of ischemic heart disease, and

Atherosclerosis is a process that begins in childhoodand is responsible for 35% of mortality. The processbegins intra-arterially and only at a late stage begins toobstruct the lumen of the vessel [1]. Imaging ofatherosclerosis would be the ideal method of diag-nosis and monitoring, but, until recently, methodshave been either unavailable or impractical becausethey involved highly invasive procedures (intravas-cular ultrasound) for routine use in primary preven-tion. Therefore surrogate markers such as carotidintima media thickness have been used [2,3]. Bio-markers, defined as biochemical analytes measured inplasma or urine, are used in cardiovascular disease fora number of purposes. The three major uses are forrisk assessment in cardiovascular prevention, for the

Heart Metab. 2009; 43:9–11

for monitoring of the safety of therapies.

Risk assessment

As there is, as yet, no easy method of assessing theburden of atherosclerosis by imaging methods, so theentire basis of cardiovascular risk assessment relies onepidemiological data for cardiovascular disease [4]. Instudies such as the Framingham Heart Study, the riskof events is related to demographic and physiologicalparameters (body mass index, blood pressure) inaddition to a series of biochemical markers for riskassessment in the prevention of cardiovascular dis-ease [5]. The best known are total cholesterol andhigh-density lipoprotein (HDL) cholesterol, which

9


Main clinical articleAnthony S. Wierzbicki and Adie Viljoen

form part of the core risk-assessment algorithm.Hyperglycemia and diabetes are also risk predictors,but are usually excluded because diabetes is con-sidered to be a cardiovascular risk equivalent [6].Hyperglycemia and glycated hemoglobin (HbA1c)can also be used to identify higher-risk groups likelyto have insulin resistance/metabolic syndrome [7].Further information has been added in other epide-miological studies through the addition of both trigly-cerides as a marker of the atherogenic lipoproteinphenotype, and small dense particles (both low-density lipoprotein [LDL] and HDL) [8]. The combi-nation of lipids, blood pressure, hyperglycemia, andwaist circumference is used in definitions of themetabolic syndrome, although other markers suchas hyperinsulinemia, hyperuricemia, and increasedconcentrations of inflammatory markers and plasmi-nogen activator inhibitor-1 (PAI-1) also are associatedwith this syndrome [9]. Cardiovascular risk is alsoincreased in patients with renal dysfunction identifiedby measurement of plasma creatinine and increas-ingly expressed as an estimated glomerular filtrationrate (eGFR) [10]. When these are combined withthe presence of micro- or macroalbuminuria, furtherincrements of risk can be defined. The presenceof microalbuminuria in patients with hypertensiondefines a subset with target-organ damage and requir-ing extra treatment. The presence of albuminuriaallied to eGFR stratifies patients for renal dysfunctionand thus can help determine both risk of cardiovas-cular disease and how drug doses are adjusted.

The use of such marker panels allows a identifi-cation of 70–80% of cardiometabolic risk [11].Further specificity can be added through the additionof markers of inflammation, including C-reactiveprotein (CRP), fibrinogen, or sialic acid [12]. Someof these markers (eg, CRP) respond to drug therapiessuch as statins or fibrates. Recently, the use of CRP asa risk marker has been validated in the JUPITER(Justification for the use of statins in Primary preven-tion an Intervention Trial Evaluating Rosuvastatin)trial [13]. Another inflammation-associated markerthat seems to mark an oxidative phenotype is lipo-protein-associated phospholipase A2 (LpPLA2),which adds information about cardiovascular riskover and above that provided by CRP [14]. Thelimited relationship of LpPLA2 to markers of oxi-dation such as oxidized LDL and isoprostanes isunclear, but a possibly stronger association withsialic acid and electronegative LDL species meansits role has not been fully clarified. Another indirectmarker of oxidative stress involves the nitric oxidesystem, in which asymmetric dimethylarginine(ADMA) has been shown to mark the degree ofestablished atherosclerosis [15]. ADMA is correlatedwith endothelial vascular dysfunction, given its closerelationship to low concentrations of nitric oxide, but

10

– in contrast to nitric oxide – it is stable. Whether theprincipal source is vascular or renal is uncertain, butit does mark established atheroma; however, in con-trast to many biomarkers, it does not respond tocommon therapies (eg, antihypertensive agents orstatins). Natriuretic peptides are also potential mar-kers of cardiovascular risk, as they may identifypatients with left ventricular dysfunction and thuslow-grade ischemia, as may other markers of tissuehypoxia such as ischemia-modified albumin [16].Which risk markers will be added to the basic profileremains, as yet, unclear.

Established cardiovascular disease

Cardiac biomarkers are well established in thediagnosis of acute coronary disease. The release ofcardiomyocyte proteins includes (in approximatetemporal sequence): myoglobin or fatty acid bindingprotein 4, glycogen phosphorylase B, creatine kinaseMB fraction (CK-MB) and, finally, troponin (T, I or C)[17,18]. The concentrations of troponins are used inconjunction with clinical and electrocardiographiccriteria to define the extent of myocardial necrosisand to stratify patients into those with unstableangina, non-Q-wave myocardial infarction, or ST-segment-elevation myocardial infarction, whichdetermine treatment strategies. The availability ofnewer, more sensitive troponin assays is likely toresult in further redefinition between these clinicalcategories.

None of the above markers is functionally signifi-cant. In contrast, the natriuretic peptides arereleased in response to left ventricular cardiac dys-function [19]. The most commonly used is brainnatriuretic peptide (BNP), which is used as a diag-nostic marker of non specific cardiac dysfunction(including pulmonary dysfunction and pericarditis),but is better known as a definitive test to exclude thepresence of heart failure [20]. Early studies have notshown a benefit from using BNP to guide manage-ment in heart failure, but more sophisticated strat-egies correcting more accurately for age and sexmay prove more useful.

The reliability of cardiac biomarkers for ischemia issuch that many are now used in semiquantitativeassay formats in point-of-care panels. Typically, thesecombine hyperacute (myoglobin, fatty acid bindingprotein) or functional (BNP) markers with intermedi-ate markers (CK-MB), and a late definitive myolyticmarker of necrosis (troponin) [17]. There is contro-versy about the specificity, accuracy and utility ofdifferent panels and how they should be integratedwith clinical signs and electrocardiographic data, buttheir convenience is such that usage for triage inemergency rooms is increasing rapidly.

Heart Metab. 2009; 43:9–11

Main clinical articleBiomarkers of cardiovascular disease

Safety monitoring

Biomarkers are used to monitor drug therapies.The best known are markers of hepatic microsomalinduction (g-glutamyl transferase) and hepatocytenecrosis (transaminases) [21,22]. These are com-monly measured to track the toxicity of drug therapies.More specific biomarkers are used to track tissuetoxicities. In the severe case of myositis and rhabdo-myolysis, the association of statin therapy withmyopathy can be tracked by increases in creatinekinase (MM) and myoglobinuria [23]. Nowadays,even subtle toxicities detectable only by changes intransaminases and creatine kinase concentrations,from baseline, allied to genetic biomarkers of statinacid uptake (organic anion transporter), can be used topredict future myositis [24].

Conclusions

Biomarkers are central to the diagnosis and riskstratification of coronary heart disease. Although olderbiomarkers are well established, newer markers areoffering the possibility of further risk stratification,quantification of the underlying atheroma burden,and even marking the correction of cardiac dysfunc-tion by demonstrating the reappearance of normalphysiology.

REFERENCES

1. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis
GJ. Compensatory enlargement of human atheroscleroticcoronary arteries. N Engl J Med. 1987;316:1371–1375.
2. Wierzbicki AS. Surrogate markers, atherosclerosis and cardio-vascular disease prevention. Int J Clin Pract. 2008;62:981–987.

3. Wierzbicki AS. Lipid-altering therapies and the progression ofatherosclerotic disease. Cardiovasc Intervent Radiol. 2007;30:155–160.

4. Adams GJ, Greene J, Vick GW III et al. Tracking regression andprogression of atherosclerosis in human carotid arteries usinghigh-resolution magnetic resonance imaging. Magn ResonImaging. 2004;22:1249–1258.

5. Anderson KM, Odell PM, Wilson PW, Kannel WB. Cardio-vascular disease risk profiles. Am Heart J. 1991;121:293–298.

6. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M.Mortality from coronary heart disease in subjects with type2 diabetes and in nondiabetic subjects with and withoutprior myocardial infarction. N Engl J Med. 1998;339:229–234.

Heart Metab. 2009; 43:9–11

7. Khaw KT, Wareham N, Luben R, et al. Glycated haemoglobin,diabetes, and mortality in men in Norfolk cohort of Europeanprospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ. 2001;322:15–18.

8. Austin MA. Triglyceride, small, dense low-density lipoprotein,and the atherogenic lipoprotein phenotype. Curr AtherosclerRep. 2000;2:200–207.

9. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome – anew worldwide definition. Lancet. 2005;366:1059–1062.

10. Mann JF, Gerstein HC, Dulau-Florea I, Lonn E. Cardiovascularrisk in patients with mild renal insufficiency. Kidney Int Suppl.2003;S192–S196.

11. Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction oflifetime risk for cardiovascular disease by risk factor burden at50 years of age. Circulation. 2006;113:791–798.

12. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactiveprotein and other circulating markers of inflammation in theprediction of coronary heart disease. N Engl J Med. 2004;350:1387–1397.

13. Ridker PM, Danielson E, Fonseca FA, et al., for the JUPITERStudy Group. Rosuvastatin to prevent vascular events inmen and women with elevated C-reactive protein. N Engl JMed. 2008;359:2195–2207; Published online, doi:NEJMoa0807646 [pii];10.1056/NEJMoa0807646 [doi].

14. O’Donoghue M, Morrow DA, Sabatine MS, et al. Lipoprotein-associated phospholipase A2 and its association with cardio-vascular outcomes in patients with acute coronary syndromesin the PROVE IT–TIMI 22 (PRavastatin Or atorVastatin Evalua-tion and Infection Therapy–Thrombolysis In MyocardialInfarction) trial. Circulation. 2006;113:1745–1752.

15. Boger RH. Asymmetric dimethylarginine (ADMA): a novel riskmarker in cardiovascular medicine and beyond. Ann Med.2006;38:126–136; Published online, doi:X68476T031657H96 [pii];10.1080/07853890500472151 [doi].

16. Emberson JR, Ng LL, Armitage J, et al., for the Heart ProtectionStudy Collaborative Group. N-terminal pro-B-type natriureticpeptide, vascular disease risk, and cholesterol reductionamong 20,536 patients in the MRC/BHF heart protectionstudy. J Am Coll Cardiol. 2007;49:311–319.

17. Jaffe AS. Use of biomarkers in the emergency department andchest pain unit. Cardiol Clin. 2005;23:453–465; vi. Publishedonline, doi:S0733-8651(05)00061-5 [pii];10.1016/j.ccl.2005.08.013 [doi].

18. Collinson PO, Gaze DC. Biomarkers of cardiovasculardamage and dysfunction – an overview. Heart Lung Circ.2007;16 (suppl 3):S71–S82; Published online, doi:S1443-9506(07)00222-3 [pii];10.1016/j.hlc.2007.05.006 [doi].

19. Silver MA. The natriuretic peptide system: kidney and cardio-vascular effects. Curr Opin Nephrol Hypertens. 2006;15:14–21; Published online, doi:00041552-200601000-00004 [pii].

20. Machado M, Falcao LM, Ravara L. The clinical role ofnatriuretic peptides – importance of BNP and NT-proBNP.Implications in heart failure and acute coronary syndrome.Rev Port Cardiol. 2004;23:1005–1032.

21. McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Finalconclusions and recommendations of the National LipidAssociation Statin Safety Assessment Task Force. Am J Cardiol.2006;97:89C–94C; Published online, doi:S0002-9149(06)00305-5 [pii];10.1016/j.amjcard.2006.02.030 [doi].

22. Vasudevan AR, Hamirani YS, Jones PH. Safety of statins: effectson muscle and the liver. Cleve Clin J Med. 2005;72: 990–1001.

23. Guyton JR. Benefit versus risk in statin treatment. Am J Cardiol.2006;97:S95–S97.

24. Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy – a genomewide study. N Engl J Med.2008;359:789–799.

11

Metabolic imaging

Troponin compared with lateenhancement in the assessment of

myocardial injuryEvangelos Giannitsis and Hugo A. Katus

Medizinische Universitatsklinik Heidelberg, Department of Cardiology, Heidelberg, Germany

Correspondence: Prof. Dr Evangelos Giannitsis, Medizinische Universitatsklinik Heidelberg, Abteilung furInnere Medizin III, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.Tel: +49 6221 56 8670; e-mail: [email protected]


Abstract

Cardiac troponins are regarded as the reference standard for detection of myocardial cell necrosis.Contrast-enhanced cardiac magnetic resonance imaging (CE-MRI) represents a modern technology thatallows comprehensive evaluation of the heart after myocardial infarction. It enables assessment of globaland regional myocardial function, confirmation and quantification of myocardial infarction,identification of viable myocardium suitable for revascularization procedures, and detection ofspecific complications including microvascular obstruction. Thus CE-MRI represents a usefulcomplementary diagnostic tool after acute coronary syndromes. However, increased concentrationsof troponin may also be encountered in symptomatic patients without acute coronary syndrome – ie, inpatients with acute pulmonary embolism, myocarditis, cardiac ischemic amyloidosis, and dilated andhypertrophic cardiomyopathies. As increased concentrations of troponin are associated with adverseoutcomes in most of these differential diagnoses, the reason for the myocardial damage must be activelypursued. Along with typical morphological and functional findings on cardiac MRI, different patterns ofnon ischemic late hyperenhancement have proved to be useful in discriminating ischemic from nonischemic myocardial damage, and to establish a correct differential diagnosis.

Heart Metab. 2009;43:13–18.

Keywords: Cardiac MRI, cardiac troponin, differential diagnoses, infarct size, late hyperenhancement,microvascular obstruction

Introduction

Prognosis after acute myocardial infarction is stronglydetermined by the extent of myocardial injury [1].Assessment of left ventricular function after myo-cardial infarction is helpful for risk stratification andselection of patients requiring an implantable cardio-verter defibrillator for prevention of sudden cardiacdeath [2], and the presence and extent of ‘‘late hyper-enhancement’’ on contrast-enhanced cardiac magne-tic resonance imaging (CE-MRI) has been shown togive information on the ability of the myocardium to

Heart Metab. 2009; 43:13–18

resume contractility after revascularization pro-cedures [3,4].

Echocardiography has emerged as the most con-venient method for the quantification of left ventri-cular function, but this technique does not allowdirect quantification of infarct size, and gives onlylimited information on the presence of viable myo-cardium and the potential for functional recovery afterrevascularization procedures. Currently, several ima-ging techniques, including thallium sestamibi andpositron emission tomography, are used for quantifi-cation of infarct size [5]. Among the novel techniques,

13


Metabolic imagingEvangelos Giannitsis and Hugo A. Katus

Figure 1. Typical late enhancement (‘‘bright is dead’’)starting from the endocardial border after extensive anteriorwall myocardial infarction.

CE-MRI is noninvasive and does not involve exposureof the patient to radiation or potentially toxic contrastmaterial. It has been shown to provide a good approxi-mation of histological infarct size as assessed bytriphenyltetrazolium chloride staining [6]. This tech-nique is therefore preferred by some, because it allowsnoninvasive assessment of myocardial function andviability in vivo. It has a high spatial resolution, and issuperior to single-photon emission computed tom-ography (SPECT) for the identification of subendocar-dial myocardial infarction [6,7]. Furthermore, CE-MRIis highly sensitive and permits quantification of smallareas of myocardial injury attributable to native cor-onary artery disease or percutaneous coronary inter-ventions, or both [8,9]. However, the use of cardiacMRI for quantification of infarct size is limited byavailability and high cost. A convenient alternative,therefore, is to estimate infarct size from concen-trations or activities of cardiac proteins in peripheralblood – as has been practiced for some years [5].Today, cardiac troponins are established as the pre-ferred biochemical markers for the diagnosis of myo-cardial infarction [10]. Moreover, there is increasingevidence that measurement of cardiac troponins mayalso allow estimation of infarct size and detection ofthe presence of microvascular obstruction.

Cardiac troponin and MRI infarct size

The cardiac troponins C, T, and I (cTnC, cTnT, andcTnI) are structural proteins of the myofilament thatare exclusively expressed in cardiomyocytes. Uponirreversible cardiac injury, serum concentrations ofcTnT show a biphasic curve, with an early peak within24 h, resulting from the release of a small cytoplasmicpool, and a ‘‘plateau phase’’ 72–96 h after the onset ofsymptoms, resulting from continuous proteolyticdegradation of the contractile apparatus [11,12].

Animal and human studies using thallium SPECTand MRI have demonstrated an excellent correlationbetween infarct size and cTn concentrations [13–17].Using cardiac MRI, the pattern of late hyperenhance-ment is distinctive for myocardial infarction, with acompact area of subendocardial late hyperenhance-ment visible after the administration of gadolinium[18]. In patients with myocardial infarction, thisarea typically starts from the endocardial borderof the myocardium, with a variable extent towardsthe epicardial border (Figure 1). The areas of latehyperenhancement correspond to the territory ofthe infarct-related coronary artery; the extent of latehyperenhancement is usually given as percent trans-murality and is reported either semiquantitatively, orquantitatively as absolute or relative infarct size. Thetransmurality of hyperenhancement has been shownto correlate with the ability of myocardial contractility

14

to recover after revascularization [3,4]. In contrast,several other nonischemic patterns of late hyper-enhancement have been reported in patients withmyocarditis, cardiomyopathies, cardiac amyloidosis,and other systemic diseases with cardiac involvement[18].

Regarding quantification of infarct size without theneed to perform MRI, an increasing amount of evi-dence coming from CE-MRI studies shows that anysingle measurement of cTn concentration between 24and 96 h after the onset of symptoms allows an excel-lent estimation of infarct size [13–17]. The relation-ship between cTnT and cTnI is excellent for largeST-segment elevation myocardial infarction (STEMI)and useful – albeit less impressive – for the hetero-genous group of non-STEMI episodes [19,20].Although serial measurements are as effective assingle-time-point protocols, the latter may be betteraccepted in clinical practice, because a simple algor-ithm is more convenient and more cost-effective thanserial measurements [19,20].

The diagnosis of periprocedural myocardial infarc-tion after percutaneous coronary intervention (PCI) isrelatively straightforward, as myocardial ischemia isthe mechanism underlying PCI-related myocardialnecrosis. Johansen et al [21] were able to demonstrateconsistently that the majority of increases in cTnT afterPCI persisted for at least 96 h, indicating continuingrelease of cTnT from the contractile apparatus andreflecting irreversible myocardial injury. In cardiacCE-MRI, areas of myocardial infarction have beenidentified as the source of increased concentrationsof minor serum markers [8,9]. Ricciardi et al [8] usedCE-MRI and demonstrated that even mild increasesin CK-MB concentrations after PCI were attributableto discrete microinfarction [8]. All patients withincreased CK-MB concentrations had discrete hyper-enhancement in the target-vessel perfusion territory.

Heart Metab. 2009; 43:13–18

Metabolic imagingTroponin versus late enhancement

Cardiac troponin for prediction of thepresence and magnitude of microvascularobstruction

Microvascular obstruction (MVO) is believed to berelated to peripheral embolization of platelet micro-aggregates, intimal edema, vasoconstriction, or leuko-cyte sticking [22,23]. The findings of experimental andclinical studies clearly demonstrated that, irrespectiveof cause, MVO is associated with a greater degree ofmyocardial damage, more severely depressed leftventricular function, and a higher mortality [24–27].Therefore, identification of patients with MVO wouldbe useful for risk stratification at minimum, and mightbe helpful also in eventually elucidating both its patho-physiology, and possible therapeutic approaches.

Sophisticated techniques such as contrast echocar-diography, delayed radionuclide imaging, and CE-MRI have been shown to be capable of identifyingthis lack of small-vessel perfusion [28–31]. Data havealso confirmed that the presence and maximal extentof MVO are best evaluated by early post-contrast MRI[32]. With CE-MRI, zones of hypoenhancement sur-rounded by areas of hyperenhancement are believedto represent areas of microvascular obstruction inpatients after acute myocardial infarction (Figure 2).These areas correspond well to anatomically definedno-reflow zones determined by histological thioflavinS staining [33]. Several studies have clearly demon-strated that patients with MVO have suffered largerinfarcts (as determined by CE-MRI, maximal creatinekinase, and cTnI) than those without MVO [24,34]. Itis noteworthy that the extent of MVO also correlatedpositively (r¼0.754, P<0.0001) with infarct size[24]. In agreement with this, Tarantini et al [30]reported a progressive increase in peak cTnI con-centrations, with the lowest values in those patients

Figure 2. Late hyperenhancement (arrow) surrounding darkarea of no reflow, the hallmark of microvascular obstruc-tion.

Heart Metab. 2009; 43:13–18

without transmural necrosis or severe MVO, inter-mediate values in those with transmural necrosiswithout MVO, and highest values in patients withtransmural necrosis and MVO. Our own (as yetunpublished) findings suggest that cTnT valuesbetween 24 and 96 h after AMI are significantlygreater in the presence of MVO. The best single valuefor the prediction of MVO is a cTnT concentrationgreater than 2.52 mg/L at 24 h after the patient’s admis-sion to hospital, and the ability of cTnT to predictMVO persists after adjustment for potential confoun-ders such as duration of ischemia and success ofepicardial reperfusion.

As a general limitation, the rates of MVO reported instudies vary widely. This variation may be explained bythe use of different MRI techniques for determination oftheobstruction. The twomost commonly used methodsfor assessing no-reflow include first-pass perfusiontechniques [35–37] and late-enhancement imaging[24,34,36]. The first-pass perfusion technique has theshortcoming that a perfusion mismatch might be inter-preted as an area of no-reflow [38].

Cardiac troponin and nonischemic patternsof late enhancement

MyocarditisSeveral cardiac MRI studies have demonstrated thathyperenhancement can be found in at least 85% ofpatients with acute myocarditis evolving within thefirst 2 weeks after the onset of symptoms [39]. The tworelevant CE-MRI approaches described so far dependon the measurement of myocardial global (early)relative enhancement [39] or the visualization of lategadolinium enhancement. Early enhancement prob-ably reflects myocardial hyperemia and increasedcapillary permeability as features of present inflam-mation, whereas late enhancement mostly indicatesirreversible myocardial injury (Figure 3). Morerecently, T2-weighted imaging was found to be usefulin a combined imaging approach [40]. The incidenceof late hyperenhancement in myocarditis is a con-troversial issue. Reported incidences vary between44% and 55% using antimyosin scintigraphy[41,42], and the 88% incidence reported by Mahr-holdt et al [43]. The reason for such discrepancies maybe related to differences in patient populations orstudy designs.

Cardiomyopathies

Dilated cardiomyopathy

Increased concentration of cTnT have been reportedin dilated cardiomyopathy in the absence of coronarystenoses, and were related to an adverse prognosis[44]. There are substantial differences between

15


Figure 3. Spotted diffuse non ischemic late hyperenhance-ment within the lateral wall in a patient with myocarditis.

Figure 5. Patchy non ischemic late hyperenhancement atthe junctions of the interventricular septum and the rightventricular walls in a patient with hypertrophic cardiomyo-pathy.

concentrations of biomarkers in patients who presentwith acute decompensated chronic heart failure,depending on the underlying etiology of the heartfailure syndrome [45]. Hyperenhancement inischemic cardiomyopathy characteristically spreadsfrom the subendocardium up to the epicardium, and isconfined to the perfusion territories of the coronaryarteries [46]. In contrast, several patterns of infarct-atypical, nonischemic late hyperenhancement havebeen reported in dilated cardiomyopathy, including apattern in the midventricular rim of hyperenhance-ment that predominantly involves the septum and isfound in 9–28% of patients (Figure 4). This hyper-enhancement is presumed to reflect patchy areas ofreplacement fibrosis [47]. The presence of thisparticular pattern of hyperenhancement has been

Figure 4. Typical mid-septal rim of non ischemc hyper-enhancement in a patient with dilated cardiomyopathy.

16

shown to be an independent predictor of all-causemortality and the onset of potentially life-threateningventricular arrhythmias.

Hypertrophic cardiomyopathy

Increased concentrations of cTn may be encounteredin hypertrophic cardiomyopathy, may be prognosti-cally important, and correlate with worsening of leftventricular function [48]. The exact reason for this isunclear, but it may include relative myocardial ische-mia resulting from an imbalance between inappropri-ate hypertrophy of the myocardium and insufficientcoronary arterial supply, and myocyte abnormalitiesdetermined by gene mutations causing myocyte injury[48].

Myocardial scarring is a common finding in patientswith hypertrophic cardiomyopathy; it occurs mostlyin hypertrophied regions and is usually patchy withseveral foci, predominantly affecting the midventri-cular wall, the junctions of the interventricular sep-tum, and the right ventricular walls (Figure 5) [49–51].The extent of hyperenhancement measured byCE-MRI correlates with conventional risk markers,and has also been related to the occurrence of ven-tricular arrhythmias and an increased number ofclinical risk factors for sudden death [51–53]. How-ever, the prognostic value of the presence and extentof hyperenhancement in patients with hypertrophiccardiomyopathy remains unknown, and the results ofcurrent studies are awaited [51].

Amyloidosis

Cardiac involvement is common in systemic amyloi-dosis. Usually, it is either diagnosed by a positive heartbiopsy, or suspected from left ventricular hypertrophy(interventricular septal thickness 12 mm or more) in

Heart Metab. 2009; 43:13–18

Metabolic imagingTroponin versus late enhancement

Figure 6. Diffuse late hyperenhancement and inability to‘‘null’’ the myocardium in a patient with cardiac amyloi-dosis.

the absence of hypertension or other potentialcauses of the hypertrophy [54]. In conjunction withN-terminal pro brain natriuretic peptide, cardiactroponin T has been found to represent a powerfulstaging system for patients with immunoglobulinlight-chain amyloidosis, with the objective of providingan easily available tool allowing comparison betweenoutcomes of therapeutic interventions in the absenceof randomized trials [55,56]. Cardiac amyloidosistypically shows an ill-defined global subendocardialpattern of hyperenhancement, matching the distri-bution of the amyloid deposition. This pattern of hyper-enhancement is very characteristic for cardiac involve-ment of amyloidosis, and can therefore be used todiscriminate this disease from other forms of restrictiveor hypertrophic cardiomyopathies. Although most pro-found in the subendocardial layer of myocardium,amyloid deposition occurs throughout the entire myo-cardium, causing the entire myocardium to have ahigher signal on CE-MRI images than normal myo-cardium. Therefore, ‘‘nulling’’ of myocardium can beextremely difficult when amyloidosis is present. Thetypical pattern of hyperenhancement, together with theincreased T1 signal of myocardium, yields a diagnosticaccuracy of 97% in patients with biopsy-proven amy-loidosis (Figure 6).

REFERENCES

1. The Multicenter Postinfarction Research Group. Risk stratifi-cation and survival after myocardial infarction. N Engl J Med.1983; 309:331–336.

2. Moss AJ, Zareba W, Hall WJ, et al., for the MulticenterAutomatic Defibrillator Implantation Trial II Investigators.Prophylactic implantation of a defibrillator in patients withmyocardial infarction and reduced ejection fraction. N Engl JMed. 2002;346:877–883.

Heart Metab. 2009; 43:13–18

3. Selvanayagam JB, Kardos A, Francis JM, et al. Value ofdelayed-enhancement cardiovascular magnetic resonanceimaging in predicting myocardial viability after surgical re-vascularization. Circulation. 2004;110:1535–1541.

4. Kim RJ, Wu E, Rafael A, et al. The use of contrast-enhancedmagnetic resonance imaging to identify reversible myocardialdysfunction. N Engl J Med. 2000;343:1445–1453.

5. Gibbons RJ, Valeti US, Araoz PA, Jaffe AS. The quantificationof infarct size. J Am Coll Cardiol. 2004;44:1533–1542.

6. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRIdelayed contrast enhancement to irreversible injury, infarctage, and contractile function. Circulation. 1999;100:1992–2002.

7. Wagner A, Mahrholdt H, Holly TA, et al. Contrast-enhancedMRI and routine single photon emission computed tomogra-phy (SPECT) perfusion imaging for detection of subendocardialmyocardial infarcts: an imaging study. Lancet. 2003;361:374–379.

8. Ricciardi MJ, Wu E, Davidson CJ, et al. Visualization ofdiscrete microinfarction after percutaneous coronary interven-tion associated with mild creatine kinase-MB elevation. Cir-culation. 2001;103:2780–2783.

9. Selvanayagam JB, Porto I, Channon K, et al. Troponin eleva-tion after percutaneous coronary intervention directly repre-sents the extent of irreversible myocardial injury: insights fromcardiovascular magnetic resonance imaging. Circulation.2005;111:1027–1032.

10. Thygesen K, Alpert JS, White HD, on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Redifinition of Myocar-dial Infarction. Universal definition of myocardial infarction.Circulation. 2007;116:2634–2653.

11. Katus HA, Remppis A, Scheffold T, Diederich KW, Kuebler W.Intracellular compartmentation of cardiac troponin T andits release kinetics in patients with reperfused and nonreper-fused myocardial infarction. Am J Cardiol. 1991;67:1360–1367.

12. Katus HA, Remppis A, Neumann FJ, et al. Diagnostic effi-ciency of troponin T measurements in acute myocardial in-farction. Circulation. 1991;83:902–912.

13. Remppis A, Ehlermann P, Giannitsis E, et al. Cardiac troponinT levels at 96 hours reflect myocardial infarct size: a pathoa-natomical study. Cardiology. 2000;93:249–253.

14. Gallegos RP, Swingen C, Xu XJ, et al. Infarct extent by MRIcorrelates with peak serum troponin level in the canine model.J Surg Res. 2004;120:266–271.

15. Steen H, Giannitsis E, Futterer S, Merten C, Juenger C, KatusHA. Cardiac troponin T at 96 hours after acute myocardialinfarction correlates with infarct size and cardiac function.J Am Coll Cardiol. 2006;48:2192–2194.

16. Licka M, Zimmermann R, Zehelein J, Dengler TJ, Katus HA,Kubler W. Troponin T concentrations 72 hours after myocar-dial infarction as a serological estimate of infarct size. Heart.2002;87:520–524.

17. Panteghini M, Cuccia C, Bonetti G, Giubbini R, Pagani F,Bonini E. Single-point cardiac troponin T at coronary careunit discharge after myocardial infarction correlates withinfarct size and ejection fraction. Clin Chem. 2002;48:1432–1436.

18. Mahrholdt H, Wagner A, Judd RM, Sechtem U, Kim RJ.Delayed enhancement cardiovascular magnetic resonanceassessment of non-ischaemic cardiomyopathies. Eur Heart J.2005;26:1461–1474.

19. Giannitsis E, Steen H, Kurz K, et al. Cardiac magnetic reso-nance imaging study for quantification of infarct size compar-ing directly serial versus single time-point measurements ofcardiac troponin T. J Am Coll Cardiol. 2008;51:307–314.

20. Vasile VC, Babuin L, Giannitsis E, Katus HA, Jaffe AS. Rela-tionship of MRI-determined infarct size and cTnI measure-ments in patients with ST-elevation myocardial infarction. ClinChem. 2008;54:617–619.

21. Johansen O, Brekke M, Stromme JH, et al. Myocardial damageduring percutaneous transluminal coronary angioplasty asevidenced by troponin T measurements. Eur Heart J.1998;19:112–117.

22. Kloner RA, Ganote CE, Jennings RB. The ‘‘no-reflow’’ phe-nomenon after temporary coronary occlusion in the dog. J ClinInvest. 1974;54:1496–14508.

23. Topol EJ, Yadav JS. Recognition of the importance of embo-lization in atherosclerotic vascular disease. Circulation. 2000;101:570–580.

17


24. Hombach V, Grebe O, Merkle N, et al. Sequelae of acutemyocardial infarction regarding cardiac structure and functionand their prognostic significance as assessed by magneticresonance imaging. Eur Heart J. 2005;26:549–557.

25. Ito H. No-reflow phenomenon and prognosis in patients withacute myocardial infarction. Nat Clin Pract Cardiovasc Med.2006;3:499–506.

26. Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significanceof microvascular obstruction by magnetic resonance imagingin patients with acute myocardial infarction. Circulation.1998;97:765–772.

27. Ito H, Okamura A, Iwakura K, et al. Myocardial perfusionpatterns related to thrombolysis in myocardial infarction per-fusion grades after coronary angioplasty in patients with acuteanterior wall myocardial infarction. Circulation. 1996;93:1993–1999.

28. Garot P, Pascal O, Simon M, et al. Time course and relation tolocal viability of microvascular function and volume afterreperfused acute myocardial infarction. Am J Cardiol.2002;89:1341–1346.

29. Gassler JP, Topol EJ. Reperfusion revisited: beyond TIMI 3flow. Clin Cardiol. 1999;22:IV20–IV29.

30. Tarantini G, Razzolini R, Cacciavillani L, et al. Influence oftransmurality, infarct size, and severe microvascular obstruc-tion on left ventricular remodeling and function after primarycoronary angioplasty. Am J Cardiol. 2006;98:1033–1040.

31. Wu KC, Kim RJ, Bluemke DA, et al. Quantification and timecourse of microvascular obstruction by contrast-enhancedechocardiography and magnetic resonance imaging follow-ing acute myocardial infarction and reperfusion. J Am CollCardiol. 1998;32:1756–1764.

32. Bogaert J, Kalantzi M, Rademakers FE, Dymarkowski S, Jans-sens S. Determinants and impact of microvascular obstructionin successfully reperfused ST-segment elevation myocardialinfarction. Assessment by magnetic resonance imaging. EurRadiol. 2007;17:2572–2580.

33. Judd RM, Lugo-Olivieri CH, Arai M, et al. Physiological basisof myocardial contrast enhancement in fast magnetic reso-nance images of 2-day-old reperfused canine infarcts. Circula-tion. 1995;92:1902–1910.

34. Younger JF, Plein S, Barth J, Ridgway JP, Ball SG, GreenwoodJP. Troponin-I concentration 72 hours after myocardial infarc-tion correlates with infarct size and presence of microvascularobstruction. Heart. 2007;93:1547–1551.

35. Baks T, van Geuns RJ, Biagini E, et al. Effects of primaryangioplasty for acute myocardial infarction on early and lateinfarct size and left ventricular wall characteristics. J Am CollCardiol. 2006;47:40–44.

36. Lund GK, Stork A, Saeed M, et al. Acute myocardial infarction:evaluation with first-pass enhancement and delayed enhance-ment MR imaging compared with 201Tl SPECT imaging.Radiology. 2004;232:49–57.

37. Taylor AJ, Al-Saadi N, Abdel-Aty H, Schulz-Menger J, Mess-roghli DR, Friedrich MG. Detection of acutely impairedmicrovascular reperfusion after infarct angioplasty with mag-netic resonance imaging. Circulation. 2004;109:2080–2085.

38. Albert TS, Kim RJ, Judd RM. Assessment of no-reflow regionsusing cardiac MRI. Basic Res Cardiol. 2006;101:383–390.

39. Friedrich MG, Strohm O, Schulz-Menger J, Marciniak H, LuftFC, Dietz R. Contrast media-enhanced magnetic resonanceimaging visualizes myocardial changes in the course of viralmyocarditis. Circulation. 1998;97:1802–1809.

18

40. Abdel-Aty H, Zagrosek A, Schulz-Menger J, et al. Delayedenhancement and T2-weighted cardiovascular magnetic re-sonance imaging differentiate acute from chronic myocardialinfarction. Circulation. 2004;109:2411–2416.

41. Rieker O, Mohrs O, Oberholzer K, Kreitner KF, Thelen M.Cardiac MRI in suspected myocarditis [in German]. Rofo.2002;174:1530–1536.

42. Kuhl U, Pauschinger M, Bock T, et al. Parvovirus B19 infectionmimicking acute myocardial infarction. Circulation. 2003;108:945–950.

43. Mahrholdt H, Goedecke C, Wagner A, et al. Cardiovascularmagnetic resonance assessment of human myocarditis: acomparison to histology and molecular pathology. Circula-tion. 2004;109:1250–1258.

44. Sato Y, Yamada T, Taniguchi R, et al. Persistently increasedserum concentrations of cardiac troponin T in patients withidiopathic dilated cardiomyopathy are predictive of adverseoutcomes. Circulation. 2001;103:369–374.

45. Miller WL, Hartman KA, Burritt MF, Burnett JC Jr, Jaffe AS.Troponin, B-type natriuretic peptides and outcomes in severeheart failure: differences between ischemic and dilated car-diomyopathies. Clin Cardiol. 2007;30:245–250.

46. McCrohon JA, Moon JC, Prasad SK, et al. Differentiation ofheart failure related to dilated cardiomyopathy and coronaryartery disease using gadolinium-enhanced cardiovascularmagnetic resonance. Circulation. 2003;108:54–59.

47. Assomull RG, Prasad SK, Lyne J, et al. Cardiovascular mag-netic resonance, fibrosis, and prognosis in dilated cardiomyo-pathy. J Am Coll Cardiol. 2006;48:1977–1985.

48. Sato Y, Taniguchi R, Nagai K, et al. Measurements of cardiactroponin T in patients with hypertrophic cardiomyopathy.Heart. 2003;89:659–660.

49. Germans T, van Rossum AC. The use of cardiac magneticresonance imaging to determine the aetiology of left ventri-cular disease and cardiomyopathy. Heart. 2008;94:510–518.

50. Rickers C, Wilke NM, Jerosch-Herold M, et al. Utility ofcardiac magnetic resonance imaging in the diagnosis of hy-pertrophic cardiomyopathy. Circulation. 2005;112:855–861.

51. Germans T, Wilde AA, Dijkmans PA, et al. Structural abnorm-alities of the inferoseptal left ventricular wall detected bycardiac magnetic resonance imaging in carriers of hyper-trophic cardiomyopathy mutations. J Am Coll Cardiol.2006;48:2518–2523.

52. Teraoka K, Hirano M, Ookubo H, et al. Delayed contrastenhancement of MRI in hypertrophic cardiomyopathy. MagnReson Imaging. 2004;22:155–161.

53. Moon JC, McKenna WJ, McCrohon JA, Elliott PM, Smith GC,Pennell DJ. Toward clinical risk assessment in hypertrophiccardiomyopathy with gadolinium cardiovascular magneticresonance. J Am Coll Cardiol. 2003;41:1561–1567.

54. Gertz MA, Comenzo R, Falk RH, et al. Definition of organinvolvement and treatment response in immunoglobulin lightchain amyloidosis (AL): a consensus opinion from the 10thInternational Symposium on Amyloid and Amyloidosis, Tours,France, 18–22 April 2004. Am J Hematol. 2005;79:319–328.

55. Kristen AV, Meyer FJ, Perz JB, et al. Risk stratification incardiac amyloidosis: novel approaches. Transplantation.2005;80 (suppl):S151–S155.

56. Dispenzieri A, Kyle RA, Gertz MA, et al. Survival in patientswith primary systemic amyloidosis and raised serum cardiactroponins. Lancet. 2003;361:1787–1789.

Heart Metab. 2009; 43:13–18

New therapeutic approaches

Trends in genomic biomarkersBruce McManus

The James Hogg iCAPTURE Centre, University of British Columbia, St Paul’s Hospital, and The Heart andLung Institute, Providence Health Care, Vancouver, British Columbia, Canada

Correspondence: Dr Bruce McManus, The Heart and Lung Institute, Providence Health Care, Room 166,Burrard Building, St Paul’s Hospital 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.



Abstract

Cardiovascular disease continues to be a major health concern globally. Developments in genomicdiscovery have yielded valuable new candidates in the quest for better biomarkers and novel therapeutictargets. This brief perspective focuses on recent trends in this field. DNA microarrays, single nucleotidepolymorphism chips, linkage analysis, genome-wide association studies, and other strategies haveincreased our knowledge of metabolic diseases of the heart. There are many benefits from theseapproaches, but one must remain cognizant of the importance of patient phenotyping. The integration ofnew and old tools and technologies promises the discovery and validation of better markers of thepresence of cardiovascular disease, its progression, and the response to treatment.

Heart Metab. 2009;43:19–21.

Keywords: Cardiovascular disease, genomics, biomarkers, microarrays, single nucleotidepolymorphisms, linkage analysis, genome-wide association studies

Introduction arrays and single nucleotide polymorphism (SNP)

Trends in the incidence of cardiovascular disease(CVD) continue upward globally, yielding a signifi-cant impact on morbidity and mortality in both devel-oped and developing societies. As the number ofpatients suffering from CVD mounts, alongside anaging demographic, the economic and social burdensof these diseases will continue to grow, with tremen-dous consequences for overstretched health-caresystems. The search for new and better biomarkersof the presence and progression of disease, riskstratification, and response to treatment has becomea matter of urgency. Fortunately, technologicaladvances have facilitated high-throughput assessmentand mining of the human genome, proteome, andmetabolome. In this context, molecular signatures(biomarkers) will be increasingly useful in the predic-tion, diagnosis and management of heart disease.

The discovery and development of biomarkers hasbenefited from the emergence of high-performancegenomic and genetic approaches such as DNA micro-

Heart Metab. 2009; 43:19–21

chips, respectively. The ability to screen large popu-lations for levels of gene expression, polymorphisms,and genetic linkage has shed light on the complexinterplay of genetic and environmental factorsinvolved in CVD. Molecular signatures have beenidentified that may have utility both in the clinicalmanagement of disease and in elucidating the mech-anisms involved, thereby providing insights intopotentially novel therapies.

Gene expression analysis

With the rise of high-performance technologies such asDNA microarrays, analyses of gene expression havebeen applied in the setting of various cardiovasculardiseases. The level of transcribed genes and the relatedmRNAs detectable by the microarrays are oftenexamined in an attempt to discover correlations withthe presence or absence of disease, clinical outcome,disease progression, and therapeutic responses [1].

19


New therapeutic approachesBruce McManus

Microarray analysis comparing the expression ofgenes in non failing hearts and failing hearts (ie,ischemic or non ischemic cardiomyopathy) hasrevealed substantial differences at a molecular level.In a study by Kittleson et al [2], 288 genes wereidentified as differentially expressed between groupswith non failing and failing hearts. Although none ofthe genes is currently used clinically, these geneticbiomarkers can still provide therapeutic insights intothe metabolic dysregulation underlying the diseaseconditions. As described by Kittleson and Hare [2]and Tan et al [3], many of the genes upregulated infailing hearts, relative to those in the non failinghearts, were associated with fatty acid metabolism,whereas those downregulated were linked to glucosemetabolism. This has triggered an investigation intothe use of drugs such as trimetazidine and ranolazine,which can shift the lipid and glucose metabolic statesin myocardial cells, as a potential treatment for failinghearts [2,4].

In the context of atherosclerosis, gene expressionstudies have also underscored the importance ofregulation of lipid metabolism. Using mouse models,Karr et al [5] identified numerous genes involved inlipid metabolism that are differentially expressedduring early stages of progression of the atherosclero-tic lesion. In cardiovascular diseases such as ischemicand non ischemic cardiomyopathy and atherosclero-sis, it is unlikely that a single biomarker can servesensitively and specifically as the therapeutic or diag-nostic biomarker for the disease. Biomarkers of thefuture are expected to be multi-marker panels charac-teristic of the complexity of the underlying pathophy-siology of the disease process. In fact, only a smallportion of familial and sporadic atherosclerosis resultsfrom single-gene defects in lipid metabolic pathways[6,7].

Genome-wide association studies

Beyond microarray-based expression studies, gen-ome-wide association studies provide an effectiveapproach to discovering genetic biomarkers. Geneticvariants, such as those on chromosome 9 (interval9p21) and chromosome 4 (4q25), have been linked toincreased risk for CVD [8]. McPherson et al [9]applied genome-wide association scanning and dis-covered a 58 kb interval on chromosome 9p21 thatwas consistently associated with coronary heart dis-ease in six independent cohorts, containing morethan 23 000 participants, from more than four whitepopulations. A similar finding was demonstrated bythe Wellcome Trust Case Control Consortium, whichfound an association between a similar region onchromosome 9p21 and coronary artery disease[10]. In the study by Gudbjartsson et al [11], two

20

sequence variants on chromosome 4q25 were foundto be strongly associated with atrial fibrillation in threepopulations of European descent and in a Chinesepopulation from Hong Kong.

In certain cases, the risk locus identified via gen-ome-wide association studies contains genes thathave yet to be annotated and characterized (eg,the 58 kb interval on chromosome 9p21). It mayalso be unclear what cellular and molecular differ-ences are induced by these genetic variants. Cer-tainly, many of the newly identified susceptibilityloci or SNPs require further studies to determinetheir involvement in the pathogenesis of CVD andpotential therapeutic targets for testing. It is likelythat each SNP may have a modest influence on theconcentrations or function of translated protein pro-ducts, whereas a specific set of SNPs can have amajor impact on the pathobiology of a particularCVD [1]. Nonetheless, just as with genes identifiedin microarray studies, SNPs may also contain valu-able information on the mechanisms of CVD andpotential new therapeutic targets.

Linkage analysis

Linkage analysis is another approach to finding gene-tic biomarkers of cardiovascular diseases. It allows theidentification of disease DNA markers by examiningthe patterns of heredity in large high-risk families andthe occurrence of disease phenotypes among familymembers [1,12]. Using linkage analysis to look atfamilies with early-onset coronary artery disease,Connelly et al [13] have demonstrated an associationbetween GATQA2, a transcription factor, and suscep-tibility for coronary artery disease. Recent studies bythe Genetics of Early Onset Coronary Artery Diseases(GENCARD) investigators also revealed novel genecandidates, such as LSAMP, a tumor suppressor gene,and KALRN, a gene involved in the Rho GTPase-signaling pathway, to be associated with coronaryartery disease [14,15].

Discussion

It is not uncommon, in observing different genomicand genetic biomarkers studies using differing tech-nologies – microarrays, SNP chips, or linkageanalysis – that different genes or polymorphic lociare found to be associated with the same cardiovas-cular pathology. Certainly, an important factor to con-sider when comparing different genetic biomarkersstudies is the selection of patient cohort. Dependingon the heterogeneity or the size of the populationbeing analyzed, the genetic biomarkers detectedmay be significantly different. Ideally, a larger, more

Heart Metab. 2009; 43:19–21

New therapeutiTrends in genomics biomarkers

heterogeneous cohort can result in a more widelyapplicable biomarker discovery. However, thisincrease in heterogeneity may also compromise theability to find potentially more specific biomarkers thatare associated with particular extreme phenotypes.Ultimately, the key to success in genotypic charac-terization and expression studies will be the exquisitephenotyping of groups of patients of interest.

The potential genetic basis of cardiomyopathies andtherapeutic targets of heart failure have been dis-cussed in detail by Liew and Dzau [16], Kittlesonand Hare [2] and Heidecker et al [17]. The geneticswith respect to specific types of cardiomyopathiesand channelopathies was reviewed in great detailby Bezzina [18], in the previous issue of Heart andMetabolism. In the context of atherosclerosis, relevantgenetic biomarkers have also been discussed by Millerand colleagues [6].

Ultimately, the genetic biomarkers identified usingvarious technologies may be complementary to oneanother. Future systems biology studies may shed lightin this regard, and provide a more complete picture ofthe genetic mechanisms underlying each CVD. It ispossible that complex, multifactorial CVDs resultfrom a combination of effects attributable to thepresence or absence of specific genetic mutations,polymorphisms, or differential expression [19].

There are probably many effective therapeutictargets that have yet to be discovered. Genetic bio-markers may also help uncover these nuggets of gold.Just to put things into perspective, the human genomecontains more than 22 000 genes, but it has beensuggested that current medication targets only about2.3% (approximately 500) of them [6,20].

Developments in the technical capabilities under-lying high-throughput genomic approaches, coupledwith a focus on patient phenotyping and advancedcomputational strategies, will continue to add incre-mental value to our current understanding of heartdiseases, and have the potential to revolutionize themanagement of patients through earlier interventionand more effective interdiction on the processes ofdisease progression.

Heart Metab. 2009; 43:19–21

REFERENCES

c approaches

1. Seo D, Goldschmidt-Clermont P. Cardiovascular geneticmedicine: the genetics of coronary heart disease. J CardiovascTrans Res. 2008;1:166–170.

2. Kittleson MM, Hare JM. Molecular signature analysis: usingthe myocardial transcriptome as a biomarker in cardiovasculardisease. Trends Cardiovasc Med. 2005;15:130–138.

3. Tan FL, Moravec CS, Li J. The gene expression fingerprint ofhuman heart failure. Proc Natl Acad Sci. 2002;99:11387–11392.

4. Tuunanen H, Engblom E, Naum A, et al. Trimetazidine, ametabolic modulator, has cardiac and extracardiac benefits inidiopathic dilated cardiomyopathy. Circulation. 2008;118:1250–1258.

5. Karra R, Vermullapalli S, Dong C. Molecular evidence forarterial repair in atherosclerosis. Proc Natl Acad Sci. 2005;102:16789–16794.

6. Miller DT, Ridker PM, Libby P, Kwiatkowski DJ. Atherosclero-sis: the path from genomics to therapeutics. J Am Coll Cardiol.2007;49:1589–1599.

7. Breslow JL. Genetic differences in endothelial cells may deter-mine atherosclerosis susceptibility. Circulation. 2000; 102:5–6.

8. Hall J. Translating genetic discoveries to improvements incardiovascular care: the path to personalized medicine.J Cardiovasc Trans Res. 2008;1:37–40.

9. McPherson R, Pertsemlidis A, Kavaslar N, et al. A commonallele on chromosome 9 associated with coronary heart dis-ease. Science. 2007;316:1488–1491.

10. Genome-wide association study of 14,000 cases of sevencommon diseases and 3,000 shared controls. Nature 2007;447:661–678.

11. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variantsconferring risk of atrial fibrillation on chromosome 4q25.Nature. 2007;448:353–357.

12. Otto J. Analysis of Human Genetic Linkage. 3rd ed. Baltimore:John Hopkins University Press; 1999.

13. Connelly JJ, Wang T, Cox JE, et al. GATA2 is associated withfamilial early-onset coronary artery disease. PLoS Genet.2006;2:e139.

14. Wang L, Hauser ER, Shah SH, et al. Peakwide mapping onchromosome 3q13 identifies the kalirin gene as a novelcandidate gene for coronary artery disease. Am J Hum Genet.2007;80:650–663.

15. Wang L, Hauser ER, Shah SH, et al. Polymorphisms of the tumorsuppressor gene LSAMP are associated with left main coronaryartery disease. Ann Hum Genet. 2008;72:443–453.

16. Liew CC, Dzau VJ. Molecular genetics and genomics of heartfailure. Nat Rev Genet. 2004;5:811–825.

17. Heidecker B, Champion HC, Breton E, et al. Transcriptomicbiomarkers for individual risk assessment in new-onset heartfailure. Circulation. 2008;118:238–246.

18. Bezzina C. Genetics of cardiomyopathy and channelopathy.Heart Metab. 2008; 41:5-10. Available online from URL:http://www.heartandmetabolism.org/issues/HM41/HM41ba-sicartic.asp.

19. Mercadier J. How do mutations cause disease? Heart Metab.2008;41:34–37. Available online from URL: http://www.heartandmetabolism.org/issues/HM41/HM41refresherc.asp.

20. Drews J. Drug discovery: a historical perspective. Science.2000;287:1960–1964.

21

http://www.heartandmetabolism.org/issues/HM41/HM41basicartic.asp

http://www.heartandmetabolism.org/issues/HM41/HM41basicartic.asp

http://www.heartandmetabolism.org/issues/HM41/HM41refresherc.asp

http://www.heartandmetabolism.org/issues/HM41/HM41refresherc.asp

Focus on Vastarel MR

Effects of Vastarel MR on brainnatriuretic peptide and cardiac

troponin concentrationsPericle Di Napoli

Cardiovascular Section, SMDN-Centre for Cardiovascular Medicine and Cerebrovascular Disease Prevention,Sulmona, and Villa Pini d’Abruzzo Clinic, Department of Cardiology, Heart Failure Unit, Chieti, Italy

Correspondence: Dr Pericle Di Napoli, Via Trento 41, 67039 Sulmona (AQ), Italy.Tel/fax: +39 0864 52716; e-mail: [email protected]


Abstract

Metabolic therapy represents an innovative approach to the treatment of coronary artery disease andheart failure. The metabolic modulator, trimetazidine (Vastarel MR), offers particular positive effects inreducing the cell loss and reorganization that characterize the process of left ventricle remodeling, and isuseful in improving ischemic or failed cell metabolism. Correction of the metabolic alterations thatcharacterize ischemic cardiomyopathy and heart failure represents a promising novel therapeuticapproach useful in reducing left ventricle remodeling and improving the prognosis of patients sufferingthese conditions.

Heart Metab. 2009;43:23–26.

Keywords: BNP, heart failure, myocardial ischemia, trimetazidine, troponin

Introduction

Coronary artery disease (CAD) and chronic congestiveheart failure (CHF) represent major public healthconcerns that have a poor long-term prognosis [1]and, despite vigorous effort and financial input,few clinical tools have been developed to identifyvariables that have prognostic significance for patientssuffering these conditions. The New York HeartAssociation (NYHA) functional classification, and sev-eral tests – including chest X-ray, electrocardiogram,ultrasound, radionuclide and magnetic resonanceimaging, cardiopulmonary exercise, and hemody-namic measurements – are useful for estimating theseverity and prognosis of CHF.

The deterioration of cardiac function in chronicCAD and CHF is strictly related to left ventricularremodeling, a pathologic process by which ventricu-lar size, shape, and function are dysregulated byhemodynamic overload, neurohormonal activation(involving adrenergic nervous hyperactivity, the

Heart Metab. 2009; 43:23–26

renin–angiotensin system, and inflammatory cyto-kines), and genetic factors. The pathologic changesin cardiac myocytes and fibroblasts are an importantcomponent of cardiac remodeling [2,3], and bio-chemical markers of the pathophysiology of CHF mightbe helpful in monitoring its evolution and the devel-opment of remodeling, because they are usually easy tomeasure serially, without inter-observer variability.

Measurement of plasma concentrations of brainnatriuretic peptide (BNP), an amino acid peptidesecreted by the ventricular myocardium in responseto myocardial load, is now increasingly being used asa tool for clinical diagnosis and prognosis in patientswith CHF and CAD [4]. Other important biochemicalmarkers are troponins, which are strictly related to thecell loss that characterizes ventricular remodelingafter myocardial infarction, chronic ischemia, andpressure or volume overload – factors influencingthe progression of left ventricular dysfunction [5]. Inaddition, norepinephrine (noradrenaline; a marker ofadrenergic activity), renin, inflammatory cytokines,

23


Focus on Vastarel MRPericle Di Napoli

C-reactive protein, and biochemical markers associ-ated with collagen turnover may have significant rolesin the pathophysiology [6–8].

Left ventricle remodeling in ischemic heartdisease and heart failure

Cardiac remodeling is an important determinant ofCHF progression. Hemodynamic overload, activationof the renin–angiotensin and sympathetic nervoussystems, and inflammatory cytokines are believedto be implicated [1,2,9]. At cellular level, the mostimportant factor influencing ventricular remodeling isprogressive cell loss as a result of apoptotic or necroticprocesses. This is the first stage in ventricular remo-deling, in which the normal architecture of the heartwall is rearranged, with the replacement of contractilemass by noncontractile fibrous tissue. In addition tomyocyte injury, the interstitium, fibroblasts, and col-lagen turnover also have important roles.

Ischemic injury has long been considered to resultin necrotic tissue damage; however, in recent dec-ades, studies have focused attention on apoptosis as asignificant component of cell loss during reperfusioninjury, myocardial infarction, and chronic ischemia[10,11]. Myocardial apoptosis has also been docu-mented in response to a variety of other cardiacstresses, including pressure or volume overload, heartfailure, and diabetic cardiomyopathy [12,13]. Themost relevant clinical stimulants that initiate the pro-cess of apoptosis include pressure or volume over-load, cellular calcium overload, oxygen-derived freeradicals, increased concentrations of catecholamines,cytokines, and angiotensin II, and decreased coronaryflow reserve [12–14].

The relevance of metabolic therapy in heartfailure

The basic principle of current treatment in patientswith heart failure with or without CAD is to modifymyocyte dysfunction and to minimize the intensity ofthe lethal injury acting on the heart. Clinical inter-ventions such as restoration of ischemia by pharma-cological or interventional strategies, use of b-block-

Table I. Main cardioprotective effects of trimetazidine in patients with

� Improvement in metabolic efficiency: changing the source of ATPefficient pathway� Protection of endothelial function: increase in endothelial nitric s

in endothelin-1� Preservation of mitochondrial functions: reduction in mitochondri� Reduction of the myocardial inflammatory reaction: reduction of� Reduction in necrotic and apoptotic cell death� Limitation of accumulation of Naþ and Ca2þ and intracellular aci� Protection against toxicity induced by oxygen free radicals� Improvement in insulin sensitivity and glucose concentrations

24

ers, angiotensin-converting enzyme inhibitors, orangiotensin II receptor antagonists may prevent, sup-press, or restore cardiac dysfunction. However, thepreservation of cells subjected to lethal injury remainsan attractive goal, and inhibition of cardiac myocyteapoptosis by metabolic treatments may represent anovel approach for treatment of cardiac disease[9,15]. Available evidence suggests that the failingheart is an engine that is depleted of fuel. In otherwords, altered energetics plays an important part inthe pathophysiology of heart failure. Various groupshave pursued this energy-depletion hypothesis overthe past 20 years and, today, energy metabolism in theheart is a topic of considerable interest.

Major metabolic changes occurring during the earlyhours of myocardial infarction include increasedsecretion of catecholamines and production of circu-lating free fatty acids (FFAs). Under normal conditions,the myocardium depends on aerobic metabolism,with FFAs as the preferred source of energy. Duringischemia-reperfusion, FFA concentrations are greatlyincreased, and exert a toxic effect on the myocardium.This effect determines increased membrane damage,endothelial dysfunction, tissue inflammation, anddecreased cardiac function. Decreasing plasma FFAconcentrations and cardiac fatty acid oxidation,together with the stimulation of glucose and lactateuptake, might reduce these detrimental effects[9,15,16]. This might be achieved by the use of glu-cose–insulin–potassium solutions at the time of reper-fusion [17], and by inhibiting fatty acid oxidation with3-ketoacyl coenzyme A thiolase inhibitors, such astrimetazidine [9,15]. Currently, we have many remark-able experimental and clinical findings regarding thebeneficial effects of metabolic treatment in CAD andheart failure. The drug studied most is trimetazidine. Avariety of clinical studies of this drug have demon-strated that it offers a significant cardioprotection that isachieved through several mechanisms (Table I).

Plasma brain natriuretic peptide and troponinconcentrations

In contrast to other neurohormones that exhibitincreased concentrations in heart failure, natriuretic

CAD, left ventricular dysfunction, or both.

production to glucose oxidation, a more energetically

ynthase activity and nitric oxide availability; reduction

al permeabilizationneutrophil infiltration and activation

dosis

Heart Metab. 2009; 43:23–26

Focus on Vastarel MREffects of trimetazidine on biomarkers

350

300

250

200

150

100

50

0

1.2

1

0.8

0.6

0.4

0.2

0Enrollment

ng/m

lpg

/ml

Control

Trimetazidine

Control

Trimetazidine

6 months

Enrollment

cTnT

BNP

**

*

*

6 months

Figure 1. Changes in plasma concentrations of (a) brainnatriuretic peptide (BNP) and (b) cardiac troponin T(cTnT) in patients with stable ischemic cardiomyopathyafter 6 months of treatment with trimetazidine (60 mg/day;n¼25) or no treatment (Control; n¼25). Data arepresented as mean and SD. �P<0.001 compared withcontrol; ��P<0.02 compared with baseline. (From DiNapoli et al [27], with permission.)

peptides have an adaptive counter-regulatory role[18]. Plasma BNP concentrations are currently usedas diagnostic and prognostic markers in patients withCHF [18]. It is particularly noteworthy that, in multi-variate analyses, BNP and N-terminal proBNP (NT-proBNP) are stronger predictors of mortality thanNHYA functional class, norepinephrine (adrenaline),left ventricular ejection fraction (LVEF), or age[19,20]. Serum BNP is also a valid marker in assessingthe risk of ventricular tachycardia and, probably,sudden death, in patients with ischemic or nonischemic cardiomyopathy [21]. Tapanainen et al[22] showed that increased serum BNP concentrationprovided information on the risk of arrhythmic deathamong the survivors of acute myocardial infarction,independently of LVEF, and should therefore be usedas an additive marker to identify those patients whomay benefit the most from defibrillator implantation.

Serum troponins are other important prognosticmarkers in patients with dilated cardiomyopathy[23–25]. The cardiac troponins are part of the tropo-nin–tropomyosin complex in thin filaments of heartmuscle myofibrils. Troponins do not occur outsidecells; therefore, their occurrence in blood is a sensitiveand specific indicator of heart muscle cell damage.Nellessen et al [23] assessed the usefulness of tests fortroponin I (TnI) as prognostic indicators in patients withCHF. Miller et al [24] demonstrated that increases in theconcentrations of troponin T (TnT) and BNP in patientswith CHF are connected with an increased risk ofdeath, heart transplant, or admission to hospital. Thegroup at greatest risk included patients in whom anincrease in both TnT and BNP was observed. Sato et al[25] confirmed that persistently increased concen-trations of TnT in patients with dilated cardiomyopathyindicate that degeneration of myocytes is in progress,which is connected with the deterioration in thepatients’ clinical condition. Combining the measure-ments ofBNP asan indexofmyocardial load andTnT asan index of myocyte injury is of particular interest inpatients with heart failure. Measuring both BNP andTnT at the time of the patient’s admission to hospitalmight identify a group of patients with acute heartfailure who have the poorest prognosis [26].

Various studies have provided evidence that meta-bolic treatment with trimetazidine could positivelyinfluence the prognosis and quality of life of patientswith CAD and CHF [9] and reduce left ventricularremodeling and plasma concentrations of BNP andTnT [27]. In 50 patients with stable ischemic cardio-myopathy after 6 months of trimetazidine treatment,we showed a significant improvement in functionalcapacity (6 min walking test) associated with a sig-nificant reduction in plasma BNP concentration (thelatter was significantly increased in controls); TnTconcentrations also reduced significantly duringtrimetazidine treatment, whereas they were un-

Heart Metab. 2009; 43:23–26

changed in the control group (Figure 1) [27]. Fragassoet al [28] obtained similar results in 55 patients withheart failure and left ventricular dysfunction of variousetiologies. If we consider BNP to be a marker ofmyocardial load, these findings confirm that trimeta-zidine treatment has a positive affect on the neuro-hormonal pathway in patients with ischemic cardio-myopathy and reduces the cellular damage thatcharacterizes chronic evolution of left ventricle remo-deling. Another positive mechanism of action of tri-metazidine is its ability to increase myocardial resist-ance to injury in patients with ventricular dilatationor dysfunction. During acute decompensation inpatients with chronic heart failure, myocardial celldamage, expressed as the release of TnT, is signifi-cantly reduced, and the direct correlation betweenplasma concentrations of BNP (cardiac load) and TnT(cardiac damage), observed in CHF patients, is lost[9]. All these data could help to explain the reductionin ventricular remodeling and the preservation of leftventricle function that are observed during treatmentwith trimetazidine.

REFERENCES

1. McMurray JJV, Pfeffer MA. Heart failure. Lancet. 2005;365:
1877–1889.
25

Focus on Vastarel MRPericle Di Napoli

2. Cohn JN, Ferrari R, Sharp N. Cardiac remodeling-conceptsand clinical implications: a consensus paper from an inter-national forum on cardiac remodeling. J Am Coll Cardiol.2000;35:569–582.

3. St John Sutton MG, Sharpe N. Left ventricular remodeling aftermyocardial infarction: pathophysiology and therapy. Circula-tion. 2000;101:2981–2988.

4. Maisel A. Understanding B-type natriuretic peptide and its rolein diagnosis and monitoring congestive heart failure. ClinCornerstone. 2005;7:S7–S17.

5. Nishio Y, Sato Y, Taniguchi R, et al. Cardiac troponin T vsother biochemical markers in patients with congestive heartfailure. Circ J. 2007;71:631–635.

6. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrineas a guide to prognosis in patients with chronic congestiveheart failure. N Engl J Med. 1984;311:819–823.

7. Anand IS, Latini R, Florea VG, et al., for the Val-HeFTInvestigators. C-reactive protein in heart failure: prognosticvalue and the effect of Valsartan. Circulation. 2005;112:1428–1434.

8. Klappacher G, Franzen P, Haab D, et al. Measuringextracellular matrix turnover in the serum of patients withidiopathic or ischemic dilated cardiomyopathy and impacton diagnosis and prognosis. Am J Cardiol. 1995;75:913–918.

9. Di Napoli P, Barsotti A. Prognostic relevance of metabolicapproach in patients with heart failure. Curr Pharm Des.2009;15:883–892.

10. Mani K. Programmed cell death in cardiac myocytes: strate-gies to maximize post-ischemic salvage. Heart Fail Rev. 2008;13:193–209.

11. Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL.Reperfusion injury induces apoptosis in rabbit cardiomyo-cytes. J Clin Invest. 1994;94:1621–1628.

12. Gottlieb RA, Engler RL. Apoptosis in myocardial ischemia-reperfusion. Ann NY Acad Sci. 1999;874:412–426.

13. Scarabelli TM, Knight R, Stephanou A. Clinical implications ofapoptosis in ischemic myocardium. Curr Probl Cardiol.2006;31:181–264.

14. Di Napoli P, Taccardi AA, Grilli A, et al. Left ventricular wallstress as a direct correlate of cardiomyocyte apoptosis inpatients with severe dilated cardiomyopathy. Am Heart J.2003;146:1105–1111.

15. Barsotti A, Di Napoli P. Trimetazidine and cardioprotec-tion during ischemia-reperfusion. Ital Heart J. 2004;5:29S–36S.

16. Neubauer S. The failing heart: an engine out of fuel. N Engl JMed. 2007;356:1140–1151.

26

17. Dıaz R, Paolasso EA, Piegas LS, et al. Metabolic modulation ofacute myocardial infarction. The ECLA (Estudios CardiologicosLatinoamerica) Collaborative Group. Circulation. 1998;98:2227–2234.

18. Lemos JA, McGuireDK, Drazner MH. B-typenatriuretic peptidein cardiovascular disease. Lancet. 2003;362:316–322.

19. Tsutamoto T, Wada A, Maeda K, et al. Attenuation of com-pensation of endogenous cardiac natriuretic peptide system inchronic heart failure. Prognostic role of plasma brain natriure-tic peptide in patients with chronic symptomatic left ventri-cular dysfunction. Circulation. 1997;96:509–516.

20. Bettencourt P, Azevedo A, Pimenta J, Frioes F, Ferreira S,Ferreira A. N-terminal-pro-brain natriuretic peptide predictsoutcome after hospital discharge in heart failure patients.Circulation. 2004;110:2168–2174.

21. Blangy H, Sadoul N, Dousset B, et al. Serum BNP, hs-C-reactive protein, procollagen to assess the risk of ventriculartachycardia in ICD recipients after myocardial infarction.Europace. 2007;9:724–729.

22. Tapanainen JM, Lindgren KS, Makikallio TH, Vuolteenaho O,Leppaluoto J, Huikuri HV. Natriuretic peptides as predictorsof non-sudden and sudden cardiac death after acute myo-cardial infarction in the beta-blocking era. J Am Coll Cardiol.2004;43:757–763.

23. Nellessen U, Goder S, Schobre R, Abawi M, Hecker H,Tschoke S. Serial analysis of troponin I levels in patientswith ischemic and nonischemic dilated cardiomyopathy. ClinCardiol. 2006;29:219–224.

24. Miller WL, Hartman KA, Burritt MF, et al. Serial biomarkermeasurements in ambulatory patients with chronic heartfailure: the importance of change over time. Circulation.2007;116:249–257.

25. Sato Y, Yamada T, Taniguchi R, et al. Persistently increasedserum concentrations of cardiac troponin T in patients withidiopathic dilated cardiomyopathy are predictive of adverseoutcomes. Circulation. 2001;103:369–375.

26. Sato Y, Taniguchi R, Makiyama T, et al. Serum cardiactroponin T and plasma brain natriuretic peptide in patientswith cardiac decompensation. Heart. 2002;88:647–648.

27. Di Napoli P, Di Giovanni P, Gaeta MA, D’polito G, Barsotti A.Beneficial effects of trimetazidine treatment on exercise tol-erance and B-type natriuretic peptide and troponin T plasmalevels in patients with stable ischemic cardiomyopathy. AmHeart J. 2007;154:602–605.

28. Fragasso G, Palloshi A, Puccetti P, et al. A randomized clinicaltrial of trimetazidine, a partial free fatty acid oxidation in-hibitor, in patients with heart failure. J Am Coll Cardiol.2006;48:992–998.

Heart Metab. 2009; 43:23–26

Case report

Serial determination of troponinconcentrations in the diagnosis of

acute myocardial infarctionVlad C. Vasile, Lori A. Blauwet and Allan S. Jaffe

Department of Internal Medicine, Division of Cardiovascular Diseases and Department of LaboratoryMedicine and Pathology, Mayo Clinic and Mayo Medical School, Rochester, Minnesota, USA

Correspondence: Dr Allan S. Jaffe, Mayo Clinic, 200 First St SW, Division of Cardiovascular Diseases,Gonda 5, Rochester, Minnesota 55905, USA.


Conflicts of interest: Dr Vasile and Dr Lori A. Blauwet, None; Dr Jaffe is a consultant andhas received research support from Siemens and Beckman-Coulter. He is currently a consultant,

or has consulted over time for most of the major diagnostic companies.

Abstract

Contemporary guidelines for the definition of acute myocardial infarction recommend the presence ofan increase or decrease in troponin concentration in patients presenting to the hospital with chest painand electrocardiogram changes. Here we report the case of a 49-year-old woman with recurring chestpain, nausea, and diaphoresis with initially undetectable troponin concentrations that subsequentlyincreased. This case demonstrates the importance of serial determination of troponin concentrations andchanging biomarker patterns in the management of patients presenting with possible cardiac ischemicinjury.

Heart Metab. 2009;43:27–29.

Keywords: Acute myocardial infarction, chest pain, troponin changes

Case report

In April 2008, a 49-year-old woman presented to theemergency department after three episodes of chestpain, the first of which had occurred 6 h before pres-entation. The chest pain was described as a sensationof tightness associated with shortness of breath, whichawoke her during the night. The second and thirdepisodes were accompanied by mild nausea anddiaphoresis. The patient was free of pain at the timeof presentation. Her personal medical historyincluded essential hypertension, under medical con-trol. She had been told that her cholesterol was highbut, given her high high-density lipoprotein concen-trations, she did not require treatment. She hadrecently returned from a long vacation during whichshe and her spouse had driven across the country.

Heart Metab. 2009; 43:27–29

The patient’s electrocardiogram (ECG) in the emer-gency department showed normal sinus rhythm withminor anterior T-wave abnormalities. Blood tests wereunremarkable, including a cardiac troponin T (cTnT)value less than 0.01 ng/mL. Chest X-ray showed clearlungs, normal heart size, and a tortuous aorta. The D-dimer concentration was mildly increased.

The patient was placed in the observation room. Atapproximately 4 h after presentation, her ECG wasunchanged, but her cTnT concentration had increasedto 0.02 ng/mL. At 6 h after the patient’s admission, thethird cTnT value was 0.03 ng/mL, indicative of apattern of increasing values. Because of this increas-ing pattern, the patient was admitted from the emer-gency department to a cardiology service. Aspirin hadbeen given in the emergency department, but,because of the modest cTnT concentrations, the

27


Case reportVlad C. Vasile, Lori A. Blauwet, and Allan S. Jaffe

Figure 1. Computed tomography contrast-enhanced cor-onary angiogram of the left anterior descending artery.Arrows indicate noncalcified lesions.

patient was not treated with heparin or a GpIIb/IIIainhibitor. She did, however, receive a b-blocker. Acomputed tomography (CT) angiogram was obtainedto evaluate for possible pulmonary embolism and toassess her coronary arteries noninvasively. Computedtomography excluded pulmonary emboli, butrevealed discrete noncalcified lesions in her proximaland mid left anterior descending (LAD) coronaryartery, estimated at 75% each (Figure 1). The distalLAD was normal. Shortly thereafter, the patient devel-oped severe chest pain, diaphoresis, and nausea. TheECG showed changes suggestive of an acute antero-septal myocardial infarction, so she was taken expe-ditiously to the cardiac catheterization laboratory.Coronary angiogram revealed that the proximalLAD was 100% occluded and the mid LAD had adiscrete 70% obstruction lesion; the distal segmentwas of normal size. The proximal circumflex arterywas 30% obstructed by a single discrete lesion, andthe proximal right coronary artery was 20%obstructed by a single discrete lesion. Each of thetwo LAD lesions was treated with a bare metal stent.The patient continued to take aspirin 325 mg daily andwas discharged from hospital 3 days later, receivingclopidogrel 75 mg, lisinopril 5 mg, metoprolol200 mg, and simvastatin 40 mg, all daily.

Comment

This case report emphasizes the importance of apattern of increasing cTn values. The concentrationsof cTn currently measurable with contemporaryassays are far greater than those we now considerto be normal values [1], therefore increases in cTn areusually important as a marker of a cardiac abnormality[2]. There can be analytic false-positives, but they areuncommon and rarely manifest a changing pattern ofvalues. Thus an increasing pattern should promptadditional investigation.

In this patient, because of the antecedent history of along car journey and a mildly increased D-dimervalue, the diagnosis of pulmonary embolism was

28

considered. Pulmonary embolism can cause increasesin cTn, but, when they occur, they usually mark quitelarge pulmonary emboli. In this case, the patientappeared very stable, so a large pulmonary embolismwas unlikely. However, given the ability of CT angio-graphy to evaluate both the pulmonary circulationand the coronary arteries, the decision was made toobtain a CT angiogram, which excluded pulmonaryembolism but documented significant coronary arterydisease. This is perhaps not unexpected, becausecoronary artery disease is common in our society.However, we now understand that many other dis-eases can also be associated with increases in cTnconcentrations. In this context, myocarditis appears tobe a common mimicker of coronary artery disease [3]in patients who present acutely. In addition, toxicmetabolic insults such as carbon monoxide poisoningcan cause cardiac injury. Critically ill patients [4,5]often have a pattern of increasing values of cTn. Someof these increases may be the result of occult coronaryartery disease with or without supply–demandabnormalities, but they can also be result from hypo-or hypertension, or medications such as catechol-amines that are used to treat these patients. Regardlessof the etiology, increases in troponin concentrationappear to be highly prognostic, in both the short andlonger terms [4,5].

On occasion, no etiology is apparent, and thatreflects the fact that there are causes for cardiac injuryof which we are unaware or for which we lack knowl-edge as to their assessment. A word of caution isnecessary, however. At times, we overestimate theaccuracy of some of our tests. We [6] and others havereported a pattern of acute myocardial infarction(AMI) that was revealed by magnetic resonance ima-ging in patients, mostly women, with what appearedto be normal coronary arteries on coronary angiogra-phy. Therefore, in our view, an apparently normalcoronary angiogram does not always exclude AMI,especially in women.

This case report illustrates the importance, asrecommended by the recent guidelines for the diag-nosis of AMI [7], of serial determination of troponinconcentrations, and the significance of a changingpattern of troponin concentrations, in the manage-ment of patients presenting with possible cardiacdisease.

REFERENCES

1. Todd J, Freese B, Lu A, et al. Ultrasensitive flow-based immuno-assays using single-molecule counting. Clin Chem. 2007;53:1990–1995.

2. Jaffe AS. Chasing troponin: how low can you go if you can seethe rise? J Am Coll Cardiol. 2006;48:1763–1764.

3. Assomull RG, Lyne JC, Keenan N, et al. The role of cardiovas-cular magnetic resonance in patients presenting with chestpain, raised troponin, and unobstructed coronary arteries.Eur Heart J. 2007;28:1242–1249.

Heart Metab. 2009; 43:27–29

Case reportTroponin in the diagnosis of AMI

4. Babuin L, Vasile VC, Rio Perez JA, et al. Elevated cardiactroponin is an independent risk factor for short- and long-termmortality in medical intensive care unit patients. Crit Care Med.2008;36:759–765.

5. Vasile VC, Babuin L, Rio Perez JA, et al. Long-term prognosticsignificance of elevated cardiac troponin levels in critically illpatients with acute gastrointestinal bleeding. Crit Care Med.2009;37:140–147.

Heart Metab. 2009; 43:27–29

6. Martinez MW, Babuin L, Syed IS, et al. Myocardial infarctionwith normal coronary arteries: a role for MRI? Clin Chem.2007;53:995–996.

7. Thygesen K, Alpert JS, White HD. Universal definition ofmyocardial infarction. J Am Coll Cardiol. 2007;50:2173–2195.

29

Refresher corner

Temporal profile of protein release inmyocardial infarction

Piero Montorsi, Marco Villa and Maria Antonietta DessanaiInstitute of Cardiology, University of Milan, Centro Cardiologico Monzino, IRCCS, Milan, Italy

Correspondence: Dr Piero Montorsi, Institute of Cardiology, University of Milan,Centro Cardiologico Monzino, IRCCS, Via Parea 4 – 20138 Milan, Italy.

Tel: +39 02 58002576; fax: +39 02 58002398; e-mail: [email protected]


Abstract

Acute myocardial infarction (AMI) is one of the most important cardiovascular diseases in developedcountries, where it represents the major cause of death and disability. The diagnosis of ‘‘classic’’ AMI isbased on the triad of typical symptoms and changes in the electrocardiogram and in biomarkers.Biomarkers are proteins that are released into the circulation by the damaged myocardial cells. The rateof appearance of these proteins depends on several factors, mainly the rate of their elimination from theblood. Each protein has a specific time course of release in terms of first detection in the blood atconcentrations above the upper reference limit, peak plasma concentration, and normalization. Bloodsample for determination of biomarker changes should be taken at the time when the patient presentsand later during the course of the disease, according to the kinetics of each marker. Currently, cardiactroponins and creatine kinase MB mass are the biomarkers most used for the diagnosis of AMI. Emergingmarkers include C-reactive protein, pentraxin-3, and brain natriuretic peptide.

Heart Metab. 2009;43:31–35.

Keywords: Acute myocardial infarction, biomarkers, protein release

Introduction

Acute myocardial infarction (AMI) is one of the mostimportant diseases in developed countries, where itrepresents a major cause of death and disability. In themajority of cases, AMI is caused by an abrupt coron-ary thrombosis as a result of erosion of, or develop-ment of a fissure in a ‘‘vulnerable’’ non flow-limitingcoronary atherosclerotic plaque. The diagnosis of‘‘classic’’ AMI is based on the triad of typical symp-toms and changes in the electrocardiogram and inbiomarkers. As acute coronary artery occlusionoccurs, myocardial cell necrosis develops after20 min and can be identified by the appearance inthe blood of different proteins released into thecirculation by the damaged cardiac myocytes [1].The rate of appearance of biomarkers depends onseveral factors, mainly the rate of their elimination

Heart Metab. 2009; 43:31–35

from the blood (greatly influenced by the patency ofthe culprit vessel). Release of each marker is charac-terized by a specific time course, including the firstdetection in the blood at concentrations above theupper reference limits, the peak concentration, andnormalization (Table I). The ideal biomarker shouldhave high sensitivity and specificity, appear earlyduring the course of the disease to allow a rapiddiagnosis, remain abnormal for several days to allowa late diagnosis, and be easily assessed by user-friendly assay. This ideal marker has not yet beendiscovered; however, cardiac troponin is an estab-lished marker for both diagnosis and prognosis inacute coronary syndromes. Emerging markers – suchas high-sensitivity C-reactive protein (CRP) and brainnatriuretic peptide (BNP) – are used as inflammatoryindexes to evaluate the extent of the necrosis and todetermine prognosis [2,3].

31


Refresher cornerPiero Montorsi, Marco Villa, and Maria Antonietta Dessanai

Table I. First detection, peak, and normalization of protein plasma concentration during acute myocardial infarction.

Marker First detection Peak Normalization

Myoglobin 2 h 4–12 h 24 hMB-CK mass 3–12 h 24 h 48–72 hTroponin 3–6 h 24–48 h 5–10 days (cTnI) 5–14 days (cTnT)C-reactive protein 4–6 h 50 h NAPentraxin TX3 2–4 h 20–24 h NABrain natriuretic peptide early 20 h to 5 days <30 days to NANA, not available.

Myoglobin

Myoglobin is a small, nonenzymatic heme protein,rapidly released into the circulation from injuredmyocardial cells. It is detectable in blood as earlyas 1 h after myocardial injury. The peak of its con-centration is reached earlier (approximately 12 h) thanthat of any other biomarker and tends to normalizewithin 1 day (Figure 1). Because of its high sensitivityand low specificity for AMI, this marker is particularlysuited to excluding AMI at the earliest phase of thedisease. As it is not cardiac specific, false-positivesmay be found in patients with acute or chronicskeletal muscle damage or in patients with chronicrenal failure. As for many other biomarkers, a morerapid increase in the plasma concentration of myo-globin is found in patients who achieve a full reperfu-sion. The early normalization of myoglobin makesthis marker particularly indicated for the diagnosis ofre-infarction [4,5]; in this event, a ‘‘double-peaked’’curve is usually detected.

Creatine kinase MB isoenzyme

Creatine kinase MB (CK-MB) is a cytosolic carrierprotein for high-energy phosphatase. For several

50

45

40

35

30

25

20

15

10

5

03 6 12 24 30 36 42 48 72 96 120 150 180 210 240

Tn-l

CK-MB

Myoglobin

Normal range

Hours after onset of AMI

Mul

tiple

s of

UR

L

Figure 1. Profile of release of troponin I (TnI), creatininekinase MB (CK-MB) and myoglobin in acute myocardialinfarction (AMI), upper reference limit (URL), data from DeGroot et al [5] and Larue et al [8].

32

years, the isoenzyme MB has been the marker ofAMI used most. The plasma concentration ofCK-MB mass starts to increase above the cutoff valuebetween 3 and 12 h after the onset of chest pain. Itreaches a peak at 24 h and reverts to normal valueswithin 48–72 h (Figure 1). Although it is found in thegreatest concentration in cardiac tissue, increasedconcentrations of CK-MB may be found in renal fail-ure, hypertension, skeletal muscle injury, and otherconditions. However, a high concentration of CK-MBmay be considered diagnostic for myocardial infarc-tion, especially if combined with the typical increaseand decrease in values [6,7].

Troponin

Cardiac troponin (cTn) is one of the biomarkers thathavebeen found tohavebothdiagnosticandprognosticimportance inAMI. It isaproteincomplex that regulatesthe calcium-modulated interaction between actin andmyosin in striated muscle, and is constituted of threesubunits: T, C, and I. Troponins I (cTnI) and T (cTnT) arehighly specific and sensitive for cardiac injury [8]. Asignificant increase in cardiac troponin value is definedas a plasma concentration exceeding the 99th percen-tile of that of a normal reference population [1].

Generally, in AMI the plasma concentration oftroponin begins to increase above the cutoff valueby 2–4 h after the onset of symptoms, reaching a peakafter 24–48 h; concentrations may remain increasedfor up to 5–10 days (cTnI) or 5–14 days (cTnT) (Figure1). This long-lasting increase, probably resulting fromthe continuous release of troponin from the degen-erating contractile apparatus of necrotic myocytes,helps in the correct diagnosis of AMI late in the courseof the disease. Detection of the typical increase anddecrease in concentrations is essential to the diagnosisof AMI, especially if there are coexisting extracardiacconditions that may be associated with high plasmaconcentrations of troponin (eg, chronic renal failure,trauma, extreme exertion) [9–11].

Measurement of troponins in AMI should be madewhen the patient is first seen and again 6–9 h later. IfAMI is highly suspected but the first measurement doesnot reveal increased concentrations of troponin, a third

Heart Metab. 2009; 43:31–35

Refresher cornerTime course of protein release in AMI

100

50

20

10

5

2

1

00 6 12 24 36 48 60 72 84 96 108 120 132 144 156 168

C-Tn no reperfusion

C-Tn reperfusion

CK-MB no reperfusion

CK-MB reperfusion


Mul

tiple

s of

UR

L

Figure 2. Kinetics of cardiac troponin (cTn) and creatininekinase MB (CK-MB) in patients who did and did notachieve reperfusion [12,13].

50

45

40

35

30

25

20

15

10

5

00 3 6 12 24 30 36 42 48 72 96 120 150 180 210 240

Normal range

CRP

PTX3


Mul

tiple

of U

RL

Figure 3. Profile of release of C-reactive protein (CRP) andpentraxin TX3 (PTX-3) [14,18].

blood sample for measurement of troponin should bedrawn after an interval of 12–24 h. Myocardial re-infarction may alter the standard time course of releaseof troponin, accounting for a renewed increase in, or aprogressively increasing, plasma concentration. Insuch an event, two additional blood sample measure-ments, 3–6 h apart, are recommended. Recurrent myo-cardial infarction is diagnosed if there is an increase ofat least 20% in the second measurement.

Myocardial reperfusion, whether spontaneous, orachieved pharmacologically with lytic agents ormechanically with percutaneous coronary interven-tion, may affect the kinetics of release of biomarkers inAMI, including troponin. Patients with ST-segmentelevation myocardial infarction who achieve an effec-tive reperfusion have a greater and earlier peakplasma concentration of troponin, followed by a fasterreturn to normal – the so-called ‘‘wash-out phenom-enon’’ – compared with those patients having nosignificant reperfusion (Figure 2) [12,13]. In this event,two blood samples should be collected – at the timeof the patient’s admission to hospital, and 90 min later– and the enzyme plasma concentrations compared.The ratio between the concentrations at these twopoints can be used to discriminate between successfuland unsuccessful reperfusion. In general, the greaterthe ratio (at least 5), the more likely it is that reperfu-sion has occurred. If reperfusion has indeed occurred,estimation of infarct size using peak biomarker con-centration may be not reliable.

C-reactive protein

Inflammation is a factor in all stages of the athero-sclerotic disease process, and represents a pathophy-siologic link between the formation of plaque and itsrupture, which are responsible for AMI. To date, CRP(an acute-phase reactant protein made in the liver) hasbeen the preferred marker for the detection of inflam-

Heart Metab. 2009; 43:31–35

mation and to define prognosis during acute coronarysyndromes [14,15]. When AMI occurs, an exponen-tial increase in CRP is observed, starting 4–6 h afterthe onset of symptoms and reaching a peak about 50 hlater (Figure 3). The increase in plasma concentrationsof CRP is strictly related to the degree of cardiacdamage [14]. High concentrations of CRP, in patientswith persistent ST-segment elevation after AMI, is animportant negative prognostic factor, in both the shortand the long term [16,17].

The specificity of CRP as a marker is very low,because increased concentrations of CRP are detectedin several conditions, such as diabetes, obesity, estro-gen therapy, hypertension, and smoking.

Pentraxin-3

Pentraxin-3 (PTX3) is related to classic pentraxins (likeC-reactive protein CRP or serum amyloid P SAP) but isstructurally different. It is made in the liver in responseto inflammatory mediators, mainly interleukin-6. It isalso produced in large amounts by the heart. PTX3 isdetected inside both normal and hypertrophic cardi-omyocytes, and is increased in AMI. Its plasma con-centration increases rapidly after the onset of symp-toms, preceding the increase in CRP concentration,and reaching a peak at 20–24 h after onset of symp-toms (Figure 3) [18,19]. In patients with unstableangina, the PTX3 concentration increases to a lowervalue than in AMI. Accumulating evidence suggeststhat PTX3, binding with C1q in the same way that CRPand SAP bind to C1q, contributes to the mechanism ofincrease in tissue damage [20].

Brain natriuretic peptide

Brain natriuretic peptide is 32-amino-acid peptidereleased in response to ventricular stretch. Its functions

33

Refresher cornerPiero Montorsi, Marco Villa, and Maria Antonietta Dessanai

400

300

200

100

00 4 8 12 16 20 24 2 3 4 5 6 7 2 3 4

WeeksDaysHours

Normal range

BNP

Time after onset of AMI

Pla

sma

leve

l of B

NP

(pg

/ml)

Figure 4. Profile of release of brain natriuretic peptide (BNP)[21].

are similar to those of atrial natriuretic peptide: mainly,reducing systemic vascular resistances and centralvenous pressure, and increasing natriuresis. Two typesof time course of change in BNP concentrations havebeen reported in association with AMI. The first is asingle-peak curve reaching a maximal plasma concen-tration approximately 20 h after symptom onset andreturning slowly to normal within 4 weeks. The secondtype of curve is characterized by a late peak at 5 days,with values remaining increased at 4 weeks (Figure 4).Reasons for the increase in BNP concentrations duringAMI are not easily understood. In a study by Morita et al[21], BNP concentration did not correlate significantlywith hemodynamic parameters in the early phase ofAMI, suggesting that the increased concentration maybe the result of myocardial necrosis or local mechan-ical stress, or both. Interestingly, the biphasic curve wasobserved more frequently in patients with anterior AMI,signs or symptoms of heart failure, lower ejectionfraction, and higher plasma concentrations of CK-MBthan was the single-peak curve. These data suggest thatincreased concentrations of BNP in the late phase ofAMImaybe related to infarct expansionandventricularremodeling [21,22]. Kaya et al [22] reported greaterplasma concentrations of BNP (single sample) ininferior AMI with right ventricular involvement, com-pared with those in isolated inferior AMI. This findingreinforces the concept that increased ventricular stretchand filling pressure are potential stimuli for thesecretion of BNP during the early phase of AMI incertain patient populations.

Conclusions

Proteins released during acute myocardial infarctioncan provide important diagnostic and prognosticinformation. Each possesses a specific time course

34

of release. Because of the rapid increase and decreasein its concentration, and its negative predictive value,myoglobin has a role in the exclusion of AMI. Tro-ponin, with its high cardiac specificity, is the preferredmarker for myocardial injury and AMI; several bloodsample should be obtained at different times along thecourse of the disease, to enable diagnosis of cases oflate AMI. CRP, PTX3 and BNP are emerging bio-markers that have specific indications in the settingof AMI.

REFERENCES

1. Thygesen K, Alpert JS. White HD, for the Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of MyocardialInfarction. Universal definition of myocardial infarction. EurHeart J. 2007;28:2525–2538.

2. Wang TJ, Gona P, Larson MG, et al. Multiple biomarkers forthe prediction of first major cardiovascular events and death.N Engl J Med. 2006;355:2631–2639.

3. Zimmerman J, Fromm R, Meyer D, et al. Diagnostic MarkerCooperative Study for the Diagnosis of Myocardial Infarction.Circulation. 1999;99:1671–1677.

4. McCord J, Nowak RM, McCullough PA, et al. Ninety-minuteexclusion of acute myocardial infarction by use of quantitativepoint-of-care testing of myoglobin and troponin I. Circulation.2001;104:1483–1488.

5. De Groot MJM, Will K, Wodzig H, Glatz JF, Hermens WT.Measurement of myocardial infarct size from plasma fattyacid-binding protein or myoglobin, using individually esti-mated clearance rates. Cardiovasc Res. 1999;44:315–324.

6. Ravkilde J, Nissen H, Hørder M, Thygesen K. Independentprognostic value of serum creatine kinase isoenzyme MB mass,cardiac troponin T and myosin light chain levels in suspectedacute myocardial infarction. Analysis of 28 months of follow-upin 196 patients. J Am Coll Cardiol. 1995;25:574–581.

7. Vikenes K, von der Lippe G, Farstad M, Nordrehaug JE. Clinicalapplicability of creatine kinase MB mass and the electrocardio-gram versus conventional enzymes in the diagnosis of acutemyocardial infarction. Int J Cardiol. 1997;59:11–20.

8. Larue C, Calzolari C, Bertinchant JP, Leclercq F, Grolleau R,Pau B. Cardiac-specific immunoenzymometric assay of tro-ponin I in the early phase of acute myocardial infarction. ClinChem. 1993;39:972–979.

9. Labugger R, Organ L, Collier C, Atar D, Van Eyk JE. Extensivetroponin I and T modification detected in serum from patientswith acute myocardial infarction. Circulation. 2000;102:1221–1226.

10. Katus HA, Remppis A, Neumann FJ, et al. Diagnostic effi-ciency of troponin T measurements in acute myocardial in-farction. Circulation. 1991;83:902–912.

11. Adams JE 3rd, Bodor GS, Davila-Roman VG, et al. Cardiactroponin I. A marker with high specificity for cardiac injury.Circulation. 1993;88:101–106.

12. French JK, Ramanathan K, Stewart JT, Gao W, Theroux P,White HD. A score predicts failure or reperfusion after fibri-nolytic therapy for acute myocardial infarction. Am Heart J.2003;145:508–514.

13. Tanasijevic MJ, Cannon CP, Antman EM, et al. Myoglobin,creatine-kinase-MB and cardiac troponin-I 60-minute ratiospredict infarct-related artery patency after thrombolysis foracute myocardial infarction: results from the Thrombolysis inMyocardial Infarction study (TIMI) 10B. J Am Coll Cardiol.1999;34:739–747.

14. Kushner I, Broder ML, Karp D. Serum C-reactive proteinkinetics after acute myocardial infarction. J Clin Invest. 1978;61:235–242.

15. Griselli M, Herbert J, Hutchinson WL, et al. C-reactive proteinand complement are important mediators of tissue damage inacute myocardial infarction. J Exp Med. 1999;190:1733–1739.

16. Canale ML, Stroppa S, Caravelli P, et al. Admission C-reactiveprotein serum levels and survival in patients with acutemyocardial infarction with persistent ST elevation. CoronArtery Dis. 2006;17:693–698.

Heart Metab. 2009; 43:31–35

Refresher cornerTime course of protein release in AMI

17. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prog-nostic value of C-reactive protein and serum amyloid Aprotein in severe unstable angina. N Engl J Med. 1994;331:417–424.

18. Peri G, Introna M, Corradi D, et al. PTX3, a prototypical longpentraxin, is an early indicator of acute myocardial infarctionin humans. Circulation. 2000;102:636–641.

19. Salio M, Chimenti S, De Angelis N, et al. Cardioprotectivefunction of the long pentraxin PTX3 in acute myocardialinfarction. Circulation. 2008;117:1055–1064.

Heart Metab. 2009; 43:31–35

20. Latini R, Maggioni AP, Peri G, for the Lipid Assessment TrialItalian Network (LATIN) Investigators. Prognostic significanceof long pentraxin PTX3 in acute myocardial infarction. Cir-culation. 2004;110:2349–2354.

21. Morita E, Yasue H, Yoshimura M, et al. Increased plasmalevels of brain natriuretic peptide in patients with acutemyocardial infarction. Circulation. 1993;88:82–91.

22. Kaya MG, Ozdogru I, Kalay N, et al. Plasma B-type natriureticpeptide in diagnosing inferior myocardial infarction with rightventricular involvement. Coron Artery Dis. 2008;19:609–613.

35

Featured research

Featured researchAbstracts and commentaries

Prognostic value of troponin I levels forpredicting adverse cardiovascular outcomesin postmenopausal women undergoingcardiac surgery
Stearns JD, Davila-Roman VG, Barzilai B,Thompson RE, Grogan KL, Thomas B, HogueCW Jr. Anesth Analg. 2009;108:719–726.
Adverse cardiac events that follow cardiac surgery arean important source of perioperative morbidity andmortality for women. Troponin I provides a sensitivemeasure of cardiac injury, but its concentrations aftercardiac surgery may vary between the sexes. Ourpurpose in this study was to evaluate the prognosticvalue of troponin I concentrations for predicting car-diovascular complications in postmenopausal womenundergoing cardiac surgery. The cohort of this studywere women enrolled in a previously reported clinicaltrial evaluating the neuroprotective potential of 17b-estradiol in elderly women. In that study, 175 post-menopausal women not receiving estrogen replace-ment therapy and scheduled to undergo coronaryartery bypass graft (with or without valve surgery)were prospectively randomly allocated to groups toreceive 17b-estradiol or placebo in a double-blindmanner, beginning the day before surgery and con-tinuing for 5 days postoperatively. Serial 12-lead elec-trocardiograms were performed and serum troponin Iconcentrations were measured before surgery, aftersurgery on arrival of the patient in the intensive careunit, and for the first 4 days after operation. Theprimary endpoint of the present study was majoradverse cardiovascular events (MACE), defined as aQ-wave myocardial infarction, low cardiac outputstate or death within 30 days of surgery. The diagnosisof Q-wave myocardial infarction was made indepen-dently by two physicians blinded to the treatment andpatient outcomes, with the final diagnosis requiringconsensus. A low cardiac output state was defined ascardiac index <2.0 L/min per m2 for >8 h, regardlessof treatment. Troponin I concentrations on postopera-tive day 1 were predictive of MACE (area under thereceiver operator curve¼0.862). A cutoff point fortroponin I of>7.6 ng/mL (95% confidence interval 6.4to 10.8) provided the optimal sensitivity and specifi-city for identifying patients at risk for MACE. Thenegative predictive value of a troponin I concentrationfor identifying a patient with a composite cardiovas-cular outcome was high (96%) and the positive pre-dictive value moderate (40%). Postoperative troponin

36

I concentrations were not different between womenreceiving perioperative 17b-estradiol treatment andthose receiving placebo, and the frequency of MACEwas not influenced by 17b-estradiol treatment. Weconclude that, in postmenopausal women, increasedtroponin I concentrations on postoperative day 1 arepredictive of MACE. Monitoring of perioperative tro-ponin I concentrations might provide a means forstratifying patients at risk for adverse cardiovascularevents.

Commentary

A small increase in troponin concentration may occurin clinically stable populations, and is frequentlyobserved after successful percutaneous coronaryintervention (PCI) or bypass surgery.

With the new universal definition of myocardialinfarction, routine dosage of troponin I after revascu-larization procedures could result in an overdiagnosisof myocardial infarction. A recent American HeartAssociation/American College of Cardiology state-ment defined an increase of troponin I greater than3 times the 99th percentile after PCI as ‘‘periproce-dural myocardial infarction’’. In patients with stablecoronary disease, troponin increases significantlyafter PCI in 31% of patients and is independentlyand significantly associated with an increase in majoradverse cardiac events at 1 and 18 months [1]. Con-versely, in a more recent study [2], such an increaseoccurred in 23.4% of patients who underwent PCI,but was not associated with a greater rate of adversecardiac events at 1 year. The investigators concludedthat the definition of myocardial infarction may be toostrict, and that measurement of troponin I after PCI isof questionable use. A meta-analysis of 20 studiesinvolving 15 581 patients undergoing PCI [3] led itsauthors to conclude that an increase in troponin I issignificantly associated with increased mortality andnon-fatal myocardial infarction.

In this study by Stearns et al in postmenopausalwomen, increased postoperative troponin I concen-trations were, again, predictive of major adversecardiac events.

It may be concluded that monitoring of periproce-dural troponin I in patients undergoing percutaneousor surgical coronary revascularization is helpful instratifying those at risk, and in predicting adverseevents.

Heart Metab. 2009; 43:36–39


REFERENCES

1. Nageh T, Sherwood RA, Harris BM, Thomas MR. Prognosticrole of cardiac troponin I after percutaneous coronary inter-vention in stable coronary disease. Heart. 2005;91:1181–1185.

2. De Labriolle A, Lemesle G, Bonello L, et al. Prognostic sig-nificance of small troponin I rise after a successful electivepercutaneous coronary intervention of a native artery. Am JCardiol. 2009;103:639–645.

Mario Marzilli

Impaired insulin signaling acceleratescardiac mitochondrial dysfunction aftermyocardial infarction
Sena S, Hu P, Zhang D, Wang X, et al. J Mol CellCardiol. 2009 Feb 26 [Epub ahead of print].
Diabetes increases mortality and accelerates left ven-tricular dysfunction after myocardial infarction. Thisstudy sought to determine the impact of impairedmyocardial insulin signaling, in the absence of dia-betes, on the development of dysfunction after myo-cardial infarction. Mice with cardiomyocyte-restricted knockout of the insulin receptor (CIRKO)and wildtype (WT) mice were subjected to proximalleft coronary artery ligation (MI) (groups CIRKO-MIand WT-MI, respectively) and followed for 14 days.Despite equivalent infarct size, mortality wasincreased in CIRKO-MI mice compared with WT-MI mice (68% compared with 40%, respectively).In surviving mice, left ventricular ejection fractionand dP/dt were reduced by >40% in CIRKO-MIanimals compared with those in WT-MI mice. Rela-tive to shams, isometric developed tension in leftventricular papillary muscles increased in WT-MImice, but not in CIRKO-MI mice. Time to peak tensionand relaxation were prolonged in CIRKO-MI micecompared with WT-MI animals, suggesting impaired,load-independent myocardial contractile function. Toelucidate mechanisms for impaired left ventricularcontractility, mitochondrial function was examinedin permeabilized cardiac fibers. Whereas maximalADP-stimulated mitochondrial rates of O2 consump-tion (VADP) with palmitoyl carnitine as substrate wereunchanged in WT-MI mice relative to sham-operatedanimals, VADP was significantly reduced in CIRKO-MImice (13.17�0.94 compared with 9.14�0.88 nmolO2/min per mg dry weight; P<0.05). Relative to thosein WT-MI, in CIRKO-MI the levels of expression ofglucose transporter 4 (GLUT4), peroxisome prolifera-tor activated receptor-alpha (PPARa), sarcoplasmicreticulum Ca2þ-ATPase (SERCA2), the fatty acid oxi-dation genes, MCAD, LCAD, CPT2, and the electrontransfer flavoprotein, ETFDH, were repressed. Thusreduced insulin action in cardiac myocytes acceler-ates after myocardial infarction left ventricular dys-

Heart Metab. 2009; 43:36–39

function, in part because of a rapid decline inmitochondrial fatty acid oxidative capacity, com-bined with limited glucose transport capacity thatmay reduce substrate utilization and availability.

Commentary

Diabetes increases the risk of cardiovascular disease,with diabetic individuals having a two- to fourfoldgreater risk of death from myocardial infarction thannon-diabetic individuals [1,2]. Multiple abnormalitiesassociated with diabetes mellitus – such as hypergly-cemia, hyperlipidemia, and insulin resistance – havebeen postulated to contribute to adverse outcomes indiabetes following myocardial ischemia [3]. How-ever, the specific contribution of impaired myocardialinsulin action per se in the response of the heart tomyocardial ischemia is incompletely understood.Sena et al sought to determine the impact of impairedmyocardial insulin signaling, in the absence of dia-betes, on the development of left ventricular dysfunc-tion after myocardial infarction.

To examine the role of altered cardiomyocyteinsulin signaling in the adaptation to myocardialinfarction, independently of confounding systemicfactors, the authors subjected CIRKO mice and wild-type mice to proximal left coronary artery ligation(myocardial infarction) and followed them up for14 days. The goal was to assess potential mechanismsof left ventricular dysfunction during the period ofgreatest risk. Echocardiographic data, mitochondrialrespiration, and gene expression data collected14 days after infarction in both groups showed that,despite equivalent infarct size, mortality wasincreased in CIRKO mice compared with wildtypemice, whereas, in surviving mice, left ventricularejection fraction and dP/dt were reduced by morethan 40% in the CIRKO group.

To elucidate the mechanisms for the acceleratedleft ventricular dysfunction in CIRKO mice, theauthors examined mitochondrial function by deter-mining oxygen consumption in cardiac fibers thatwere exposed to fatty acid. They found that, whereasthe maximal ADP-stimulated mitochondrial rate ofconsumption of O2 (VADP) with a fatty acid substratewas unchanged in wildtype mice relative to sham-operated animals, it was significantly reduced incardiac fibers of infarcted CIRKO mice. They alsofound that accelerated left ventricular dysfunctionin CIRKO mice after myocardial infarction was asso-ciated with the rapid decline in mitochondrial func-tion, and that this decline in mitochondrial functionparalleled a specific reduction in the expression of thetranscriptional regulator PPARa, a key regulator offatty acid metabolism, an additional reduction inexpression of genes the products of which determine

37


mitochondrial b-oxidation capacity, and a decrease inlevels expression of the gene for GLUT4 (an importantmediator of glucose uptake). These findings indicatethat insulin signaling might play an important part insustaining left ventricular metabolic capacity postmyocardial infarction.

This study has some limitations. CIRKO mice havetotal deletion of insulin signaling, rather than insulinresistance. It is therefore possible that, under suchconditions, the absence, not only of insulin-depen-dent metabolic pathways, but also of insulin signaling– particularly the absence of pro-survival mechanismsmediated by insulin signaling [4] – could have con-tributed to the accelerated rate of left ventriculardysfunction. Genetic deletion of insulin signaling isobviously more drastic than the more partial degreesof cardiac insulin resistance that might occur in indi-viduals with insulin resistance or diabetes. Althoughthis study provides an indication of some major meta-bolic and functional consequences of defects in insu-lin signaling, additional work in models with partialimpairment in myocardial insulin action will berequired to determine the consequences of lesserdegrees of insulin resistance on the myocardial adap-tations that occur after myocardial infarction.

REFERENCES

1. Yusuf S, Hawken S, Ounpuu S, et al., for the INTERHEARTStudy Investigators. Effect of potentially modifiable risk factorsassociated with myocardial infarction in 52 countries (theINTERHEART study): case–control study. Lancet. 2004;364:937–952.

2. Abbud ZA, Shindler DM, Wilson AC, Kostis JB. Effect ofdiabetes mellitus on short- and long-term mortality rates ofpatients with acute myocardial infarction: a statewide study.Myocardial Infarction Data Acquisition System Study Group.Am Heart J. 1995;130:51–58.

3. Kromhout D, Bosschieter EB, Drijver M, de Lezenne CoulanderC. Serum cholesterol and 25-year incidence of and mortalityfrom myocardial infarction and cancer. The Zutphen Study.Arch Intern Med. 1988;148:1051–1055.

4. Jonassen AK, Sack MN, Mjøs OD, Yellon DM. Myocardialprotection by insulin at reperfusion requires early administra-tion and is mediated via Akt and p70s6 kinase cell-survivalsignaling. Circ Res. 2001;89:1191–1198.

Danielle Feuvray

Body-mass index and cause-specificmortality in 900 000 adults: collaborativeanalyses of 57 prospective studies
Sena S, Hu P, Zhang D, Wang X, et al. J Mol CellCardiol. 2009 Feb 26 [Epub ahead of print].
The main associations of body-mass index (BMI) withoverall and cause-specific mortality can best beassessed by long-term prospective follow-up of large

38

numbers of people. The Prospective Studies Colla-boration aimed to investigate these associations bysharing data from many studies. Collaborative ana-lyses were undertaken of baseline BMI versus mortal-ity in 57 prospective studies with 894 576 participants(mean recruitment age 46 [SD 11] years; mean BMI 25[SD 4] kg/m2; 541 452 men), 61% in western Europeand North America. The median recruitment year was1979 (interquartile range 1975–1985). The analyseswere adjusted for age, sex, smoking status, and study.To limit reverse causality, the first 5 years of follow-upwere excluded, leaving 66 552 deaths of known causeduring a mean of 8 (SD 6) further years of follow-up(mean age at death 67 [SD 10] years): 30 416 vascular;2070 diabetic, renal, or hepatic; 22 592 neoplastic;3770 respiratory; 7704 other. In both sexes, mortalitywas lowest at BMI about 22.5–25 kg/m2. Above thisrange, positive associations were recorded for severalspecific causes and inverse associations for none, theabsolute excess risks for greater BMI and smokingwere roughly additive, and each 5 kg/m2 greaterBMI was, on average, associated with about 30%greater overall mortality (hazard ratio per 5 kg/m2

1.29, 95% confidence interval [CI] 1.27 to 1.32):40% for vascular mortality (hazard ratio 1.41, 95%CI 1.37 to 1.45); 60–120% for diabetic (hazard ratio2.16, 95% CI 1.89 to 2.46), renal (hazard ratio 1.59,95% CI 1.27 to 1.99), and hepatic (hazard ratio 1.82,95% CI 1.59 to 2.09) mortality; 10% for neoplasticmortality (hazard ratio 1.10, 95% CI 1.06 to 1.15]);20% for respiratory (hazard ratio 1.20, 95% CI 1.07 to1.34) and all other mortality (hazard ratio 1.20, 95%CI 1.16 to 1.25). Below the range 22.5–25 kg/m2, BMIwas associated inversely with overall mortality, mainlybecause of strong inverse associations with respiratorydisease and lung cancer. These inverse associationswere much stronger for smokers than for non-smokers,despite cigarette consumption per smoker varying littlewith BMI. Although other anthropometric measures(eg, waist circumference, waist-to-hip ratio) could welladd extra information to BMI, and BMI to them, BMI isin itself a strong predictor of overall mortality bothabove and below the apparent optimum of about22.5–25 kg/m2.Theprogressiveexcessmortality abovethis range is mainly attributable to vascular disease andis probably largely causal. At 30–35 kg/m2, mediansurvival is reduced by 2–4 years; at 40–45 kg/m2, it isreduced by 8–10 years (which is comparable to theeffects of smoking). The definite excess mortalitybelow 22.5 kg/m2 is mainly attributable to smoking-related diseases, and is not fully explained.

Commentary

This Herculean analysis leaves little room for doubt. Itis best to have a BMI around 22.5–25 kg/m2. Either

Heart Metab. 2009; 43:36–39


side of this narrow range, mortality increases. How-ever above 25 kg/m2 this increase follows a log-linearrelationship and is therefore most obvious for BMIvalues greater than 30 kg/m2. In fact, it seems it is saferto be slightly above the ideal range (BMI 27.5–30 kg/m2) than below it (18.5–22.5 kg/m2).

The power of this study lies in its size and in itsdesign. Events were collected prospectively, but16 000 deaths occurring within 5 years of first enrol-ment were excluded to remove bias from reversecausality – established disease affecting baselineBMI, rather than BMI affecting occurrence of subse-quent disease. Potential participants with overt pre-existing heart or cerebrovascular disease were notenrolled. Despite the exclusion of the first 5 years offollow-up, the study still included 6.5 million person-years of observation during which 72 749 deaths wereidentified. Approximately 60% of these deathsoccurred in patients aged 35–69 years, reflectingthe demographics of the populations recruited tothe constituent studies. The average duration of fol-low-up beyond the 5th year was 8 years. The sheernumber of events allowed separate analyses of deathby cause. The positive correlation between BMI above22.5 kg/m2 and death was seen most clearly forischemic heart disease, stroke, other vascular dis-eases, diabetes-related death, and deaths related tonon neoplastic kidney and liver disease. The determi-nation of cause of death varied by constituent study,but was most commonly by death certificate.

Finally, the excess mortality seen in individualsweighing less than the ideal BMI was primarily relatedto respiratory disease, and this was most marked insmokers. It is possible that this was the result of pre-existing chronic respiratory disease with a naturalhistory that exceeded the arbitrary 5 year cutoff,and thus the result of reverse causality.

The main difficulty in translating this powerfulstudy into changes in practice is knowing whichcomponent of the excess mortality seen with BMI>25 kg/m2 is a direct result of BMI and which is the

Heart Metab. 2009; 43:36–39

result of established risk factors that are associatedwith BMI. The authors demonstrate a clear positivecorrelation between low-density lipoprotein (LDL)cholesterol and systolic and diastolic blood pressureand BMI, and clear negative correlation betweenhigh-density lipoprotein (HDL) cholesterol and BMI.Thus the authors estimate that much, if not all, theincreased cardiovascular mortality can be explainedby these risk factors, up to a BMI of approximately30 kg/m2. Beyond this, mortality increases more stee-ply than blood pressure, LDL cholesterol or LDL:HDLratio. Thus the excess mortality must be explained byother factors, such as insulin resistance, which werenot systematically assessed. The other problem is that,although some of the constituent studies performedmore sophisticated analyses of fat distribution andlean body mass, these were not performed sufficientlyfrequently to be included in the analyses. It is possible,therefore, that individuals with similar BMI valuesmay have different risks according to the presenceand distribution of fat. There was no analysis of‘‘normal weight obesity’’, although most participantswere from Western countries. The lack of these refine-ments makes it difficult to translate the findings of thestudy to an individual patient, although the findingssend a very clear message regarding population riskand the increasing prevalence of obesity (BMI>30 kg/m2) in most countries.

The clear and unambiguous findings of this studysuggest that it is best to have a BMI of 22.5–25 kg/m2 –a target that is very difficult to achieve for most over-weight and obese individuals. They provide somereassurance that, up to a BMI of 30 kg/m2, risk seemslargely to accrue through established risk factors thatare more easily modified than BMI itself. Beyond aBMI of 30 kg/m2, risk increases sharply, and it is evenmore unclear how this risk can be reduced indepen-dently of tackling BMI directly.

Michael Marber

39

Glossary

GlossaryGary D. Lopaschuk

Asymmetric dimethylarginine (ADMA)

ADMA is a guanidino-substituted analogue of L-argi-nine that acts as an endogenous, inhibitor of nitricoxide synthase (NOS) by competitively displacingL-arginine from the NOS active site. The concen-tration of ADMA is increased in the plasma of humanpatients with hypercholesterolemia, atherosclerosis,hypertension, chronic renal failure, and chronic heartfailure. Moreover, ADMA concentrations are elevatedin proportion to the severity of carotid, coronary, andperipheral atherosclerosis, leading to the suggestion ofADMA as a novel marker of cardiovascular risk.

B-type natriuretic peptide

Also known as brain natriuretic peptide, is a 32 aminoacid polypeptide that is produced and secreted by theventricles of the heart during excessive stretching ofcardiac myocytes. Although it is produced primarilyin the ventricles of the heart in humans, its nameoriginates from it initially being discovered in porcinebrain extracts.

Genomics

Genomics is the study of an organism’s genome(full DNA sequence). Genomics includes an intensiveeffort to determine the complete DNA sequence oforganisms and fine-scale genetic mapping efforts.Also included in this field are studies of intragenomicphenomena such as epistasis, heterosis, pleiotropy,and other interactions between alleles and loci withinthe genome.

Lipoprotein-associated phospholipase A2(Lp-PLA2)

A protein predominantly synthesized by macrophagesthat belongs to the calcium-independent family ofphospholipase A2 proteins. Lp-PLA2 is considereda vascular-specific inflammatory marker. In plasmaLp-PLA2 is bound to low density lipoproteins (LDL)and high density lipoproteins (HDL), with higheraffinity for LDL molecules that have been minimallyoxidatively modified. Elevated Lp-PLA2 (mass concen-

40

tration and/or elevated activity) is recommended as anovel risk factor and risk marker involved in the causalpathway of atherosclerotic plaque inflammation andthe formation of rupture-prone plaque, as such is anemerging candidate for future cardiovascular disease(CVD) risk.

Protein kinase C

Is a family of �10 isozymes divided into 3 classes(classical, novel, and atypical) capable of controllingthe function of other proteins via phosphorylation ofhydroxyl groups on serine and threonine amino acidresidues of these proteins. Protein kinase C isozymesin general are activated by signals that elevate theconcentration of Ca2+ and diacylglycerol. Proteinkinase C isozymes play important roles in the regu-lation of several signal transduction cascades.

Proteolysis

Is the degradation (digestion) of proteins by a family ofcellular enzymes known as the ‘‘proteases’’.

Phosphorylation

Is the addition/introduction of a phosphate group(PO4) onto a protein or other organic molecule bythe action of a wide class of enzymes known as the‘‘kinases’’. Protein phosphorylation by kinases plays amajor role in many signalling cascades, such as insu-lin regulation of glycogen mobilization.

Troponin

A regulatory protein present in striated muscle (skeletaland cardiac muscle) that in conjunction with tropo-myosin forms a regulatory complex that controls theinteraction of actin and myosin. The binding of Ca2+ totroponin permits muscle contraction. Cardiac tropo-nins are released from cardiac myocytes followingmyocardial damage and loss of membrane integrity,and serve as highly sensitive and specific biomarkersfor establishing the diagnosis of myocardial infarction


change of editor-in-chief of heart and metabolism · biomarkers: past, present, and future graham...

Documents