Cardiac Update 2009

Educational Objectives

The goal of this program is to improve the management of acute myocardial infarction (AMI), and cardiac-related syncope and palpitations. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe the attributes of an ideal cardiac marker.

2.   Review the strengths and limitations of various cardiac markers.

3.   Utilize the multimarker approach in the diagnosis of AMI.

4.   Apply the guidelines recommended for cardiac marker testing.

5.   Discuss the possible cardiac causes of syncope and palpitations.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committe to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Kirk reported that he is a consultant and speaker for Biosite, Otsuka, sanofi-aventis, and Schering Plough. Dr. Ahern and the planning committee reported nothing to disclose.

Acknowledgements

Dr. Kirk was recorded at Emergency Medicine 2009, held February 9-13, 2009, in Olympic Valley, CA, and sponsored by the University of California, Davis, Health System, Office of Continuing Medical Education, and Department of Emergency Medicine. Dr. Ahern was recorded at the Primary Care Summer Conference: Office Urgencies and Emer­gencies, held August 1-3, 2008, in San Diego, CA, and sponsored by Scripps Clinic. The Audio-Digest Foundation thanks The speakers and the sponsors for their cooperation in the production of this program.

Cardiac Biomarkers

J. Douglas Kirk, MD, Professor and Vice-Chair for Clinical Operations, Department of Emergency Medicine, and Medical Director, Chest Pain Evaluation Unit, University of California, Davis, Medical Center

Attributes of ideal cardiac marker: found in high concentrations in heart; not found in other tissues, even in trace amounts or under pathologic conditions; low molecular weight, resulting in early release into serum (ideally, before cardiac necrosis); peaks early and remains detectable for long time (to identify early presenters); provides risk strat­ification, with elevation proportional to size of injury and risk to patient; if marker positive, it triggers beneficial therapy (not just identification of myocardial infarction [MI]); short turnaround time (TAT); inexpensive; no marker meets all criteria

History of biochemical markers: aspartate transaminase (AST)  —  previously used as measurement of myocardial injury; in mid 1950s, secretory granules in myocardium related to increased stretch and increased urine flow identi­fied; creatine kinase (CK)  —  more reliable; identified in 1960s; first clinically usable application of CK measure­ment with electrophoresis (also lactate dehydrogenase [LD]); electrophoresis cumbersome and difficult; myoglobin by radioimmunoassay identified in late 70s, with resurgence in 2000; atrial natriuretic peptide (ANP) identified as protein related to urine output and left ventricular (LV) end diastolic pressure; in late 80s, myocardial band (MB) isoenzyme of CK (CK-MB) measured by mass; B-type or brain natriuretic peptide (BNP)  —  isolated in porcine brain; in late 90s, cardiac troponin T (cTnT) challenged CK-MB as gold standard; BNP now identified as being from heart (not brain); troponin I (TnI)  —  rivals TnT (only one assay); identifies high- and low-risk patients of MI cohort; redefinition of MI in early 2000s, in which patients with Tn >99th percentile of normal reference range con­sidered MI; BNP assay used mostly for heart failure; TnI assay standardization not yet successful

Release kinetics of cardiac markers: time of appearance from onset of index event; myeloperoxidase (MYO)  —  rises early; myoglobin  —  rises within first 2 to 3 hr and peaks in 3 to 6 hr; CK-MB  —  replaced by Tn as definitive marker for necrosis; rises in 3 to 5 hr and peaks at 12 hr; TnI  —  rises slightly later than CK-MB, then peaks and lasts for several days; TnT  —lasts longer than TnI; BNP  —  lasts for few days after index event; C-reactive protein (CRP)  —  inflammatory marker; rises relatively early; multimarker approach advocated by speaker

Myoglobin: early marker that allows substantial shortening of rule-out time; using Tn or CK-MB as index marker, rule-out time >8 hr in most cases; pros  —  early rising necrosis marker (within 1-3 hr); doubling over 90-min or 2-hr period highly predictive of acute MI (AMI); 2 negative readings 2 hr apart effectively rule out AMI; used with ³1 Tn to ensure that patient not presenting late, after myoglobin curve falls; ideal for detection of reinfarction (as is CK-MB); allows to gateway patients to early exercise testing; cons  —  cleared quickly; present in skeletal muscle (may lead to false positives in patients with skeletal muscle injury)

Cardiac troponin: pros  —  closest to ideal; highly sensitive with serial draws; supersensitive or ultrasensitive Tn can measure extremely small amounts; cardiospecific (not falsely elevated in patients with renal disorders or skeletal muscle involvement); remains elevated in circulation for £7 days; excellent for retrospective diagnosis of AMI; superior prognostic indicator to other markers (eg, CK-MB, myoglobin) for identifying patients and their degree of risk (degree of elevation corresponds to risk for death, reinfarction, or need for revascularization); triggers risk-appropriate therapy; dramatic differences in outcome risk seen with Tn positivity; if Tn positive, risk much higher; if negative, does not rule out risk completely; higher Tn value confers higher risk; in Tn-negative patients  —  outcome remains same, regardless of whether therapy provided; risk for death at 30 days from MI same; should be selective in treating patients with expensive drugs that carry some risk; in Tn-positive patients  —  those who received therapy obtained substantial benefit; same relationship true whether patient taken to catheter­ization laboratory, and stent deployed via percutaneous coronary intervention (PCI); study by Cannon  —  Thrombolysis in Myocardial Infarction (TIMI) 18; invasive vs conservative strategy; if Tn-negative, both strate­gies have same outcome; if Tn-positive, risk for outcome (death or MI) reduced by 50%; minor Tn elevations  —  also called Tn leak, troponosis, or troponitis; terms refer to elevation of Tn that does not represent AMI; most re­cent definition of AMI requires compatible symptoms (eg, chest pain, shortness of breath), positive marker spe­cific for myocardial injury, and rise and fall of marker; meta-analysis by Waxman  —  patients who presented to emergency department (ED) with symptoms of angina or chest pain suggestive of ACS; 50% of patients admitted and classified into 4 groups (those with no Tn detected, negative Tn value [0.0 to 0.8, reflecting 99th percentile value], indeterminate, and clearly positive); found that as Tn value increased in different groups, risk substan­tially increased (in-house mortality); those with clearcut Tn elevation had 10% risk for in-house mortality, 5% in indeterminate group, and 3.5% in negative group

Renal failure: common for patient with renal failure or chronic kidney disease to have elevated Tn because such pa­tients at high risk for coronary disease; heart and kidney intertwined; study  —  looked at 30-day all-cause mortal­ity in patients with variety of renal insufficiencies; found that elevation of Tn conferred increased risk; patients with renal failure, irrespective of Tn elevation, had high risk for all-cause mortality; need not admit every patient with elevated Tn; persistently elevated Tn in patients with chronic apoptosis of myocardial cells; many nonath­erothrombotic causes for elevated Tn, eg, sepsis; look for symptoms compatible with MI, accompanied by Tn el­evation and fall

National Academy of Clinical Biochemistry (NACB): class 1 recommendation that Tn preferred marker for risk stratification in all patients with symptoms suggestive of ACS; should measure Tn and act on it with appropriate therapy if result positive

Limitations: not early marker; however, with supersensitive Tn, early rise seen and measurement of myoglobin probably not necessary; issue of low level of Tn in patients without AMI and actions to take as assays become more sensitive; no standardization; at present, no single marker adequate to utilize as rule in/rule out strategy; in low-risk patients, serial samples within 2 hr adequate to rule out; in high-risk patients, extend testing longer, par­ticularly if not clear when index event occurred; for patients seen in ED with Tn elevation, functional studies (treadmill test, exercise echocardiography, computed tomographic angiography [CTA]) recommended for further risk stratification

American College of Emergency Physicians: clinical policy statement  —  no single serum marker, used alone, has sufficient sensitivity to exclude AMI within 6 hr after symptom onset; for early presenter, use of early marker with more late marker recommended; measurement of myoglobin in first few hours from onset of pain has better sensitivity, although with lower specificity, compared to CK-MB or Tn; for early presenter, add myoglobin to multimarker approach; in early presenter, if first Tn negative but myoglobin level elevated, continue testing with myoglobin and Tn to determine whether myoglobin level doubles; if both negative and still another marker nega­tive, can stop; in patient with certain AMI, and first myoglobin positive but Tn negative, speaker takes patient to catheterization laboratory; lesser approach earlier anticoagulation and aspirin (given to all patients); in patients with ST segment depression and negative Tn, risk lower than if Tn-positive, but ACS nonetheless

Recommendations: graded A (strongest), B, and C , mirroring level of supporting evidence; 1) in patients who pres­ent late (>8 hr), measure single CK-MB or TnI or TnT to rule out MI; if using single marker to rule out AMI, critical to know when index pain occurred (clearcut onset); 2) in patient who presents <8 hr with negative myo­globin and negative Tn at baseline and 90 min, MI excluded; 3) can also use delta values of CK-MB or Tn in early presenters and typically, 30% to 35% change in initial baseline values seen; Tn increase by 35%, consid­ered substantial change, and patient probably positive; bottom line  —  unless patient presents >8 hr, multimarker approach necessary

Study by McCord: 800 patients, »10% with AMIs; myoglobin, CK-MB, and Tn measured at 0 and 90 min; com­bining myoglobin and Tn at 0 and 90 min, negative predictive value almost 100%, and measuring samples £3 hr added nothing

Other markers: include ischemia, plaque rupture, thrombosis, and endothelial activation (after necrosis); most markers identify patients after fact (infarction); ideally, patients identified when platelets reactivated due to plaque rupture and before infarction; ischemia-modified albumin (IMA)  —  marker for ischemia; Food and Drug Adminis­tration (FDA)-approved; no longer used due to lack of specificity; BNP  —  initially, heart failure marker; good marker in patients with ACS, identifying patients at high risk; other 2 markers with FDA approval and on market include high sensitivity CRP (hs-CRP) and myeloperoxidase (MPO)

Criteria for assessing novel biomarkers: ability to measure  —accurate and reproducible analytical methods; prean­alytical issues that prevent success of markers; available assay; reasonable cost; addition of new information  —  most important; association between marker and outcome of disease process; information adds to or improves upon existing tests; also  performance superior to that of existing diagnostic tests

B-type natriuretic peptide: pros  —  provides powerful risk stratification across spectrum of ACS; in some studies, shown superior to Tn for identifying these patients; cons  —  not specific to ACS (elevation also seen in patients with asymptomatic heart failure), so of limited value as screening marker; study by de Lemos  —  looked at patients with ST segment elevation MI (STEMI) and unstable angina; found that patient’s risk for mortality increases substan­tially at 10 mo, as BNP value increases; if BNP <80 pg/mL, risk for death 1.8% (>80 pg/mL, risk 8.5%); dominant marker of death or disability in patients with ACS; useful across different groups of patients with ACS; incremental increase important, ie, how high it goes; NACB  —  class 2a recommendation for BNP or N-terminal pro-BNP as marker for assessment of risk

High-sensitivity CRP: acute-phase protein that identifies patients with systemic inflammation; important predictor of poor outcomes in patients with ACS and other cardiovascular diseases; utility in ED patients with undifferenti­ated chest pain not yet established; Lindahl showed substantial increase in mortality if CRP >10 mg/dL vs normal (<2 mg/dL); in patient Tn-negative and CRP-positive, cardiac death rate substantially higher at 2 yr; similarly, as Tn and CRP increase, risk amplified (does not bear out in undifferentiated population); study by Sabatine  —  found that irrespective of combination, the more markers positive, the higher the risk

Myeloperoxidase (MPO): not FDA-approved; heme protein produced by neutrophils; marker of inflammation in walls of coronary arteries; in some studies, shown important signal of potential risk for future MI; study by Brennan  —  MPO predicts risk of developing MI in patients with chest pain when Tn negative; all patients TnT-neg­ative throughout ED stay; as MPO level increases, odds ratio of adverse event (eg, death, MI, revascularization) in­creased substantially; study by Tang  —  if MPO and BNP negative, good outcome; if both positive, event-free survival over 4 yr poor; if either marker positive, outcome between good and poor

American College of Cardiology and American Heart Association guidelines: markers required for diagnosis of non-STEMI (NSTEMI); myoglobin efficient in rapidly ruling out NSTEMI; Tn highly specific and efficient in late diagnosis of MI; BNP valuable as prognostic marker; multimarker approach advocated

NACB recommendations for: serial sampling of markers upon arrival and throughout ED stay; for patients who present within 6 hr, early marker of myocardial necrosis (eg, myoglobin) in addition to cTn recommended; rapid rule-in protocol with frequent early sampling (at 0, 30, 60, and 90 min) advocated if tied to therapeutic strategies; TAT of <60 min goal

Cardiac Causes of  Syncope and Palpitations

Thomas S. Ahern, MD, Cardiologist, Scripps Clinic, La Jolla, CA

Syncope: cause not identified in £40% of patients; issue of whether able to identify patients at high risk; patients with significant cardiac disease have mortality of £10% in next 6 mo; work-up  —  carotid duplex ultrasonography, CT of head, electrocardiography (ECG); more ischemic symptoms with global hypoperfusion; in unexplained syncope, important to determine whether patient has structural heart disease or abnormal ECG; syncope with structural heart disease — eg, severely enlarged hypokinetic left ventricle, with low ejection fraction;  speaker considers syncope due to ventricular tachycardia until proven otherwise;  consider aortic stenosis, mitral stenosis, hypertrophic cardio­myopathy, left ventricular (LV) systolic dysfunction, and myxoma; Brugada syndrome  —genetic mutation of third chromosome; affects repolarization; causes sudden death due to ventricular fibrillation; hallmark on ECG R¢ wave in V₁ and V₂ and downsloping of ST segment; in patient with syncope, long PR interval, bundle branch block, evi­dence of previous MI, long QT interval, Brugada syndrome, or Wolff-Parkinson-White (WPW) syndrome; WPW syndrome  —  presence of extra electrical pathway that connects atrium to ventricle; pathway, unlike atrioventricular (AV) node, often has no limit on how fast impulses conducted; delta wave seen on ECG; for patient with recurrent syncope, insertion of implantable loop recorder (small device inserted transcutaneously) for 18 mo option; syncope common  —  take history; if patient has recurrent problems with no identified structural heart disease and no evi­dence of ECG changes, perform tilt table test and refer patient

Palpitations: high risk in those with structural heart disease, abnormal ECG, or LV dysfunction; in patient with par­oxysmal symptoms, determine  —  whether sustained, brief, or associated with hemodynamic symptoms, eg, light­headedness, dizziness; family history of sudden death or syncope; previous MI (if palpitations started since MI, think ventricular tachycardia); work-up should look for evidence of structural heart disease; speaker uses event monitoring; in sustained palpitations  —  obtain ECG and determine whether patient hemodynamically stable or whether narrow complex; if narrow complex, attempt carotid sinus massage; have patient perform vagal or Valsalva maneuver; 12-lead ECG acceptable to diagnose nature of tachycardia; if patient not hemodynamically stable, car­dioversion indicated; in sustained wide-complex tachycardia  —  consider ventricular tachycardia, supraventricular tachycardia (SVT) with aberration, or rogue pacemaker; managed with intravenous procainamide (Pronestyl); should not give AV nodal blocking agents if patient has SVT over accessory pathway (blocking AV node places pa­tient at risk)

Suggested Reading

Abbott AV: Diagnostic approach to palpitations. Am Fam Physicia.71:743, 2005; Antman EM et al: Cardiac-specific tropo­nin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 335:1342, 1996; Balk EM et al: Accuracy of biomarkers to diagnose acute cardiac ischemia in the emergency department: a meta-analysis. Ann Emerg Med 37:478, 2001; Benito B et al: Brugada syndrome. Prog Cardiovasc Dis 51:1, 2008; Brennan ML et al: Emerging role of myeloperoxidase and oxidant stress markers in cardiovascular risk assessment. Curr Opin Lipidol 14:353, 2003; Brignole M: Diagnosis and treatment of syncope. Heart 93:130, 2007; de Lemos JA et al: The prognostic value of serum myoglobin in pa­tients with non-ST-segment elevation acute coronary syndromes. Results from the TIMI 11B and TACTICS-TIMI 18 studies. J Am Coll Cardiol 40:238, 2002; Maisel AS et al: A prospective study of an algorithm using cardiac troponin I and myoglobin as adjuncts in the diagnosis of acute myocardial infarction and intermediate coronary syndromes in a veteran's hospital. Clin Cardiol 23:915, 2000; McCord J et al: Ninety-minute exclusion of acute myocardial infarction by use of quantitative point-of-care testing of myoglobin and troponin I. Circulation 104:1483, 2001; Sabatine MS: Multimarker approach to risk stratifi­cation in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation 105:1760, 2002; Tang WH et al: Prognostic value and echocardiographic determinants of plasma myeloperoxidase levels in chronic heart failure. J Am Coll Cardiol 49:2364, 2007; Waxman DA: A model for troponin I as a quantitative predictor of in-hospital mortality. J Am Coll Cardiol 48:1755, 2006.