Troponin Elevation in ICU- beyond Myocardial Infarction

1. Troponin Elevation in ICU- beyond Myocardial Infarction Dr. TH De Klerk Critical Care

2. Definition • Biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmaco-dynamic response to a therapeutic intervention. • Fit-for- purpose paradigm: Exploration- Research Demonstration- Diagnosis Characterization- Prognosis Surrogacy- Surrogate clinical end-points

3. Background • Troponin complex consist of I, C and T subunits, that mediates actin and myosin coupling. The troponin I and T isoforms are specific to the myocardium. • Two storage forms: cytosolic and myofibrillar. The concentration is 35X higher in the myofibril. • Therefore a marker of myocardial damage- doesn’t tell about mechanism of injury. Eg. Can be inflammatory rather than ischaemic.

4. Myocardial Infarction • Definition: Myocardial cell death due to prolonged ischaemia. • 2012-Third consensus definition. • The diagnosis rests on three pillars: • Clinical setting- symptom recognition in ICU unreliable. • Raised biomarkers- levels and false positives. • New electrocardiographic, echocardiographic or angiographic evidence consistent with ischaemia. • Need 2 or more for diagnosis.

5. Clinical Classification of Myocardial Infarction • Type 1- Spontaneous coronary event. Either plaque rupture, erosion, fissure, etc. • Type 2- Supply-Demand Mismatch. Anemia, tachycardia, hypo- or-hypertension, etc. • Type 3- Unexpected cardiac death with electrocardiographic, echocardiographic, angiographic or autopsy findings indicative of myocardial ischaemia. • Type 4 a- PCI-related b- Stent thrombosis • Type 5 CABG related

6. Troponin levels and false positives. • Troponin rise or fall with at least one value above 99th percentile upper reference limit. CV< 10%. • The troponin level in myocardial infarction predicts extent of infarct, risk for complications, morbidity, mortality and length of stay. • The troponin level outside setting of myocardial infarction independently predicts severity of illness, mortality, duration of ventilation, as well as length of ICU stay. • Troponin release without necrosis- increased myocyte membrane permeability of cytosolic content. This still correlates with myocardial depression, mostly fully reversible.

7. Non-Ischaemic Conditions with Raised Troponins • Myocarditis • Cardiac contusion • Burns • Pulmonary embolism • Aortic dissection • Heart failure • Sepsis • Acute neurological disease • Cardiotoxic drugs • Renal failure

8. Myocardial Oxygen Supply • Supply determined by magnitude of coronary flow and oxygen carrying capacity. • Oxygen carrrying capacity influenced by anaemia, hypoxia and Hb-O2 affinity. • Coronary blood flow determined by • Metabolic control- adenosine, K+, CO2, lactate and pH. • Autoregulation: Myogenic and neurogenic factors. • Extravascular compressive forces-intramyocardial. • Diastolic phase of cardiac cycle • Humural factors: angiotensin, nitric oxide, etc. • Neural control- autonomic innervation.

9. Myocardial Oxygen Demand • Heart rate • Contractility • Systolic wall tension: proportional to systolic ventricular pressure x radius/ ventricular wall thickness.

10. Common conditions in ICU with Troponin leaks • Tachycardia- severe and especially dysrhythmias. Atrial fibrillation with raised tropononins predict risk for embolism much better than CHA2DS2-VASc score. • Direct trauma- minority of patients with troponin elevation develop significant complications such as hypotension, dysrhythmias, etc. • Burns- >25% Total body surface area. • Chronic hypertension with left ventricular hypertrophy- demand increase with left ventricular mass, coronary flow reserve decrease due microcirculatory remodelling. • Heart failure- Increased strain: Volume and/or pressure overload. Myocyte death: Inflammation, apoptosis and catecholamine toxicity.

11. Common conditions in ICU with Troponin leaks • Pulmonary and pulmonary vascular disease- including ARDS: Severe right heart strain. • Acute central nervous system injury eg. Trauma, stroke, etc. Autonomic imbalance- Sympathetic hyperactivity. • Renal failure-endothelial dysfunction, impaired excretion, left ventricular hypertrophy, loss cardiac myocyte membrane integrity.

12. Troponins and Sepsis • Direct injury: Endotoxin, inflammation, etc. • Indirect: Supply-demand mismatch. • Septic cardiomyopathy: Reversible systolic and/or diastolic dysfunction. • Genetic factors- iNOS deficiency. • Calcium channel dysregulation- decrease L-type receptors. • Nitric Oxide- myocardial depression via mitochondrial dysfunction. • Cytokine- “MDF”- TNF-alpha, IL-1, IL-6. • Toll-like receptor activation- negative inotropic. • Endothelin-1- myocardial apoptosis. • No evidence suggestive of microthrombosis

13. Troponins and Sepsis Metabolic alterations: • Maldistribution of coronary blood flow with unchanged global myocardial blood flow. • Inhibition of cytochrome C oxidase, with myocardial oxygen depletion. • Reactive oxygen species causes impaired myocardial contraction. • Autonomic dysregulation, decreased receptor density, catecholamine myocyte toxicity. • Myocardial infiltration –immune cells with subsequent necrosis and apoptosis.

14. Troponins and sepsis • 44% of patients with septic shock- diastolic dysfunction. • 24% both systolic and diastolic dysfunction. • Septic shock often accompanied by ARDS with hypoxic pulmonary vasoconstriction with reversible pulmonary hypertension. • Troponin elevation in sepsis correlates best with echocardiographic parameters of left ventricular diastolic dysfunction and right ventricular dilatation. These parameters as well as troponin elevations seems to be the best independent cardiac predictors of mortality in sepsis.

15. Treatment of troponin elevations in sepsis • Fluid therapy remains cornerstone to restore euvolemic state. • Dobutamine used in the setting of decreased cardiac output. High dose >10mcg/kg/min cardiotoxic. • Calcium channel sensitizers- Levosimendan. • Beta blockers in septic shock- 2013 JAMA RCT with Esmolol titrated to heart rate 80-95/min, decrease mortality. • Role of statins in myocardial dysfunction unknown. • Aspirin reasonable- if no contra-indications.

16. Utility of Troponin Elevations in Peri-operative Period in Non-cardiac Surgery • Most commonly used cardiac risk evaluating tool in the peri-operative period is the Revised Cardiac Risk Index (Lee index). • Pre-operative hs-Troponin substantially improves risk stratification when added to this index. • Hs-Troponin elevation was shown to be the strongest independent risk predictor for serious peri-operative cardiac events. • Currently a class 1A recommendation by European Society of Cardiology guidelines.

17. References • Antonucci E, Fiaccardori E, Donadello K, Taccone FS, Tranchi F, Scoletta S. Myocardial depression in sepsis: From pathogenesis to clinical manifestations and treatment. J of Crit Care 2014;29:500-511. • Ventetuolo CE, Levy MM. Cardiac Biomarkers in the Critically Ill. Crit Care Clin 2011;27:327-343. • Landesberg G, Jaffe As, Gilon D, Levin PD, Goodman S, Abu-Baih A, et al. Troponin Elevation on Severe Sepsis and Septic Shock: The Role of Left Ventricular Diastolic Dysfunction and Right Ventricular Dilatation. Crit Care Med 2014;42:790-800. • Weber M, Luchner A, Manfred S, Mueller C, Liebetrau C, Schlitt A, et al. Incremental value of high-sensitivity troponin T in addition to the revised cardiac index for peri-operative risk stratification in non-cardiac surgery. Eur Heart J 2013;34:853-862.