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. 2019 Oct 21;36(1):141–153. doi: 10.1016/j.ccc.2019.08.011

Biomarkers and Right Ventricular Dysfunction

Natasha M Pradhan a, Christopher Mullin b, Hooman D Poor a,∗
PMCID: PMC9982435  PMID: 31733676

Abstract

Right ventricular failure is common in critically ill patients, as it frequently results from pulmonary embolism or pulmonary hypertension, and can complicate sepsis and the acute respiratory distress syndrome. Right ventricular dysfunction can be challenging to manage and is associated with poor outcomes in this wide array of disease. Laboratory biomarkers are rapid, noninvasive, accurate, and widely available and thus are useful in the diagnosis and management of right ventricular dysfunction in the critically ill patient. This article discusses the pathophysiology of right ventricular failure and reviews the applications of commonly used biomarkers in right ventricular dysfunction in critical care.

Keywords: Right ventricular dysfunction, Biomarkers, Pulmonary embolism, Pulmonary hypertension, Troponin, Brain natriuretic peptide

Key points

  • •

    Right ventricular failure is commonly encountered in critically ill patients, most often due to pulmonary embolism or pulmonary hypertension, and is associated with poor prognosis and outcomes.

  • •

    Laboratory biomarkers such as troponin and brain natriuretic peptide are sensitive, but not specific, indicators of right ventricular dysfunction and aide in the risk stratification, prognosis, and management of right ventricular failure in various critical illnesses.

  • •

    Cardiac biomarkers are most widely studied and clinically used to risk stratify patients with acute pulmonary embolism.

  • •

    Novel biomarkers such as heart-type fatty acid–binding protein, growth differentiation factor 15, and neutrophil gelatinase–associated lipocalin have been shown to predict mortality in acute pulmonary embolism but are not currently used in routine clinical practice.

  • •

    Although awareness of the possibility of right ventricular dysfunction in common critical illnesses such as acute respiratory distress syndrome and sepsis is imperative, biomarkers are not standardly used to assess right ventricular function.

Introduction

Right ventricular failure is defined as the inability of the right ventricle (RV) to maintain adequate cardiac output in the presence of sufficient preload.1 RV dysfunction may result from increased RV afterload, decreased RV contractility, or a combination of both. RV failure is common in critically ill patients, as it frequently results from pulmonary embolism (PE) or pulmonary arterial hypertension (PAH), and it often complicates common critical illnesses such as the acute respiratory distress syndrome (ARDS) and sepsis. Acute PE increases RV afterload and is a common cause of RV dysfunction, estimated to affect up to 900,000 people and resulting in more than 60,000 deaths per year in the United States.2 PAH, although rare in comparison, can result in devastating RV failure, cardiogenic shock, and death. In both acute PE and PAH, RV function is the most important determinant of survival.2, 3 Hypoxemic respiratory failure, particularly ARDS, can result in pulmonary hypertension (PH) and RV dysfunction. Echocardiographic evidence of RV dysfunction can be seen in 22% to 50% of patients with moderate ARDS and is associated with increased mortality.4, 5 Increased circulating cytokines in sepsis may cause myocardial depression and increased pulmonary vascular resistance (PVR), resulting in RV dysfunction, which is ultimately associated with increased mortality.6, 7, 8 RV ischemia, cardiomyopathy, or myocarditis can result in decreased RV contractility and primary RV failure, often in the presence of normal pulmonary vascular impedance. Although this is less commonly encountered, it is important to diagnose because there are critical differences in management between RV failure resulting from increased RV afterload and decreased RV contractility.1

Given the poor outcomes and challenges with managing RV dysfunction, the intensivist must be equipped to recognize RV dysfunction, identify the underlying pathophysiology, and intervene appropriately. Echocardiography, advanced cardiac imaging such as cardiac MRI, and invasive hemodynamic measurements are often used in the diagnosis and management of RV dysfunction; however, they are costly, time consuming, challenging to obtain in the intensive care unit (ICU), and may require specialized skill for performance and interpretation. Laboratory biomarkers are rapid, noninvasive, accurate, inexpensive, and widely available and thus are attractive for use in the recognition and management of RV dysfunction in critically ill patients. Understanding the role of biomarkers in RV dysfunction requires insight into normal and abnormal RV function.

Normal right ventricular function

The RV consists of the interventricular septum and a free wall that embraces the left ventricle (LV). The RV is efficient because it matches the same cardiac output as the LV with one-fifth of the energy expenditure. Its ability to do so stems from unique structural and functional adaptations to the low-resistance, high-capacitance pulmonary circulation.9 The RV free wall is thinner than that of the LV and lacks the middle circumferential layer of constrictor fibers of the LV that provides the contractility against higher systemic pressures.9, 10 Instead, the RV relies on longitudinal shortening for systolic ejection, bringing the apex toward the tricuspid annulus, along with flattening of the free wall, producing a bellows movement.9, 11 Its high compliance allows for a greater surface area to volume ratio, enabling the RV to eject a large volume of blood with minimal changes in wall stretch.12 In addition, the lower RV cavity pressures allow for myocardial perfusion throughout both diastole and systole, in contrast to the LV, where perfusion occurs only when cavity pressures are lower than aortic root pressures during diastole.13 These mechanisms allow the RV to function efficiently under physiologic conditions.

Pathophysiology of right ventricular failure

A significant increase in RV afterload or a significant decrease in RV contractility, often compounded by excessive RV preload, can set into motion a downward spiral of RV failure. Although the normal RV is capable of accommodating increases in preload, it is not tolerant of significant increases in RV afterload, particularly when the increase occurs acutely.12 When subjected to acute pressure overload, the RV dilates and maintains its stroke volume by the Frank-Starling mechanism.14 Once this compensatory capacity is exceeded, maladaptive dilation results in further worsening of RV performance and a precipitous drop in RV cardiac output.15 Because the RV and LV are arranged in series, a drop in RV cardiac output reduces LV preload and subsequently LV cardiac output. Dilation of the RV chamber extends to the tricuspid annulus, producing functional tricuspid regurgitation, increasing preload, and furthering RV stretch.

The progressively rising RV end-diastolic pressure and volume cause thinning of the RV myocardium and increase RV wall stress.16, 17 The higher wall stress increases myocardial oxygen demand and also reduces RV myocardial perfusion as the myocardium becomes perfused only during diastole.18, 19 This mismatch between RV myocardial oxygen demand and supply leads to RV ischemia, myocyte necrosis, and impaired RV contractility.

Because constraint from the pericardium prevents the RV free wall from dilating outwards, progressive RV dilation displaces the interventricular septum, leading to decreased LV cavity size in diastole and LV deformation during systole.20 Decreased LV cavity size during diastole reduces LV preload and LV deformation during systole impairs LV contractility, both of which lead to decreased LV cardiac output20, 21, 22, 23 (Fig. 1 ).

Fig. 1.

Fig. 1

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Pathophysiology of RV failure.

Biomarkers in right ventricular dysfunction

Biomarkers are disease-associated molecular changes in body tissues and fluids24 that can serve as standardized, reproducible, noninvasive, and objective measures to assist in the diagnosis, assess prognosis, and monitor response to therapy in specific disease states. Laboratory biomarkers serve as sensitive, but not specific, indicators of RV dysfunction and aide in risk stratification, prognosis, and management in various critical illnesses. These biomarkers are often used in combination with clinical assessment, risk scores, and imaging modalities such as echocardiography and computed tomography. Many of the biomarkers are linked to the underlying pathophysiologic changes that occur during RV failure.

Troponin

Troponin is most commonly used for detection of myocardial ischemia and infarction because it relates to the LV.25, 26 However, troponin I and T are also released into the systemic circulation from myocardial injury due to RV ischemia. Troponin I and T are largely structurally bound to myofilaments, with a small soluble unbound cytoplasmic pool of 3% and 6%, respectively.18 This cytoplasmic pool is thought to be released due to myocardial injury from RV ischemia and may explain the distinct pattern of troponin release seen in PE compared with non-ST-elevation myocardial infarction (MI).27 In MI, extensive myocardial necrosis causes troponin T to appear as early as 3 hours after onset of symptoms, peak at 24 hours, and remain detectable for up to 10 to 14 days. In PE, however, troponin peaks at 10 hours after presentation and remains detectable for only 40 hours. The peak is lower than that of MI, and remains detectable for a shorter period of time.28 In patients presenting greater than 72 hours after symptom onset, troponin is undetectable despite the presence of RV dysfunction on echocardiogram.29 Understanding the kinetics of troponin release is essential to determine optimal timing of blood sampling for accurate risk stratification.

Brain natriuretic peptide

Secretion of brain natriuretic peptide (BNP) is stimulated by an increase in wall stress from pressure overload in the failing RV. Ventricular cardiomyocytes secrete the inactive prohormone pro-BNP, which is split into biologically active BNP hormone and inactive N-terminal pro-BNP (NT-proBNP). Both hormones are measurable in plasma and serve as biomarkers of RV dysfunction.30 Timing of measurement, mechanism of secretion, half-life, and clearance all affect plasma levels and are important considerations in the interpretation of BNP and NT-proBNP levels. In contrast to troponin, which is a normal constituent of the cardiomyocyte, only small amounts of BNP and NT-proBNP are stored in the cell under physiologic conditions. Instead, BNP and Nt-proBNP secretion is stimulated by a constitutive mechanism in response to stretch and may take several hours before it appears in circulation.30, 31, 32 BNP has a half-life of 20 minutes, whereas NT-proBNP has a half-life of 60 to 120 minutes. BNP and NT-proBNP levels are inversely related to glomerular filtration rate; therefore, these peptides can accumulate in patients with impaired renal function.33

Lactate

End-organ hypoperfusion occurring as a result of decreased cardiac output from RV failure may result in the release of lactate. The use of lactate as a biomarker in critically ill patients is addressed in a separate chapter.

Novel biomarkers

Heart-type Fatty Acid–Binding Protein

Heart-type fatty acid–binding protein is a 15 kDa cytoplasmic protein, highly expressed in cells with active lipid metabolism such as the heart and liver. Its small size allows it to be released into the circulation as soon as 2 hours after myocardial damage, peak within 6 to 8 hours, and return to normal at 24 to 36 hours.34 It has become recognized as an early, sensitive, and specific marker of myocardial injury, with so far best studied in for early risk stratification of PE.35

Other Novel Biomarkers

Several novel biomarkers have been investigated in the diagnostic and prognostic assessment of PE. Growth differentiation factor 15 (GDF-15) is a cytokine that is produced in cardiomyocytes in the setting of ischemia or pressure overload. Elevated GDF-15 is an independent predictor of complicated 30-day outcome in acute PE.36 Elevated levels of copeptin, a stable precursor protein of vasopressin, were also associated with increased risk of 30-day adverse outcome in normotensive patients with PE.37, 38 Various markers of impaired renal function have prognostic value in acute PE. In normotensive patients with acute PE, a GFR less than 35 mL/min was an independent predictor of 30-day mortality and improved troponin-based risk stratification.39 Neutrophil gelatinase–associated lipocalin (N-GAL) is produced by the kidney and has been shown to rapidly accumulate in acute kidney injury.40 Likewise, cystatin C is also a marker of renal dysfunction that has been used to diagnose acute kidney injury in critically ill patients 24 to 48 hours before increase in creatinine level.41 Elevated levels of N-GAL and cystatin C have been shown to predict 30-day all-cause mortality in acute PE.42

Applications

Biomarkers for Right Ventricular Dysfunction in Acute Pulmonary Embolism

Acute PE is one of the most common causes of RV dysfunction in the emergency room and ICU. Several biomarkers are well established as predictors of mortality and morbidity in acute PE and as such play an important role in prognostication and risk stratification in patients with acute PE.

Troponin is released into the systemic circulation in response to RV myocardial ischemia in acute PE. In a subgroup of normotensive patients with acute PE, elevated levels of troponin (greater than 99th percentile of healthy subjects) measured on admission and/or up to 24 hours after admission were associated with a higher risk of in-hospital or 30-day mortality (odds ratio [OR] 5.90, 95% confidence interval [CI] 2.68–12.95) and need for cardiopulmonary resuscitation, vasopressors, mechanical ventilation, and thrombolysis. Although a greater proportion of patients with a positive troponin had RV dysfunction on echocardiography, both troponin and echocardiographic RV dysfunction had independent, additive prognostic value without significant interaction.43, 44 The prognostic value of troponin has been supported with subsequent meta-analyses.45, 46

High-sensitivity troponin (Hs-TnT) also has predictive value in acute PE and may be more accurate than troponin T. In one study, an Hs-TNT greater than 14 pg/mL in normotensive patients with acute PE predicted 30-day mortality and adverse outcomes with better accuracy than troponin T. Unlike troponin T, which has not been shown to correlate with long-term prognosis, patients with acute PE with Hs-TnT greater than 14 pg/mL had a reduced probability of long-term survival over a median period of 965 days.45, 46 Although this is a promising option to optimize risk stratification in acute PE, the number of studies is small and widespread application of Hs-TnT is still limited.

BNP is released as a result of increased myocardial wall stress in the setting of RV dysfunction due to PE. As would be expected, increased levels of BNP or NT-proBNP in patients with acute PE have been shown to be associated with RV dysfunction.47 In a meta-analysis of 1132 patients with acute PE, elevated BNP and NT-pro BNP were associated with an increased risk of 30-day mortality (OR 6.5; 95% CI 2–21) and in-hospital adverse clinical outcomes, including death, cardiopulmonary resuscitation, mechanical ventilation, use of vasopressors, thrombolysis, thrombosuction, surgical embolectomy, or admission to the ICU (OR 8.7; 95% CI 2.8–27).48 This meta-analysis, however, also included hemodynamically unstable patients, in whom RV dysfunction is likely clinically apparent and in whom risk stratification with biomarkers may be unnecessary. In another study that included only normotensive patients with acute PE, BNP and NT-proBNP levels similarly predicted short-term mortality.45 Because their values can be elevated in other conditions such as LV dysfunction, renal impairment, chronic respiratory illness, and advanced age, elevation of BNP and NT-proBNP are nonspecific and have a low positive predictive value for RV dysfunction.49

Heart-type fatty acid–binding protein (hFABP) is an early marker of myocardial damage, and because it is both sensitive and specific, it has been used for early identification of low-risk patients with acute PE.35, 45 In a study of 126 normotensive patients with acute PE, hFABP greater than 6 ng/mL predicted death or complications at 30 days with a sensitivity of 0.89 and specificity of 0.82.50 All patients who developed complications had an elevated hFABP level, whereas troponin T and NT-proBNP levels did not significantly differ,50 which suggests that hFABP may be a more useful biomarker in acute PE; however, more studies of this biomarker are necessary.

Risk stratification in acute pulmonary embolism

Once the diagnosis of PE has been confirmed by computed tomography pulmonary angiography (CTPA), ventilation-perfusion scan, or pulmonary angiography, prompt risk stratification using validated predictive models is used to estimate early mortality risk and help guide management decisions. The European Society of Cardiology 2014 guidelines recommend stratifying patients into low-, intermediate-, and high-risk groups,51 using biomarkers to differentiate between low- and intermediate-risk groups. Assessment of hemodynamic status is the first step in risk stratification for a patient with confirmed or suspected PE. Shock or sustained hypotension (defined as systolic blood pressure less than 90 mm Hg or drop of >40 mm Hg for 15 minutes or longer) classifies patients as high risk, with an estimated 90-day mortality as high as 58% (Fig. 2 ).52 Patients without sustained hypotension or shock are further classified into low and intermediate risk. These 2 groups are distinguished from each other with the evaluation of the pulmonary embolism severity index (PESI), imaging assessment (eg, echocardiography, CTPA) of the RV, and biomarkers. Specifically, patients with low-risk PE demonstrate no imaging signs of RV dysfunction, do not have elevations in cardiac biomarkers, and do not have elevated PESI risk score. Intermediate-risk PE, on the other hand, requires only the presence of one of those listed abnormalities. Intermediate-risk patients are further stratified into intermediate-high or intermediate-low risk. Patients with imaging evidence of RV dysfunction and positive biomarkers (especially troponin) are classified as intermediate-high risk, whereas those with only one abnormality (RV dysfunction or positive biomarkers) are deemed intermediate-low risk. This distinction is important to make because it enables the identification of a group of normotensive patients with more significant RV dysfunction who are at increased risk of the short-term mortality and may benefit from ICU monitoring and the consideration of reperfusion therapy.53

Fig. 2.

Fig. 2

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Risk stratification of pulmonary embolism.

Negative biomarkers when measured at the appropriate time can help identify patients with PE at low risk of death or complications and allow for shorter duration of hospital stay or early discharge from the emergency department. NT pro-BNP of less than 500 ng/L to less than 1000 ng/L measured on admission predicts a benign clinical outcome in patients with PE with a negative predictive value between 97% and 100%.46, 54 Admission BNP values of less than 50 pg/mL have better negative predictive value for short-term adverse events than the more widely used cut-off less than 90 pg/L.55 However, with a negative likelihood ratio (NLR) of 0.33 for all-cause mortality and NLR of 0.41 for short-term adverse events, BNP does not accurately identify low-risk patients.45 Hs-TnT of less than 14 pg/mL was 100% sensitive in identifying patients who would not experience short-term adverse events.46 A meta-analysis also confirmed NLR of 0.21 for all-cause mortality, making it a useful marker for early risk stratification. Low hFABP measured on admission is a sensitive, early marker with excellent negative predictive value for short-term adverse events.50

Biomarkers for right ventricular dysfunction in pulmonary hypertension

PH is a pathophysiologic disorder, defined by a mean pulmonary artery pressure of more than 20 mm Hg at rest, measured via right heart catheterization.56 PAH, a type of PH, is a chronic, progressive pulmonary arterial vasculopathy, characterized by medial hypertrophy, intimal fibrosis, and in situ thrombosis of the pulmonary arterioles that causes an increase in PVR.57 PAH can result in progressive RV failure, multiorgan dysfunction, and ultimately death.58 RV failure is a leading cause of death in PAH,59 and patients with PAH admitted to the ICU have high mortality rates.17 Cardiac biomarkers are frequently used in both the chronic management of patients with PAH as well as in the intensive care setting. BNP and NT-proBNP are the most commonly used biomarkers in PH, as they correlate with functional and hemodynamic measures60, 61, 62 and are independent predictors of mortality.63, 64 In addition, changes in hemodynamics correlate with changes in BNP, making BNP a useful tool to noninvasively assess response to therapy.61 Troponin is used less frequently but has been identified as an independent marker of mortality in patients with precapillary PH.65 There is less data for the use of biomarkers in the patients with PAH with RV failure. One study of 46 patients with PAH or inoperable chronic thromboembolic pulmonary hypertension with acute RV failure in the ICU found BNP to be an independent predictor of mortality.66 Practically speaking, biomarkers are used in conjunction with other clinical, laboratory, and echocardiographic parameters in management of acute RV failure in patients with PAH.17

Biomarkers for right ventricular dysfunction in intensive care unit

RV dilation and dysfunction has been shown to be an independent predictor of mortality in patients with moderate to severe ARDS.67, 68 A myriad of factors contribute to the elevated PVR in ARDS that leads to RV dysfunction, including hypoxic pulmonary vasoconstriction, elevated Paco 2, acidemia, endothelial dysfunction, imbalance between vasoconstrictors and vasodilators, microthrombosis, and pulmonary vascular remodeling.69, 70, 71, 72 Biomarkers specific to acute RV dysfunction in ARDS have yet to be investigated.

RV dysfunction during sepsis stems from a combination of decreased RV myocardial contractility and increased PVR.6 Circulating cytokines such as tumor necrosis factor alpha increased oxidative free radicals, endothelial dysfunction, and toll-like receptors activation that occur in sepsis have been implicated in the pathogenesis of myocardial dysfunction.73, 74 Bacterial endotoxins have been shown to decrease the production of nitric oxide in vascular endothelial cells in vitro and may play a role in the increased PVR that occurs in sepsis.75 The coexistence of ARDS in patients with sepsis also contributes to RV dysfunction as previously described. In a retrospective cohort study that evaluated 100 patients with sepsis or septic shock with RV dysfunction, isolated RV dysfunction was independently associated with worse 1-year survival (hazard ratio 1.6, 95% CI 1.2–2.1, P = .001) when adjusted for age, comorbidities, illness severity, septic shock, and the use of mechanical ventilation.8

RV dysfunction due to decreased myocardial contractility may occur due to several reasons, namely RV MI, myocarditis, and pericarditis. Clinically significant RV infarction usually occurs in conjunction with left-sided acute inferior-posterior MI and is due to occlusion of the proximal right coronary artery.76, 77, 78 The hemodynamic compromise in RV MI may be compounded by bradycardia that is frequently seen in conjunction with inferior MI and left atrial ischemia due to proximal right coronary artery occlusion, which leads to loss of left atrial augmentation to preload.79, 80, 81 Cardiac biomarkers used to aide the diagnosis of RV MI are similar to those used in LV MI, such as troponin T, troponin I, and creatine kinase-MB.82

Summary

RV dysfunction is an important prognostic marker in the wide array of cardiopulmonary diseases that frequently cause or contribute to critical illness. Assessment of RV function is vital in the intensive care setting for management of acute PE, pulmonary hypertension, ARDS, and sepsis. Biomarkers used to assess RV dysfunction are primarily cardiac in origin, being released into circulation as a result of RV stretch and ischemia that are central in the pathophysiology of RV dysfunction. These biomarkers, namely troponin and brain natriuretic peptides, have several applications in RV dysfunction, most notably in acute PE, where they play an important role in risk stratification and assessment of prognosis.

Footnotes

None of the authors have any financial disclosures.

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