Personalising Management of Cardiac Surgery Patients Through Right Heart Biomarkers

Louise Y Sun, Division of Cardiac Anesthesiology, University of Ottawa Heart Institute

The field of biomarker discovery has advanced rapidly over past decades. Many cardiovascular biomarkers are available to assist in the management of ischemia and left heart failure. However, perioperative Right Heart (RH) failure remains an underexplored area. We propose ST-2, sST-2 and Gal-3 as potential RH-specific markers to provide rapid, non-invasive insight for personalized, etiology-specific therapy, to be validated in the perioperative setting.

Biomarkers were first introduced to clinical practice in the 1980s and have since become a staple of diagnosis and prognosis in many areas of medicine. A variety of biomarkers have been implicated in clinical care and research in the cardiovascular realm. These are used mostly in the diagnosis and evaluation of left heart failure and pulmonary hypertension, with little attention paid to the diagnosis and response to treatment for Right Heart Failure (RHF). The right heart is often overlooked in medical practice, and RHF has especially been poorly understood in the dynamic perioperative setting, where the stakes are higher. We in this article will summarize the importance of the perioperative RHF and introduce new, non-invasive adjuncts for RHF diagnosis and prognosis in this setting.

Why is RHF important?

Medicine and medical research have traditionally focused on diseases of the left heart, where much advance has been made over the past few decades. Progress on RHF has lagged behind that of the left heart, and there are relatively few options for the treatment of RHF. RHF is especially relevant to clinical management and patient outcomes in the perioperative setting. In the setting of cardiac surgery, it contributes highly to end organ complications such as stroke, acute kidney failure and death. It is also implicated in poor later survival after cardiac surgery. RHF is especially deadly when occurring in combination with left heart failure. It is much more common in the context of cardiac as compared to non-cardiac surgery, and is most frequent after heart transplantation and implantation of Left Ventricular Assist Devices (LVAD).The prediction and diagnosis of RHF are difficult, and treatment is often challenging in the perioperative setting.

Practical challenges

In a broad sense, RHF is defined as the inability of the right heart to support the circulation when preload is optimal. The most common cause of RHF is left heart failure. In patients undergoing cardiac surgery, other potential causes for RHF could be classified according to that arising from increased after load, increased circulating volume, as well as intrinsic failure of the right heart myocardium.

RHF in the perioperative setting is complex and heterogeneous in nature. Clinicians still have trouble in coming up with a universal perioperative definition of RHF in non-LVAD patients in the modern era, although criteria such as haemodynamic instability, reduction in right heart contractile function by Transesophageal Echocardiogram (TEE) and direct visual inspection have been proposed. To complicate things further, there is no consistent and reproducible method for measuring right heart function in the perioperative setting. This is in part due to dynamic fluctuations in preload, the presence of mechanical ventilation, as well as changes in intrathoracic pressure during different stages of cardiac surgery.

The so-called gold standard for right heart function assessment are cardiac Magnetic Resonance Imaging (MRI) and right heart catheterisation. MRI is non-invasive but costly, and is limited by long scanning sessions and incompatibility in patients with pacemakers and other metallic implants and devices. Pulmonary artery catheters are invasive procedures, are associated with complications and are impractical in the context of certain congenital or acquired cardiac structural abnormalities.

Several modalities have been implicated in the assessment of right heart function in the perioperative setting. Pulmonary artery pressure and cardiac index used to be a routine part of intraoperative monitoring for cardiac surgery. However, these measures could be confounded by the presence of left ventricular systolic or diastolic dysfunction, raised intrathoracic pressure in mechanically ventilated patients, pre-existing pulmonary hypertension and tricuspid regurgitation. Although a mainstay of perioperative monitoring, two-dimensional TEE is limited by the complex geometry of the right heart and is subject to inter- and intra-observer variability. Additionally, there is often a disconnect between how the right heart looks on TEE, and the actual degree of clinical deterioration.

Biomarkers as an innovative, noninvasive solution

There has been escalating interest in the utilisation of biomarkers to provide diagnosis and prognostication in patients with heart failure. Biomarkers provide information at the cellular and molecular level, and offer important mechanistic insight to help with personalised monitoring and management. As an overview, heart failure biomarkers are generally classified into four categories: 1) inflammation, 2) myocyte stress/ injury, 3) neurohormonal activation, and 4) extracellular matrix turnover.

The majority of publications on heart failure biomarkers have centred on the left heart, with many studies describing the role of natriuretic peptides in disease diagnosis and prognostication across a variety of clinical settings. Natriuretic peptides are now a routine part of clinical care in patients with or suspected of having heart failure. In contrast, studies of right heart biomarkers have mostly been exploratory in nature. For instance, unique microRNAs and protein metabolites, and some inflammatory and stress/injury biomarkers are thought to have prognostic significance for the right heart in non-operative settings. We in this paper will highlight suppressor of tumorgenicity 2/soluble ST2 (ST2/sST2) and Galectin 3 (Gal-3) as Food and Drug Administration (FDA)-approved biomarkers that could be further investigated as specific measures of right heart function. These biomarkers may also help to predict the onset of clinically significant RHF, and offer prognostic insight in the perioperative setting.

ST2 and sST2 are inflammatory cytokinesfrom the interleukin -1 family, that is released in the presence of tissue injury. These biomarkers have been evaluated both in the context of left and right heart failure in non-operative settings. In the general context, high serum levels of sST2 are moderately predictive of one-year mortality in patients presenting with acute decompensated heart failure. These biomarkers also correlate with many aspects of right heart size and function, preload (i.e., venous congestion) and after load (i.e., pulmonary hypertension) in patients with isolated right-sided heart disease. In practice, sST2 is unaffected by age, sex, body habitus, rhythm, kidney function, and interferences by contaminants. It is therefore more specific than natriuretic peptides in providing right heart-specific information in the complex cardiac surgical population.

Gal-3 is a macrophage product of the lectins family, which has been implicated in contractile regulation of the heart as well as inflammation and injury. It was incidentally found in a general heart failure study to be a better predictor of mortality and hospitalisation in patients with preserved left heart function. It also correlates well with many aspects of right heart size and function in patients with isolated pulmonary hypertension without left heart impairment. In the LVAD population, Gal-3 was associated with major sequelae of RHF.

Practical considerations

The advent of point of care ST2, sST2 and Gal-3 assays bring these biomarkers closer to the bedside. Indeed, biomarkers offer rapid, non-invasive molecular level insight that may be used to inform prompt personalized therapy. This is especially valuable in the high-acuity perioperative cardiac surgery setting, where changes are dynamic and rapid. Biomarkers could also be measured in a sequential manner, to assess disease progression and monitor response to treatment. We advocate for discovery and investigation of biomarkers as non-invasive adjuncts to overcome the limitations of existing diagnostic modalities for RHF, to help to piece together a comprehensive snapshot of right heart structure, function, and loading conditions. It should also be noted that multiple biomarkers could be profiled together to provide a more comprehensive picture at the molecular level. Before widespread clinical use, biomarkers would need to be validated in different clinical care jurisdictions, and meaningful cut-off values would need to be derived through large studies in representative populations with isolated RHF.

References:

Jabagi H, Ruel M, Sun LY. (2019). Can Biomarkers Provide Right Ventricular- Specific Prognostication after Cardiac Surgery? Journal of Cardiac Failure. S1071-9164(19): 30516.

Jagabi H, Mielniczuk LM, Liu PP, Ruel M, Sun LY. (2019). Role of Biomarkers in the Diagnosis, Management, and Prognostication of Perioperative Right Ventricular Failure after Cardiac Surgery. J Clin Med, 8(4), 559

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Author Bio

Louise Y Sun

Louise Sun is an Associate Professor of Anesthesiology and Epidemiology and Director of Big Data and Health Bioinformatics Research at the University of Ottawa Heart Institute, Canada. Her team applies machine learning, advanced statistical methodology and modern technology in the field of cardiovascular epidemiology and biomarker discovery, integrating perspectives from population and precision health and patient engagement.

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