16 minute read
Personalising Management of Cardiac Surgery Patients
Personalising Management of Cardiac Surgery Patients Through Right Heart Biomarkers
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.
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Louise Y Sun, Division of Cardiac Anesthesiology, University of Ottawa Heart Institute
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
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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
AUTHOR BIO 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 VentricularSpecific 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
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.
What’s behind the success of Guerbet?
An exclusive interview with Mathieu Elie, Chief Commercial Officer, Asia Pacific, Member of Guerbet's Executive Committee.
Can you share with us the history of Guerbet and your vision for Asia-Pacific?
Guerbet is known as a leader in medical imaging worldwide, offering a broad range of pharmaceutical products, medical devices, digital and AI solutions for diagnostic and interventional imaging, that improve the diagnosis and treatment of patients. Our headquarters are in Villepinte near Paris, and the company was established there by André Guerbet in 1926, to expand production and distribution of the first iodinated contrast medium discovered by his father Marcel Guerbet in 1901.
At Guerbet, we build lasting relationships, to enable people to live better. This is our Purpose and it is the driving force for our actions and a source of inspiration for all our new initiatives and innovations. It is a shared energy which supports the sustainable growth of our company. MATHIEU joined Guerbet in 2007 as Financial and Administrative Director of Guerbet in Korea, then took over as the Head of Business Operations in Korea, Asia-Pacific and Latin America before becoming Vice President of the APAC region in 2015. He was appointed as the Chief Commercial Officer for APAC in September 2020.
Today, we are a global company specialising in medical imaging solutions and want to be recognised as the best partner for diagnostic and interventional imaging.
Guerbet has a broad range of products, a long history of innovation and a strong reputation, especially in Europe and the US after the acquisition of the imaging business of Mallinckrodt in 2015. Our core products have been established over many decades.
Asia-Pacific now significantly contributes to Guerbet global business. Having first established a strong base in Korea in 1998 followed by Japan, we have been growing our reach in Asia-Pacific, opening offices in many countries and key markets. We opened in India last year to be in close proximity to the doctors there, which is an important part of our strategy. We have also been significantly reinforcing our presence in China.
The Asia-Pacific region is an important clinical development platform for Guerbet. We run numerous clinical trials here and have realised advantages in terms of quality and speed.
Having started small with only five people in 1998, we decided to invest in Asia-Pacific and now have over 200 employees in nine countries. We continue to invest in our people with development programs to help them grow together with the company.
With such a long and rich history, what are your thoughts on innovation?
Patient safety is our first priority. At Guerbet, we care for all patients at every touch point of their journey to recovery.
We are keen to keep investing in and exploring new techniques and methods to deliver state-of-the art technology. Originally, our focus was on diagnostics, but we have expanded into interventional radiology to support increased use of minimally invasive guided procedures, and digital/AI solutions that improve operational efficiency and diagnostic confidence. Our objective is to bring value ‘now and in the future’ for our stakeholders.
Indeed, we have invested significantly in interventional radiology, based on our strong foundation product ‘Lipiodol’, and we are building a full range of interventional radiology products that are best-in-class across many product lines.
In diagnostic imaging, we strongly believe in integrated delivery solutions combining contrast medium, injectors, consumables, software and services. Advanced data analytics allows us to improve the workflow in the radiology centre by reducing the reporting and compliance burden via automation while providing meaningful insights. This common ecosystem of interconnected products allows noticeable productivity gains, we call this ecosystem “UNIK”.
In this data-driven era, we have decided to invest massively in Artificial Intelligence (AI) to accompany physicians in their clinical decisions: AI to help detect, characterise and stage lesions on imaging findings, and eventually AI to help quantify risk. We believe in proven and reliable outcomes, and we spend a lot of time and effort to clinically validate our algorithms.
Guerbet also focuses on delivering a range of best-in-class education programmes, which are shifting from physical to online models with webinars, videos and social media.
We play an important role in linking medical communities with exchange programmes between countries in Asia-Pacific and France that provide a catalyst for knowledge transfer, sharing of best clinical practices, network cultivation and relationship among the healthcare community.
What are the healthcare needs that Guerbet addresses?
We see many healthcare challenges. Diagnostics have become central to many medical decisions, including biopsy, pathology, in vitro and in vivo
A world leader in medical imaging, Guerbet is a publicly traded company on the Paris Stock Exchange, headquartered in France with offices and production facilities in Europe, the Americas and Asia-Pacific. It has a longstanding reputation as a pioneer in the research and development of contrast media for radiology. In 2015, Guerbet doubled in size with the acquisition of Mallinckrodt’s contrast media and delivery systems’ business unit. It also expanded its portfolio in the interventional imaging business with the acquisition of Accurate Medical Therapeutics in 2018.
Today, Guerbet contributes to progress made in the diagnosis of major disease areas including cancer, cardiovascular, inflammatory and neurodegenerative diseases. The company’s novel and effective imaging solutions help to improve patient management throughout the world. Guerbet offers a comprehensive range of imaging products, solutions, and services for Diagnostic Imaging – MRI, X Ray, Digital Solutions / AI – and Interventional Imaging, to enhance clinical decisionmaking, from diagnosis to treatment and follow-up, and improve patients’ quality of life.
diagnostics. The right diagnostics at the right time are increasingly important in enabling clinicians to make data-driven decisions. The 2020s is the decade for data and at Guerbet we see ourselves moving from being a contrast medium provider to also becoming an informatics data provider in diagnostic imaging.
The global population will reach 10 billion by 2050 with roughly two billion people aged over 60. Half of us will be living in Asia-Pacific (APAC), giving the region a significant share of the ageing population. Given the advances in oncology treatment, there will be increased survival times for patients with chronic diseases and a greater need for imaging, which is likely to create immense pressure on healthcare.
This demand for imaging procedures is likely to skyrocket in the next decades not only because of demographics and better chronic disease survival time, but also because of the extensive use of imaging modalities in health check-ups. Adding a new MRI machine or a new CT scanner is not always possible or wanted in hospitals.
Enhancing the imaging workflow in the hospital is our answer to this challenge. We are uniquely positioned as the only player with a strong foundation in contrast, injection systems, advanced informatics and AI algorithms.
How did you overcome challenges as Chief Commercial Officer (APAC) under the COVID-19 situation?
COVID-19 has been a difficult time for everyone. We adapted really fast as a company because we knew early on that imaging diagnostics were important for COVID-19 patient management.
We knew we couldn’t fail; our first priority was ensuring our employees were safe and our factories were up and running to produce contrast, which is essential in the diagnosis of COVID-19. We also managed to source PPE kits for our employees worldwide and to produce thousands of litres of hydroalcoholic solutions in our factories that were given to the medical community.
We took extra precautions in our factories to ensure seamless operations and no factories have been closed because of COVID-19. This crisis demonstrated there is great solidarity and resilience within Guerbet, with staff actively committed to ensure continuity in production and distribution activities.
Many hospitals required support for diagnostic imaging, and we continued to deliver and install injectors in hospitals including in Wuhan, China, where Guerbet APAC delivered an OptiVantage Dual Head injector to a newly built hospital at the end of January 2020. To make sure diagnostic centres could still operate during COVID-19, we quickly trained field service technicians so that they could fix and service injectors in a safe manner. We created guidelines on the disinfection of injectors, to help technicians and nurses in hospitals prevent the spread of COVID-19.
Although we had to overcome disruption in logistics, we managed to sustain supply to our consumers and are proud that we were able to help in the battle against COVID-19 by meeting government demands for immediate shipment of injectors to allow thoracic imaging.
COVID-19 made us rethink how we share our expertise with the medical community. We created Guerbet APAC TV, Medical Imaging Institute, and are considering expanding the Guerbet APAC Preceptorship Program (GAPP) training centre. Throughout this period, we contributed to educating communities on how to tackle the pandemic.
What is your view on the use of AI for the future of medical imaging?
We are expanding very fast, with a focus on new markets and geographies, creating more educational programs and investing in research to develop new products, such as our new MRI contrast medium, which is at the last stage of its development.
Artificial Intelligence (AI) is transforming the imaging field. New data analytic methods can augment clinicians’ ability to interpret and act on large and complex data sets. As an innovator in medical imaging, Guerbet has identified AI partners with validated software technology to expand its portfolio of augmented intelligence solutions with the same aim of helping radiologists diagnose better and faster than ever before.
Today, we partner with icometrix for the exclusive distribution* of icobrain, an AI software that extracts clinically meaningful information from brain CTs or MRI scans of patients with multiple sclerosis, dementia or brain injury.
And in the US, we are starting to distribute IBM Watson Imaging Patient Synopsis**, a radiologist-trained AI tool that extracts patient information and summarises that data in a dashboard tailored to help clinicians make better decisions faster and more efficiently.
With IBM Watson Health we are developing two AI solutions to help clinicians diagnose and monitor patients with liver or prostate cancer.
The liver solution is a diagnostic support tool that will use AI to automate the detection, staging, tracking, monitoring, and eventually therapy prediction and therapy response of primary and secondary liver cancer for clinicians.
In the prostate program, we are developing a tool using AI with the goal of helping to detect, segment, characterise and monitor lesions over time. This AI approach may allow for faster and more informed diagnosis of prostate cancer.
AI is obviously a major trend and Guerbet is determined to be at the forefront of its application. It showcases our continued contribution to building the future of medical imaging, just as we have done since our foundation some 95 years ago.
* in Brazil, Italy and France ** in the United States
