Integrated Cardiovascular Function

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1 23 Integrated Cardiovascular Function Leader Otto A. Smiseth, Professor, MD, PhD, (OUH/UiO) Deputy Leader Thor Edvardsen, Professor, MD, PhD, (OUH/UiO) Scientific staff Espen W. Remme, PhD, Senior Scientist (JEBSEN) Helge Skulstad, MD, PhD Senior Researcher (OUH) Kristina H. Haugaa, MD, PhD, Postdoctoral Fellow (SEN- RHA) Ola Gjesdal, MD, PhD (OUH) Morten Eriksen, MD, PhD, Senior Scientist (CCI) Thomas Helle-Valle, MD, PhD-student (NCCD) Trond Vartdal, MD, (UIO) Anders Opdahl, MD, PhD-student (OUH) Marit Kristine Smedsrud, MD, PhD-student (NRC) Kristoffer Russell, MD, PhD (OUH) Sebastian Imre Sarvari, MD, PhD-student (FP 7, EU) Espen Bøe, MD, PhD-student (NCCD) Nina Eide Hasselberg, MD, PhD-student (CCI) Jørg Saberniak, MD, PhD-student (CCI/OUH) Petter Storsten, MD, PhD-student (OUH) Aurora Pamplona, Operating Theatre Nurse (OUH) General objectives The Integrated Cardiovascular Function Group studies cardiac mechanics in experimental studies and studies in patients. The idea is to develop better diagnostic understanding and solutions into clinical practice. The group includes the Center for Cardiological Innovation (CCI) which focuses on improving diagnostic methods for patients with heart failure and patients at risk of sudden cardiac death. The group is also participating in the KG Jebsen Cardiac Research Center which focuses mainly on left ventricular dyssynchrony and diastolic heart failure. Specific objectives 1.To investigate mechanisms of left ventricular (LV) dyssynchrony and develop better methods for selecting patients for cardiac resynchronization therapy (CRT). 2.To investigate hemodynamic effects of CRT in patients with heart failure and narrow QRS. 3.To investigate mechanisms of LV diastolic dysfunction. 4.To develop better diagnostic methods to identify viable myocardium. 5.To investigate LV electro-mechanical interactions and 6.To investigate LV function in patients after heart transplantation in order to predict prognosis. Professor Otto A. Smiseth 1. Left ventricular dyssynchrony: A large number of heart failure patients suffer from dyssynchronous electrical activation of the heart muscle. Implantation of a pacemaker is land 2005). In principle it works by sending electrical activation pulses to electrodes placed in the muscle and by stimulating these simultaneously to restore synchronous contraction of the muscle around the ventricles. This is referred to as Cardiac Resynchronization Therapy (CRT). However, in about 30% of patients who receive CRT, there is no improvement in symptoms or worsening (Jarcho, 2006). The high number of non-responders represents a major problem with CRT, and better criteria for selection of candidates for this treatment are therefore needed. Our group works with ultrasound methods to better diagnose the patients. In 2012 we published a novel method that non-invasively estimates the regional work performed by the heart muscle. Each region of the muscle around the ventricle will normally contract through systole when pressure rises and blood is ejected out to the body and subsequently stretches when pressure drops and the ventricle x-axis and the left ventricular pressure (LVP) on the y-axis over one cardiac cycle, an index of the regional work can be observed as the loop area of this pressure-strain loop (Figure 1). Strain can be measured non-invasively by ultrasound, while pressure had to be measured invasively by inserting a pressure-catheter into the ventricle. In our study we developed a method for non-invasive estimation of the pressure-waveform by constructing a standard pressurewaveform which was adjusted to the individual patient by scaling it with cuff pressure measurement and timing of valve events from ultrasound imaging. By combining strain measured by ultrasound and the non-invasive estimate of pressure, we were able to give a non-invasive estimate

2 24 Figure 1. Pressure-strain loops indicating regional myocardial work in different segments of the left ventricular wall. Panel A shows 2 segments during normal condition on the left (Baseline) and during left bundle branch block (LBBB), i.e. electrical activation delay of the lateral segment, on the right. Panel B shows 2 segments before and after the anterior segment becomes ischemic. The narrow loop in the septal segment during LBBB and anterior segment during ischemia is easily seen and a good indication of dysfunction. The dashed loop which is from our non-invasive method corresponds well with the solid loop which is the invasive reference method. (From Russell 2012). of regional work. The results were validated and showed very good agreement with invasive measurements and glucose metabolism measured by PET-imaging (Figure 2). The study was primarily a development and validation of a new method, but the preliminary measurements in patients showed distinct differences in different situations and it may provide valuable clinical information about rently performing clinical trials with this new method. The paper was published in the European Heart Journal (Russell 2012). 2. Narrow QRS: While CRT is designed to correct electrical dyssynchrony, it has also been reported that some patients get better with CRT despite having no indication of electrical dyssynchrony (i.e. the duration of the ventricular activation wave, QRS of the ECG signal is narrow). As more than two thirds of heart failure patients do not have electrical conduction disturbances, extending the indications for CRT into this patient group is going to have considerate implications. The mechanisms of possible effects of this treatment in heart failure patients with narrow QRS have not been studied properly. Two possible mechanisms have been suggested: CRT may correct electrical dyssynchrony not seen on ECG, or CRT induces changes the interventricular interaction. The change in ventricular interaction can be obtained by pacing in the left ventricular lateral wall. The left ventricle (LV) is then activated earlier than the right ventricle (RV), and the LV will both duces the LV external constraint. External constraint is determined by the RV pressure and the pericardial pres- The hemodynamical result of reduced external constraint experimental dog model is used to explore these electromechanical and hemodynamic consequences of CRT. The study is ongoing, but some preliminary results have already been presented at international congresses. 3. Diastolic dysfunction: About half the patients with heart as the ejection fraction is normal. Main challenges are therefore to understand what causes diastolic dysfunction and how it can be diagnosed. During systole the LV wall twists as it contracts and ejects blood, then it sub- untwisting has been proposed as a marker of how fast a parameter to evaluate diastolic function. Furthermore, untwisting rate may be easily measured noninvasively by ultrasound, making it a potential attractive diagnostic parameter. However, we investigated if other variables untwisting rate. We found that a higher degree of contraction and twist during systole caused increased rate of untwisting during diastole, similar to a spring which lengthens faster the more it has been compressed. Furthermore, creased untwisting rate, which may be interpreted as the higher pressure acts as a stronger force that expands and untwists the ventricle at a faster rate. Thus, untwisting rate depends on load and systolic function as well as relaxation rate. Hence, the results suggest that untwisting rate is not a pure measure of diastolic function, which has implications for its diagnostic use (Opdahl A). 4. Coronary artery occlusion: Myocardial ischemia and infarct result from occlusion of the coronary arteries that supply the myocardium with blood. The part of the myocardium that is affected by lack of blood supply may be rescued by reperfusion therapy if it is still viable (i.e. the dium and necrotic myocardium is therefore important. By ultrasound imaging the shortening and lengthening of the different parts of the myocardium during the heart cycle can be measured. In two different studies analyses of this deformation have revealed characteristic strain patterns for ischemic myocardium. Ischemic myocardium tends to lengthen when pressure increase at the beginning of

3 25 Figure 2. (A) Bull s eye plot showing relative glucose metabolism by fluorodeoxyglucose positron emission tomography (FDG-PET) in a representative patient with left bundle branch block. The point in the left ventricular myocardium with the highest FDG uptake was used as a reference (100%), and segmental values were reported as percentages of this value. (B) Bull s eye plot with similar anatomical distribution as in (A), showing relative loop area by estimated left ventricular pressure and speckle-tracking echocardiography. The segment with the largest loop area was used as a reference the cycle and starts shortening sometime during ejection when pressure rise decreases. The duration of the lengthening phase correlated well with the amount of ischemic myocardium, which may be an important parameter to apy. The studies have been published in Journal of the American College of Cardiology. (Smedsrud 2012) and in Journal of the American Society of Echocardiography (Vartdal 2012). (100%), and segmental values were reported as percentages of this value. (C) Correlation between regional metabolism by FDG-PET and loop area by estimated left ventricular pressure and speckletracking echocardiography. (D) Representative pictures showing regional distribution of glucose metabolism by FDG-PET for short-axis (left panel) and fourchamber (right panel) views. (E) Estimated left ventricular pressure and speckle-tracking echocardiography loops from the septum and lateral wall. (Russell 2012). 5. LV electro-mechanical interactions: Evaluating patients with susceptibility for cardiac arrhythmias and sudden cardiac death is a major challenge in daily cardiology practice. Electrophysiological studies have demonstrated that damaged myocardium (e.g. infarcted or genetically altered) provides the substrate for malignant arrhythmias. Echocardiographic techniques can accurately quantify regional myocardial function. Over the last few years we have studied the interactions between myocardial mechanical function and risk for ventricular arrhythmias and demonstrated that mechanical dispersion can predict ventricular arrhythmias in patients with long QT syndrome

4 26 and in patients after myocardial infarction. The novel measurement principle has been tested on other patient populations to investigate if it provides clinical diagnostic value, including patients with ischemic dilated cardiomyopathy, mutations in the Lamin A/C gene or arrhythmogenic right ventricular cardiomyopathy. These studies have resulted in new publications and awarded posters on international congresses; see the Center for Cardiological Innovation section of this annual report for further details. Western world. Heart transplantation (HTx) remains the gold standard therapy for selected patients with endstage heart failure, with 1-year survival approaching 90%. Graft (the transplated heart) dysfunction is a major cause of morbidity and mortality in HTx recipients. The search for non-invasive techniques to assess cardiac allograft function remains a high priority objective for HTx professionals. Two-dimensional speckle-tracking echocardiography (2D-STE) is a semi-automated quantitative technique for assessment of cardiac function based on gray-scale images. Strain echocardiography has been introduced as an accurate tool for assessment of regional and global myocardial function and has demonstrated to be more sensitive and accurate compared to conventional echocardiographic measures of systolic function such as fractional shortening and LVEF, especially in early stages of myocardial disease. Collaborators Baltimore, Maryland, USA The Netherlands Vascular Center, Houston, Texas Belgium. Research group: Molecular Cardiology Medical Research Sørlandet hospital, Arendal. We assessed LV global longitudinal strain (i.e shortening of LV in long-axis direction during ejection) in all HTx recipients in the period We found that reduced LV global longitudinal strain early after heart transplantation was related to increased 1-year mortality. Thus, it seems that early assessment of strain provides important prognostic information which may have clinical and therapeutic implications in HTx recipients. Strain echocardiography has the potential to be a useful non-invasive screening tool, in addition to invasive right heart catheterization and endomyocardial biopsy, to identify HTx recipients with a high risk of poor clinical outcome. The study was published in Journal of American Society of Echocariography (Sarvari 2012). In June 2012 professor Otto A. Smiseth was appointed as Honorary Fellow of American Society of Echocardography (F.A.S.E.)

5 27 Center for Cardiological Innovation Center Leader and Management Thor Edvardsen, Professor, MD, PhD. Center Leader (Oslo University Hospital/University of Oslo) Eigil Samset, PhD, Center Coordinator (GE Vingmed Ultrasound AS) Marianne Weberg, MSc, Administrative Coordinator (Oslo University Hospital) Samuel Wall, PhD, Deputy Director for Scientific Computing (Simula Research Laboratory) Scientific Staff, Oslo University Hospital Arne Kristian Andreassen, MD, PhD, Consultant Cardiologist Christian Eek, MD, PhD, Consultant cardiologist Einar Gude, MD, PhD, Department of cardiology Erik Kongsgård, MD, PhD, Head Section of Electrophysiology Erlend Aune, MD, PhD Espen Wattenberg Remme, PhD, Senior Researcher Hans Henrik Odland, MD, Consultant Cardiologist Helge Skulstad, MD, PhD, Consultant Cardiologist Jan Otto Beitnes, Acting Consultant Cardiologist Kristina Hermann Haugaa, MD, PhD, Post doctoral fellow Lars Aaberge, MD, PhD, Head Section of Treatment and Diagnostics Morten Eriksen, MD, PhD, Senior Researcher Ole-Gunnar Anfinsen, MD, PhD, Consultant Cardiologist Otto Smiseth, Prof, MD, PhD, Head, Div of Cardiovasc and Pulm Diseases Svend Aakhus, MD, PhD, Head Section of Echocardiography Thorbjørn Holm, Consultant Cardiologist Willian E. Louch, Permanent Scientific Staff Margareth Ribe, Research Nurse PhD- Students Jan Vecera, MD, PhD-student Jørg Saberniak, MD, PhD-student Nina Eide Hasselberg, MD, PhD-student Sebastian Imre Sarvari, MD, PhD-student Wasim Zahid, MD, PhD-student Thomas Muri Stokke, MD Student, UiO Introduction The Center for Cardiological Innovation (CCI) was formally established 31st October It is one out of seven new centers that was awarded status as a Centre for Research- Based Innovation (SFI) through the Research Council of Norway SFI program. The CCI has a total budget of roughly 210 MNOK, in which 80 MNOK is to be allocated via the Research Council of Norway. The CCI is hosted by Oslo University Hospital and is a collaborative effort between Oslo University Hospital, Simula Research Laboratory, the University of Oslo, and the industry partners GE Vingmed Professor Thor Edvardsen Ultrasound, CardioSolv and Kalkulo. In December 2012, Medtronic Bakken Research Center B.V. joined the CCI as a research partner. Medtronic is a leading international medical technology company and brings world class expertise in therapy and disease management to the consortium. Each research partner represents a unique and required element in the research and development chain leading to the industrial innovations targeted by the CCI. Aim The aim of the Center for Cardiological Innovation (CCI) is to develop the next generation of ultrasound systems for cardiology. The proposed tools and technologies will be created through linking currently isolated diagnostic systems with advanced biomedical research, advanced patient-specific computer simulation, and multi-modality visualization techniques. The targeted clinical uses of the proposed innovations are for better triage and treatment of patients at risk of sudden cardiac death or suffering from heart failure, two of the biggest challenges in cardiology today. LV electro-mechanical interactions Evaluating patients with susceptibility for cardiac arrhythmias and sudden cardiac death is a major challenge in daily cardiology practice. Electrophysiological studies have demonstrated that damaged myocardium (e.g. infarcted or genetically altered) provides the substrate for malignant arrhythmias. Echocardiographic techniques can accurately quantify regional myocardial function. We have studied the interactions between myocardial mechanical function and risk for ventricular arrhythmias and demonstrated that mechanical dispersion can predict ventricular arrhythmias in patients with long QT syndrome and in patients after myocardial infarction. In a new study we showed that mechanical dispersion was a predictor of ventricular arrhythmias in patients with non ischemic dilated cardiomyopathy (Haugaa KH et al JASE 2012) (Figure 1).

6 28 Figure 1. Strain curves in patients with nonischemic DCM with (left) and without (right) arrhythmic events during follow-up. White arrows indicate peak negative strain. Time interval from peak R on electrocardiography to peak negative strain is shown for the apical segments (green and pink curves) in the patient with ventricular tachycardia (VT) during follow-up. Mechanical dispersion was defined as the standard deviation of time to peak negative strain in a 16-segment model of the left ventricle, reflecting contraction inhomogeneity. The red arrow indicates the initial stretch of a segment. The patient with VT (left) shows a more dispersed contraction pattern compared with the patient without VT. Global longitudinal strain and LVEF are reduced in both patients. (From Haugaa KH et al, JASE 2012) Ejection fraction (EF) 35% serves as an inclusion criterion for implantable cardioverter defibrillator (ICD) and, in patients with wide QRS, for additional cardiac resynchronization therapy (CRT). However, EF has limited abilities to predict arrhythmic events and further risk stratification tools are needed. Global myocardial strain is an emerging parameter which detects subtle and regional myocardial dysfunction. The group has explored the ability of global strain to predict ventricular arrhythmias in patients with several cardiac diseases and showed that global longitudinal strain may be superior to EF in predicting arrhythmic events. This was published in JASE 2012 (Haugaa KH et al). Ongoing studies explore the relationship of new echocardiographic markers of myocardial function and patients physical exercise capacity and in patients with CRT. A particularly malignant variant of dilated cardiomyopathy is caused by mutations in the Lamin A/C gene. These patients typically have concomitant AV conduction delay, atrial fibrillation, malignant ventricular arrhythmias and dilated cardiomyopathy and prognosis is worse compared to dilated cardiomyopathy of other etiology. The electrical alterations often precede the structural remodeling, and sudden cardiac death may occur in patients with apparently normal structural hearts which makes risk stratification for sudden cardiac death even more challenging. Mechanisms of the specific features of the Lamin A/C phenotype are not fully known. In an ongoing study performed in collaboration with Rigshospitalet, Copenhagen, Denmark, we explore the relationship between myocardial electrical, mechanical and structural properties in patients with Lamin A/C mutations. Preliminary results are presented at several international conferences. The study won the prize as the best abstract presentation at the annual conference of the center for heart failure research in Sudden cardiac catastrophes continue to occur in highly trained athletes, usually in the absence of prior symptoms, and they have a considerable emotional and social impact on the community. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is one of the leading causes of sudden cardiac death in young, highly trained athletes. ARVC is an inherited cardiomyopathy caused by mutations in the desmosomal proteins leading to a progressive RV and LV

7 29 dysfunction along with malignant ventricular arrhythmias. Animal models have shown a relationship between high physical activity and progression of ARVC disease. Human studies are lacking. We participate in the prospective Nordic ARVC registry together with multiple centers from Denmark and Sweden. We are conducting a study in collaboration with Denmark and Sweden, including > 100 individuals with ARVC with the aim to explore the impact of physical activity on the progression of ARVC disease. The study was funded by Helse Sør Øst as a 3 years Ph.D student project. Preliminary results were presented at the European Heart conference in 2012 and won the prize of Outstanding Abstract. Media outreach Employees at CCI have appeared several times in the media throughout CCI s center leader has commented on current issues, especially concerning genetic heart disease and sudden cardiac death. New echo-cardiographic method for calculation of cardiac workload Researchers working at Integrated Cardiovascular Function and Prof Otto Smiseth have developed a new ultrasound method for assessing regional and global work of the heart in close collaboration with CCI. To quantify the heart s left ventricular function is an important part of the assessment of patients with heart disease. In recent years, new ultrasound methods have been introduced to quantify global and regional ventricular function. Speckle tracing echocardiography (STE) provides information on regional and global contractions as a percentage of resting time. The problem of indexes based on myocardial shortening is that they do not reflect myocardial work and oxygen demand. This is because these measurements only reveal information about the degree of shortening, but not the resistance the myocardium must shorten against. Experimental studies have shown that by combining information from the left ventricular pressure and regional deformation can construct loops and that the area of these loops provides information that reflects regional workload and oxygen demand. It is not possible to measure the invasive pressure in the left ventricle of all patients. Kristoffer Russell. Interview with CCI s center leader, Professor Thor Edvardsen on the morning news at NRK (Norwegian state television) The aim of the study published in 2012 with Kristoffer Russell as first author was to introduce a non-invasive method for calculating the heart s workload. The present study showed that regional efforts can be determined noninvasively using ultrasound STE and an estimated left ventricular pressure curve. The findings were validated in an experimental animal model and in patients with invasive left ventricular measurements. Furthermore, the new non-invasive method reflected regional glucose uptake of the heart using positron emission tomography (PET), which strengthens the conclusion that the method reflects regional work. To assess regional differences are especially important for patients with pathological changes that are not affecting the ventricle equally, such as ischemia and electrical dyssynchrony as with left bundle branch block. Thus, this new method has great potential for better quantification for this large patient group. The research partners at CCI are currently working to further development of the method. Research Ultrasound Sandbox The software embedded in the GEVU scanner and workstation is subject to strict QA procedures for development, testing and release. In order to allow researchers within the CCI to develop and test methods without the restrictions of corporate procedures, the design of research software for sandboxing of new methods has been initiated. This software will communicate closely with the EchoPAC workstation

8 30 or GEVU scanner, to avoid duplication of functionality already present in the product. The sandbox has been designed in such a way that it will be possible to port functionality from the sandbox to the commercial product line. An initial version of this research ultrasound sandbox has been made during 2012 including the principles of mechanical dispersion and cardiac workload. 3D TEE probe Ultrasound imaging of the heart is limited by the narrow imaging windows between the ribs, as ultrasound cannot penetrate bone. However, more up-close imaging can be achieved by using a trans esophageal echocardiogram (TEE) probe. Such a probe is inserted down the esophagus while the patient is lightly sedated or intubated. It can give a non-obstructed, high-resolution view of the heart. 2D TEE has been available for a long time, but to make a 3D TEE probe (with many hundreds more transducer elements) is an engineering challenge. 3D imaging can acquire volumes in real-time, which can be rendered semi-transparently in 3D, or as multiple 2D slices. GEVU released such a probe in Scientific staff from collaborating partners Simula Research Laboratory Simula Research Laboratory Christian H. Tarrou, PhD, Director, Kalkulo Ultrasound AS Simula Research Laboratory AS Research Laboratory Laboratory University of Oslo University of Oslo search and Innovation Simula Research Laboratory Kalkulo tal Medical Research, University of Oslo Ultrasound AS Laboratory med Ultrasound Ulstrasound AS Oslo Collaborators more, Maryland, USA Netherlands Bel gium. Molecular Cardiology tal, Arendal. hagen, Denmark Sweden