Prognostic value of global longitudinal strain in patients with myocardial infarction and normal LVEF

Transkript

1 Prognostic value of global longitudinal strain in patients with myocardial infarction and normal LVEF Supervisor: Tomasz Baron

2 Contents Abbreviations... 2 Abstract... 4 Background... 4 Objectives... 4 Method and Results... 4 Conclusions... 4 Popular scientific summary in Swedish... 5 Introduction... 6 Myocardial infarction... 6 Cardiac remodeling... 7 Echocardiography... 8 Mitral annular plane systolic excursion-mapse... 9 Global longitudinal strain (GLS) Biochemical markers Purpose Method Statistical methods Study population Ethical permission Results Baseline patient characteristics Echocardiographic parameters Outcome Discussion Limitationes Conclusion Acknowledgement References

3 Abbreviations ACE-I ACS ARB AMI CABG CI ctn ctni ECG EF EPN Angiotensin converting enzyme inhibitors Acute coronary syndrome Angiotensin receptor blockers Acute myocardial infarction Coronary artery bypass grafting Confidence interval Cardiac troponin Cardiac troponin I Electrocardiogram Ejection fraction Etikprövningsnämnderna GDF-15 Growth differentiation factor 15 GLS HF HR IQR LBBB LV LVEDV LVEDVi LVEF LVESV LVESVi MAPSE MI NSTEMI NT-proBNP Global longitudinal strain Heart failure Hazard ratio Interquartile range Left bundle branch block Left ventricle Left ventricular end- diastolic volume Left ventricular end- diastolic volume index Left ventricle ejection fraction Left ventricular end- systolic function Left ventricular end- systolic function index Mitral annular plane systolic excursion Myocardial infraction Non-ST elevation myocardial infraction N-Terminal prohormone of Brain Natriuretic Peptide 2

4 PCI SD STE STEMI SWEDEHEART TGF-β TOTAL-AMI TTE URL WHO Percutaneous coronary intervention Standard deviation Speckle tracking echocardiography ST elevation myocardial infarction Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies Transforming growth factor beta Tailoring Of Treatment in All comers of Acute Myocardial Infarction Trans thoracic echocardiogram Upper reference limit World health organization 3

5 Abstract Background Around two thirds of patients hospitalized for myocardial infarction have a normal left ventricular ejection fraction (LVEF). Other markers of LV function such as global longitudinal strain (GLS) and mitral annular plane systolic excursion (MAPSE) have shown ability to detect early subclinical stages of left ventricular (LV) impairment. Emerging biochemical biomarkers such as galectin-3 and growth differentiation factor 15 (GDF-15) have reflected early phases of myocardial damage. Objectives The aim of this study was to evaluate the predictive value of newer and conventional echocardiographic parameters and biomarkers in relation to left ventricular ejection fraction. Method and Results This study prospectively included consecutive patients hospitalized for myocardial infarction and used SWEDEHEART-data for patent characteristics outcome and biomarker analysis. With echocardiography- LVEF, LV-volumes, MAPSE and GLS was obtained. 296 patients were included and divided into groups with normal and impaired LVEF We found that almost four fifths of patients had a normal LVEF and among them 86.6 % (n=200) had a pathological GLS. GLS was predictive for total mortality (p=0.013) and composite endpoint (p=0.024), while LVEF, MAPSE, and LV-volumes was not. Conclusions This study showed that LV deformation analysis and novel biomarkers provide additional prognostic information in patients with myocardial infarction and normal LVEF. 4

6 Popular scientific summary in Swedish Hjärtkärlsjukdom är den ledande orsaken till död i världen och hjärtinfarkt står för en stor del. För att diagnostisera hjärtinfarkt frågar man efter bröstsmärta hos patienten, letar efter förändringar på EKG och undersöker förekomst av skada på hjärtmuskulaturen i blodprover. För att få klarhet i hur mycket infarkten har påverkat hjärtfunktion används hjärtultraljud. Med hjälp av bildsekvenser från hjärtultraljud kan man uppskatta vänsterkammarens ejektionsfraktion (LVEF) som visar hur stor del av blodvolymen i vänster kammare som pumpas ut vid varje hjärtslag, som ett mått på hjärtats funktionsgrad. Skattning av LVEF är idag rutin vid många sjukhus hos patienter som genomgått en hjärtinfarkt. Tidigare studier har visat att kring två tredjedelar av patienterna som genomgår en hjärtinfarkt, efteråt har en normal LVEF. Den stora andel av patienter med normal LVEF efter hjärtinfarkt ger behov av en analysmetod för att upptäcka skada på hjärtmuskulaturen hos denna patientgrupp. Exempel på sådana är global longitudinal strain (GLS) som förenklat tittar på förändringen av hjärtmuskulaturens längd under en hjärtcykel och Mitral annular plane systolic excursion (MAPSE) som tittar på skiljeväggen mellan förmak och kammares rörlighet. Denna studie har till syfte att titta på fördelarna med dessa analysmetoder jämfört med LVEF och även jämföra med blodprover som mäter nivå av skada på hjärtmuskulaturen. Studien omfattade 296 patienter som delades in i grupperna normal och sänkt LVEF. Lite mindre än fyra femtedelar av patienterna hade en normal LVEF, vilket var fler än vad tidigare studier av likadana patientgrupper har visat. En stor del patienterna med normal LVEF hade sänkta GLS- och MAPSE värden, vilket är linje med tidigare studier och visar på bristande förmåga hos LVEF att upptäcka sänkt funktion av hjärtats muskulatur. Studien visade också att GLS hade förmåga att prediktera händelser som död och inläggning p.g.a. viss hjärtkärlsjukdom, en förmåga som LVEF saknade i denna studie 5

7 Introduction Myocardial infarction In 2015 an estimated 17.7 million people died from cardiovascular disease (CVD). This represented 31 % of all global deaths. An estimated 7.4 million were due to coronary heart disease and 6.7 million were due to stroke. CVD is the number one cause of death globally according to the World Health Organization (WHO) Cardiovascular diseases are preventable, and by addressing the major behavioral risk factors such as; tobacco use, unhealthy diet, obesity, physical inactivity and harmful use of alcohol, the incidence could drop. Some of the somatic risk factor for developing cardiovascular disease are hypertension, diabetes, hyperlipidemia, People with cardiovascular disease or who are at high cardiovascular risk highly benefit from early detection and management with counseling and medication (1). Myocardial infarction (MI) is defined as myocardial cell death due to prolonged ischemia. There is at least a 20 minute period between the onset of myocardial ischemia and histological cell death and it takes several hours before myocardial necrosis can be detected by either microscopic or macroscopic post mortem examination. The severity of the necrosis is depending on a number of factors; the presence of collateral circulation to the ischemic zone, persistent or intermittent coronary arterial occlusion, how sensitive the myocytes are to ischemia, preconditioning and individual demand for oxygen and nutrients. For the term MI to be used there should be evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Detection of rise and or fall in cardiac biomarkers values preferably cardiac troponin ctni, with at least one value above the 99 th percentile upper reference limit (URL) together with at least one of the following: 1. symptoms of ischemia, 2. new or presumed new significant ST-segment changes or new left bundle branch block (LBBB) on the electrocardiography (ECG), 3. development of pathological Q-waves, 4. imaging evidence of new loss of viable myocardium or new regional wall motion abnormality, 5. identification of an intracoronary thrombus by angiography or autopsy, meet the criteria for myocardial infarction diagnosis. Cardiac death with suggestive symptoms of myocardial ischemia, an MI caused by cardiac intervention or coronary revascularization together with an elevation of ctni values will also classify as myocardial infarction. 6

8 In clinical practice it is common to classify the myocardial infarction based on the ECG. Patients presenting with chest discomfort and ST-elevation on their ECG are subdivided as a ST elevation MI (STEMI), those without an ST-elevation is classified as a non-st elevation MI (NSTEMI). Patients presenting with chest discomfort often with ECG changes but without an elevation of ctni can be diagnosed with unstable angina. Classification can also be done on a pathophysiological bases, identifying different clinical MI types. The most common is spontaneous myocardial infarction, MI type 1. The ischemia is due to atherosclerotic plaque rupture, ulceration, fissuring, erosion or dissection. This causes an intraluminal thrombus in one or more of the coronary arteries, which leads to decreased myocardial blood flow and myocyte necrosis. Type 2 MI is a myocardial infarction secondary to an ischemic imbalance, in cases where a cause other than coronary artery disease per se roots the ischemic imbalance. Tachycardia, acute anemia, coronary vasospasm and/or endothelial dysfunction are examples of the most common triggering mechanisms. Type 3 MI includes patients who suffer cardiac death due to myocardial infarction combined with symptoms and ECG changes suggestive of ischemia, in whom cardiac biomarkers are not available. Finally, type 4 and 5 MI are associated with revascularization procedures (2). The necrosis following a myocardial infarction can cause complications early after the infarction, such as left ventricular free wall rupture, which leads to either tamponade or the formation of a pseudo aneurysm, papillary muscle rupture or ischemic ventricular septal defect. Sudden clinical deterioration of the post infarction patient, especially hypotension, shock or new heart murmur should draw attention to these types of complications (3). Arterial embolus to the brain and other organs is a well-recognized complication to MI and the necessity for intense anticoagulation therapy in the acute phase is established (4). Cardiac remodeling After infarction the myocardium is exposed to a series of structural changes known as post infarct remodeling (5). The process by which ventricular size, shape and function change is regulated by mechanical, neurohormonal and genetic factors (6). Remodeling is a part of the adaptive nature to normal growth as a response to e.g. exercise, but also might be a part of the pathological response to injury to the myocardium such as myocardial infarction, cardiomyopathy, hypertension, or valvular heart disease (5). 7

9 The infarct expands over the myocardium as a result of intermyocyte collagen degradation. Within hours of the infarction, wall thinning and ventricular dilation takes place, which elevates diastolic and systolic wall stress and a mechanical stretch. An increased wall stress is a powerful stimulus for hypertrophy and affects the ventricular performance. This comes usually with a fall in ejection fraction in direct relation with the size of infarction. However, the increase in ventricular volumes augments the stroke volume by the Frank-Starling law mechanism, which leaves the cardiac output preserved (6). Early post- infarct remodeling could be beneficial and promote survival, but has lethal long-term hemodynamic consequences, with myocyte hypertrophy and dilation, starting the journey of a failing heart. ACE-inhibitor therapy helps to attenuate the increase in apical wall stress and to reduce dilation of the left ventricle. This treatment acts in part by reducing the preload and thus the left ventricular operating volume. If left ventricular dilation is avoided, the pure hypertrophic response of surviving myocytes gives hemodynamic benefit (5). A consequence of infarction management in modern medicine is the increasing longevity of patients, but also an increasing number of patients with heart failure (7). Echocardiography Echocardiography is today the most widely used and powerful tool in the diagnostics, monitoring and management of patients with acute cardiovascular disease. It is shown to improve diagnostic accuracy and efficiency in the emergency room (8). Echocardiography is common procedure at many medical intuitions of patients with suspected acute myocardial infarction. It provides information about atrial and ventricular chamber volume and cardiac output. The ability to calculate left ventricular ejection fraction (LVEF) is a fundamental function with echocardiography. Transthoracic echocardiography (TTE) is generally the initial imaging modality used in the assessment of acute coronary conditions, it s most often available and most cardiologist are trained in using it (9). The typical patient with myocardial infarction is usually characterized by the presence of chest pain, changes in the ECG and characteristic change in cardiac enzymes. Many patients have atypical chest pain, an inconclusive ECG and normal early serum troponin levels. In these cases echocardiography plays an important role in differentiating between myocardial ischemia and other causes of chest pain such as aortic dissection and pulmonary embolism (8). The 8

10 echocardiography also plays an important role in patients with a verified acute myocardial infarction diagnosis to assess the presence and extent of regional endocardial wall motion abnormalities. It is difficult to distinguish between ongoing ischemia and infarction with echocardiographic imagery, but the absence of wall motion abnormalities excludes major myocardial ischemia (10). Echocardiography lacks the ability to rule out a transient episodes of ischemia, especially in patients with short duration of chest pain, deformation imagery of the left ventricle such as global longitudinal stain is, in these cases, a more powerful and useful technique. It is important to acknowledge that wall motion abnormality is not synonymous with ischemia and can also occur in other conditions, such as myocarditis and Takotsubo cardiomyopathy. Sudden clinical deterioration of the post infarction patient, especially hypotension, shock, or a new heart murmur, mandate immediate echocardiography (3). The primary use for echocardiography in the post care of patients with acute myocardial infarction (AMI) is to assess left ventricular (LV) function via measuring the LVEF. Ejection fraction (EF) is volumetric fraction of blood ejected from the heart with each contraction and is calculated by dividing the stroke volume (SV) with the end diastolic volume (EDV). End systolic- and end diastolic volume index (ESVi, EDVi) is calculated by dividing the ventricle volumes with the body surface area, thus relating them to height and weight and is a more precise measurement (8). Normal LVEF for men is > 52 % and >54 % for women (11). Ejection fraction (EF) = stroke volume (SV) /End diastolic volume (EDV) Stroke volume (SV) = End diastolic volume (EDV) End systolic volume (ESV) Mitral annular plane systolic excursion (MAPSE) MAPSE has been proposed as a clinically useful echocardiographic parameter for the assessment of left ventricular longitudinal function and correlates with global systolic function of the left ventricle (LV) (12). The measurements are carried out on echocardiographic imagery and assess the displacement of the atrioventricular plane in millimeters during the systolic phase (13). During the systolic phase, the heart s apex remains almost immobile and the longitudinal pump function is generated mainly by atrioventricular plane motion towards the apex (14). To get the most accurate estimation of the LV-function the measurement should be done in an apical view of the heart. Measurements are done from four sites in the atrioventricular plane corresponding to the septal, lateral, anterior and posterior walls using the apical four and two chamber 9

11 echocardiographic views (12). Since MAPSE represents the amount of displacement of the mitral annular plane towards the apex and thus assesses the change in LV cavity, a close association between MAPSE and ejection fraction has been proposed in various patient groups with normal and reduced LV-function (15 17). Based on previous studies, normal values for the four regions (septal, anterior, lateral and posterior) ranged between 12 mm and 15 mm and a MAPSE value <8 mm was associated with a depressed LVEF (<50%)(12). Cardiac pump function is the result of contraction of the longitudinal and circumferential fibers, angulated in different directions across the left ventricular wall in the heart (18). MAPSE is the result of contraction of the subendocardial and subepicardial longitudinal fibers and represents the total longitudinal shortening within one wall (12). LVEF is a result of all these components whereas MAPSE represents the longitudinal shortening within the cardiac wall. In various cardiac pathologies, longitudinal function is altered before LVEF is affected (19). Reduced MAPSE is mostly related to subendocardial ischemia or to fibrosis to some extent. In patients with poor image quality MAPSE is superior to LVEF and global longitudinal strain (GLS) to detecting early abnormalities (12). Global longitudinal strain (GLS) In echocardiography, the term strain is used to describe local shortening, thickening, and lengthening of the myocardium as a measure of left ventricular function, see figure 1. The term strain originates from the field of continuum mechanics and is used to describe a general 3D deformation of a small cube during a short time interval (20). By dividing the myocardium into large number of small cubes, the deformation can be described for each small cube at each time during the cardiac cycle (21). For the practical use of strain in echocardiography it is more convenient to use an coordinate system aligned with the three cardiac axels, longitudinal, circumferential and radial to measure the shortening and elongation in these three directions through the cardiac cycle, with reference to size, at the time of the QRS-complex (20). Strain is measured by the distance between the two material points in the myocardium, both following between in the motion during contraction and relaxation. GLS is most wildly used due to its lower variability and stronger prognostic impact, compared to both circumferential and radial strain and is defined in the following way. GLS(%) = (Myocardial length end systole Myocardial length end diastole) Myocardial length end diastole 10

12 Positive strain means elongation, whereas negative strain is shortening. The more negative the GLS value, the better LV-function (22). Figure 1. Schematic image of the endocardium showing how circumferential, radial and longitudinal strain are measured during diastole and systole. Picture from Vives- Gilabert et al 2017 The most common modality for strain evaluation is speckle-tracking echocardiography (STE). Speckle tracking utilizes the phenomena of natural occurring speckle patterns in ultrasound images of myocardial tissue. The advantage of STE is its ability to track independently of angle. To get an accurate measurement GLS measurement, echocardiographic images are made in a standard apical two, three, and four chamber view (20). Aortic valve closure (AVC) is used for timing of end systole. Normal GLS for most echocardiographic systems is reported between -18 and -25 % in healthy individuals, but the reported values differ (23). The longitudinal myocardial fibers are predominantly located in the subendocardium, which is the wall layer most susceptible to ischemia (20). A number of studies have shown that GLS is superior to LVEF as a measurement of LV function and as a predictor of mortality and cardiac events and GLS is a very promising method to identify patients with mild systolic dysfunction, which is not reflected in reduced LVEF (24 27). 11

13 Biochemical markers Troponin Troponin is a complex of three regulatory proteins (troponin C, troponin I, and troponin T), it is attached to the protein tropomyosin and lies within the groove between actin filaments in muscle tissue. In conjunction with infarction troponin is released into the blood stream. The troponin types I and T are both sensitive and specific indicators of damage to the myocardium (28). N-terminal prohormone of brain natriuretic peptide (NT-proBNP) The prohormone is used for screening and diagnosis of congestive heart failure (HF). Concentrations of NT-proBNP is usually increased in patients with left ventricular dysfunction, also in association with coronary artery disease and myocardial ischemia (29). Galectin-3 Galectin-3 is a pro inflammatory and pro fibrotic protein, which plays a role in the activation of immune mediators and causing activation of fibroblasts. It has been demonstrated to be associated with fibrosis in cardiac tissue and plays a role in cardiac remodeling (30). Studies have shown galectin 3 to be elevated in patients immediately following a STEMI. Galectin-3 is known to be involved in the pathogenesis and pathological process of atherosclerosis and its pro-inflammatory role in cardiac disease involves formation of fibrosis. Experiments found that plasma concentrations were significantly related to the degree of severity of myocardial ischemia. The same study found elevated levels of galectin-3 in plasma in direct negative correlation with the ejection fraction (31). Growth differentiation factor 15 GDF-15 is a distant member of the transforming growth factor-β (TGF-β) cytokine super family. (32). Under normal conditions it is weakly expressed in most tissues by endothelial cells and macrophages. After tissue injury, inflammation, mechanical and oxidative stress, GDF-15 is strongly expressed in these same tissues. Hours after myocardial infarction, GDF-15 levels increase in the heart tissue and stays elevated in the affected myocardium for several days. GDF- 15 role as a valid risk biomarker for CVD is yet not established. A study looking at serum levels of GDF-15 in patients with suspected AMI showed baseline GDF-15 to be significantly higher in patients with AMI, compared to patients with unstable angina pectoris and non-coronary chest pain. Elevated levels of GDF-15 was also an independent predictor of future cardiovascular events in patients presenting with suspected MI (33). On the other hand, Du et. al 2018 showed that GDF- 12

14 15 predominantly reflect stress in other tissues and not specific for cardiac remodeling, which are the changes the myocardium undergoes post myocardial infarction (34). 13

15 Purpose The purpose of this study was to evaluate ability of newer and conventional echocardiographic measures of left ventricular function to predict outcome such as total mortality, composite and readmission for heart failure in relation to selected biomarkers such as troponin I, NT-proBNP, GDF-15 and Galectin-3, in the post myocardial infarction patients with preserved ejection fraction. The main null hypotheses of this study were that the newer echocardiographic parameters (deformation analysis) have no additive value as compared with LVEF to predict outcome in patients with myocardial infarction and preserved LVEF and predictive value of newer echocardiographic parameters (deformation analysis) is not as god as novel cardiovascular biomarkers such as GDF-15 and galectin-3. 14

16 Method This study is a part of the TOTAL AMI (Tailoring Of Treatment in All comers with Acute Myocardial Infarction) project. The primary aim of TOTAL-AMI is to study the mechanics and implications off different MI subtypes and of comorbidities in MI. TOTAL-AMI uses data from SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) which is a nationwide registry enrolling consecutive patients admitted to Swedish coronary care units or other specialized facilities because of suspected acute coronary syndrome. On admission, patients receive written information about the registry, had the right to deny participation and get their data erased upon request. SWEDEHEART prospectively collects information on >100 variables. The population for the present study included consecutive patients hospitalized in the department of cardiology, Uppsala University hospital between the period , discharged with the diagnosis acute myocardial infarction, with available results for biomarkers of myocardial damage, who during their stay left their blood samples in the biobank and underwent a transthoracic echocardiography. Information on patient characteristics and biomarker levels were collected from SWEDEHEART registry, digital patient records and a TOTAL-AMI database. The echocardiographic images have retrospectively been analyzed with Echo Pac software to obtain LVEF, left ventricular end diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV) and MAPSE. To determine LVEF, Simpson s biplane method, where the volume of the left ventricles are based on both a four-and two chamber view, was used. Strain analysis was performed using an external imaging system, Image Arena V 4.6 Build (TomTec imaging system, Munich, Germany). Image arena is an automated measurement tool and a vendor independent speckle tracking software. To calculate the mean endocardial left ventricular GLS, it uses three different echocardiographic projections - apical 2-, 3- and 4 chamber views. The software automatically estimates the end-systolic and end diastolic phase of the heart cycle, but it most often needs some manual correction. The reviewer then manually traces the border wall of the left ventricle in the end systolic phase. Based on the tracing in the systolic phase the software automatically traces the moving speckles to the end diastolic frame, with the ability to correct manually. Based on the information the software calculates the mean endocardial GLS and with 15

17 segmental left ventricular strain displayed as a 16-segmental bulls eye presentation of the left ventricle. All the analyzes were performed by a fifth year medical student and a third year medical laboratory scientist student with the help and supervision of a clinical physiologist and a medical laboratory scientist, both with much experience in cardiac imaging. European Association of Cardiovascular Imaging s recommendations on normal values for systolic function, ventricular size, MAPSE and GLS were used; LVEF > 54 % in women and > 52 % in men, LVEDVi < 29 ml/m 2 in women and <32 ml/m 2 and LVESVi < 8 ml/ in women and <11 ml/m 2 in men. MAPSE >11 mm for women and >13 mm for men. GLS <-18 for both men and women were used as normal (11). Figure 2. Screenshot from the Tom Tech software used for analyzing global longitudinal strain. Picture from Figure 3 presents a flowchart illustrating the selection of patients for this study. In total 338 patients were included. 41 (12%) of these had to be excluded due to poor image quality, partly because of atrial fibrillation during the acquirement of the echocardiographic imagery, which makes it impossible to determine the end systolic- and end diastolic phase and make reliable measurements. Echocardiographic measurements were carried out on 296 patients and based on their left 16

18 ventricular ejection fraction they were divided into two groups; Normal LVEF and impaired LVEF. The cardiac troponin I (ctni)-values in this study where collected from the SWEDEHEARTregistry and in case of missing values obtained from patient records. Depending on when, during the four years the study lasted, different types of cardiac troponin (ctn) where collected, ctni and high sensitive ctni. To be able to do statistical analysis ctni values were recalculated to the same units. Statistical methods Patient characteristics such as clinical and demographic data, biomarkers and echocardiographic parameters were compared between groups with normal and impaired LVEF. Continuous variables such as age, echocardiographic parameters and biomarkers were presented as means ± standard deviations or medians with 25 th and 75 th percentiles (interquartile range (IQR)). Differences in continuous variables were assessed using independent samples t-test. Categorical variables such as sex, medical history and medical treatment where presented as frequencies and percentages with differences being analyzed with the Chi-square test. Associations between LVEF, GLS and the study outcomes were assessed using Cox proportional hazards regression models and expressed with hazard ratio (HR) and 95% confidence interval (CI). The models were adjusted for age, sex, GDF-15, ctnl, LVEF, galectin-3 in different variations. To compare models regarding predictive ability, the concordance statistics (c-statistics) were used. All analyses were performed using SAS software version 9.4 (SAS Institute). For all statistical analyses, a 2-sided P<0.05 was considered statistically significant. MAPSE, LVEDVi and LVESVi were log-transformed due to skewed data and the biomarkers were log-transformed due to skewed data and calculated with risk prediction for 10 % change. To evaluate the predictive value of LVEF, GLS and MAPSE and the biomarkers the following endpoints were constructed; all-cause mortality, a composite endpoint containing death, MI, revascularization and readmission because of stroke. A separate end-point was readmission because of HF. 17

19 Study population. Figure 3. Study population. Number of patients (n) Left ventricular ejection fraction (LVEF) Myocardial infarction (MI). Normal LVEF >52 % for men and >54 % for women. s 18

20 Ethical permission This study was approved by the regional ethics committee (EPN, Stockholm, Sweden). Dnr: 2017/

21 Results Baseline patient characteristics The mean age in the study population was 63.5 ± 8.9 years, among 296 patients finally included 84.0 % (n=238) were males. There was no significant differences between patients with normal and impaired LVEF in terms of demography and medical history including classical cardiovascular risk factors. A coronary angiography was done on 98.3 % (n=291) of all the patients without any difference between the study groups. Patients with normal LVEF underwent percutaneous coronary intervention (PCI) less often than those with impaired LVEF (87.0 vs. 98.5%, p=0.008). Coronary artery bypass grafting (CABG) was performed on 2.7 % (n=8) of all patients, without any difference between the groups. There was no difference between the groups regarding treatment on discharge from the hospital, with exception for P2Y12 inhibitors, which were more often prescribed in normal LVEF group (96.1 vs. 90.7%, p=0.003). Extent of myocardial damage as measured by median peak ctnl concentration was larger in the group with impaired LVEF as compared to those with normal LVEF (median ctnl 34300g/L. (IQR ( )) vs g/l (IQR( ) g/l), p<0.001). Any significant difference between concentrations of other biomarkers was not observed, see table 1. 20

22 Table 1. Demographic and baseline patient clinical characteristics Normal LVEF n=231 Impaired LVEF n=65 p-value Age, years (±SD) 63.4± ± Male, sex n (%) 188 (81.4) 50 (76.9) Medical history, n (%) Diabetes 41 (17.7) 9 (13.8) Myocardial infarction 31 (13.4) 16.9 (11) Congestive heart failure 13 (5.6) 5 (7.7) Hypertension 104 (45.0) 34 (52.3) 0.52 Stroke 6 (2.6) 5 (7.7) MI type, n (%) STEMI 121 (52.4) 40 (61.5) Intervention, n (%) Coronary angiography at index MI 226 (97.8) 65 (100) PCI at index MI 201 (87.0) 64 (98.5) CABG at index MI 7 (3.0) 1 (1.5) Medical treatment at discharge, n (%) Aspirin: 225 (97.4) 63 (96.9) 0.15 P2Y12 inhibitors 222 (96.1) 59 (90.7) Statins 221 (95.7) 58 (89.2) ACE-I 154 (66.7) 44 (67.7) ARB-I 37 (16.0) 12 (18.5) 0.64 β-blockers 214 (92.6) 61 (93.8) Diuretics 25 (10.8) 19 (15.4) Anticoagulants 8 (3.5) 5 (7.7) Biomarkers, median (IQR 25%-75%) Peak ctnl g/l ( ) ( ) <0.001 NT-proBNP* 5.42 ( ) 5.63 ( ) 0.06 GDF-15* 8.37 ( ) 8.66 ( ) Galectin-3* 4.65( ) 4.8 ( ) Left ventricular ejection fraction (LVEF), Standard deviations (SD), Myocardial infarction (MI), ST-elevation myocardial infarction (STEMI), Percutaneous coronary intervention (PCI), Coronary artery bypass grafting (CABG), Angiotensin receptor blockers (ARB), Angiotensin converting enzyme inhibitors (ACE), Interquartile range (IQR), Cardiac troponin (ctni), Growth differentiation factor 15 (GDF-15), Normal LVEF >52 % for men and >54 % for women. *Values have been mathematically transformed and are therefore without units 21

23 Echocardiographic parameters In the group with normal LVEF, the mean LVEF was 60.8 ± 6.8 % and in those with impaired LVEF 49.2 ± 4.0 % (p<0.001). In the latter group, the vast majority of the patients had mildly impaired LVEF (98.5 %). Patients with impaired LVEF had also significantly more impaired values of other LV function parameters with exception for LVEDVi, see table 2. Table 2. Echocardiographic parameters of systolic function in post-myocardial infarction patients with normal and impaired LVEF Parameter value ± SD Normal LVEF n=231 Impaired LVEF n=65 P-value LVEF, % 60.8± ± 4.0 <0.001 MAPSE, mm 6.7± ± GLS, % -14.0± ±3.8 <0.001 LVEDVi, ml/m ± ± LVESVi, ml/m ± ±6.8 <0.001 Left ventricular ejection fraction (LVEF), Standard deviation (SD), Mitral annular plane systolic excursion (MAPSE), Global longitudinal strain (GLS), Left ventricular end diastolic volume index (LVEDVi), Left ventricular end systolic volume index (LVESVi). Normal LVEF >52 % for men and >54 % for women. When implemented cut-offs for normal values for the studied parameters (11), 86.6 % (n=200) of patients in the group with normal LVEF had an impaired GLS and 83.1 % (n=192) of them had impaired MAPSE. Almost no patients had a pathological LVEDVii in either of the groups. LVESVii was pathologic in 0.9 % (n=2) in the group with normal LVEF and in 9.2 % (n=6) in the group with impaired LVEF. See Figure 4. 22

24 Figure 4. Percentage of post myocardial infarction patients with pathological echocardiographic values divided in to subgroups with impaired and normal LVEF. Pathological values 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% GLS > -18% MAPSE EDVii ml/m2 ESVii ml/m2 Impaired LVEF Normal LVEF Global longitudinal Strain (GLS)Mitral annular plane systolic excursion (MAPSE), Global longitudinal strain (GLS), left ventricular end diastolic volume index (LVEDVi), left ventricular end systolic volume index (LVESVi). Pathological values: GLS >-18%. MAPSE 11mm for women, 13 for men. LVEDVi 29 ml/m 2 in women and 32 ml/m 2 in men. LVESVi 8 ml/m 2 in women and 11 ml/m 2 in men. Norma LVEF >52 % for men and >54 % for women. Outcome During the time of follow-up, until 7 May 2017 (median 4.7 years and longest 6.7 years) a total of 24 patients (8.1%) died. A total of 42 patients (14.2%) met any of the composite endpoint criteria such as all-cause mortality, readmission because of stroke, MI and revascularization, while 9 patients (3%) were readmitted due to heart failure. See Table 3. 23

25 Table 3. Endpoints created and number of events for each endpoint. Endpoint variable Number of events n (%) 1. All cause mortality 24 (8.1) 2. Composite(death, readmission 42 (14.2) because of stroke, myocardial infarction+ revascularization) 3. Readmission due to heart faliure 9 (3) Figure 5. Kaplan-Meier curve showing risk for the endpoint all-cause mortality during the time for follow up of (n=296) post myocardial infarction patients. Median follow up time 4.7 years. Longest follow up time 6.7 years. In the univariate analysis LVEF was only able to predict readmission due to heart failure, while GLS was predictive for all three endpoint variables. Other left ventricular function parameters such as LVEDVi, LVESVi and MAPSE showed no ability to predict outcome in any of the created models, see table 4. 24

26 Figure 6. Kaplan-Meier curve showing risk for the composite endpoint during the time for follow up of (n=296) post myocardial infarction patients. Median follow up time 4.7 years. Longest follow up time 6.7 years. Among the studied biomarkers, GDF-15 was predictive for both crude all-cause mortality and the composite endpoint, while ctnl showed no ability to predict outcome in any of the studied models. Galectin-3 was predictive for total mortality but not for composite endpoint and heart failure readmissions, see table 4. The cumulative risk for the endpoints; all-cause mortality and composite are shown as Kaplan Meier curves. See figures 5 and 6. 25

27 Table 4. Univariate results of biomarkers and echocardiographic parameters in cox regression models All-cause mortality HR (95 % CI) LVEF ( ) GLS ( ) LVEDVi* ( ) LVESVi* ( ) MAPSE* ( ) ctni** ( ) GDF-15** ( ) Galectin- 3** ( ) p- value C-stat (95 % CI) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Composite HR (95 % CI) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 26 p- value C-stat (95 % CI) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Readmissio n due to HF. HR (95 % CI) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) *log-transformed due to skewed data. **log-transformed due to skewed data and with risk prediction for 10 % change Data in bold type represents significant values. p- value C-stat (95 % CI) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( )

28 Table 5. Multivariate analysis of relationship between GLS and the endpoint all-cause mortality HR (95 % CI) p-value C-stat (95 % CI) GLS+age+sex ( ) ( ) GLS+GDF-15** ( ) ( ) GLS+cTnI** ( ) ( ) GLS+ LVEF ( ) ( ) GLS+GDF-15**+cTnI** ( ) ( ) GLS+age+sex+cTnI** ( ) ( ) HR (95 % CI) p-value C-stat (95 % CI) GLS+age+sex ( ) ( ) GLS+GDF-15** ( ) ( ) GLS+cTnI** ( ) ( ) GLS+ LVEF ( ) ( ) GLS+GDF-15**+cTnI** ( ) ( ) GLS+age+sex+cTnI** ( ) ( ) GLS+GDF-15**+Galectin- 3**+cTnI** ( ) ( ) Global longitudinal Strain (GLS), Growth differentiation factor 15 (GDF-15) Cardiac troponin I (ctni). Left ventricular ejection fraction (LVEF) Hazard ratio data in bold type represents significant values *log-transformed due to skewed data. **log-transformed due to skewed data and with risk prediction for 10 % change GLS+GDF-15**+Galectin- 3**+cTnI** ( ) ( ) Global longitudinal Strain (GLS), Growth differentiation factor 15 (GDF-15) Cardiac troponin I (ctni). Left ventricular ejection fraction (LVEF). Hazard ratio data in bold type represents significant values *log-transformed due to skewed data. **log-transformed due to skewed data and with risk prediction for 10 % change Table 6.Multivariate analysis of the relationship between GLS and the composite endpoint. 27

29 In the multivariate analysis, GLS was predictive for both all-cause mortality and composite when adjusted for ctni and LVEF (see Table 5 and 6). Due to the insufficient number of events for the model studying heart failure readmissions, no further multivariate analyzes were performed. 28

30 Discussion A bit less than four fifths of patients included in the cohort had a normal LVEF after index MI, a large portion of patients with normal LVEF had pathological GLS and MAPSE values, reflecting subclinical LV dysfunction depending on impaired longitudinal function. During median followup of 4.7 years 8 % of patients died and 14 % met any of the composite endpoint criteria, including all-cause death, MI, revascularization and readmission because of stroke. GLS was the only LV functional parameter predictive for all outcome measures, while lower LVEF was predictive only for readmission due to heart failure. Predictive value of GLS was independent of LVEF and extent of myocardial damage measured by ctni concentrations. Among the studied biomarkers, GDF-15 was predictive for both crude mortality and the composite endpoint, galectin-3 for total mortality, while ctnl showed no ability to predict outcome in any of the studied models. The prevalence of patients with normal LVEF after myocardial infarction in our study ranged almost 80%, a bit larger comparing to earlier observations reporting between two thirds and three fourths of patients with preserved LVEF (35,36). When looking at those patients with an impaired LVEF, almost all patients had a mildly reduced LVEF. This implies a relatively good overall cardiac health in our cohort, in regards to what LVEF is able to detect. This is probably depending on relatively contemporary well medicated cohort. A large portion of patients had both impaired GLS and MAPSE. When implementing the wildly used cut-offs for impaired GLS (<-18%) not surprisingly in the group with impaired LVEF, 95 % of patients had a pathological GLS, while almost 87% of patients had impaired strain despite of normal LVEF. Similar pattern was observed for MAPSE. The percentage with pathological values in the group with impaired LVEF was 97 % and 83 % for the group with normal LVEF. A study comparing EF to GLS as a predictor of cardiac mortality in patients with advanced kidney disease found that 51 % of patients with normal LVEF had impaired GLS(37). Another study looking at patients with HF with preserved LVEF found impaired GLS in 65 % of the study population(38). A smaller portion of patients with normal LVEF and impaired GLS compared to this study, partly depending on impaired GLS being defined as GLS >-16, but it demonstrates the advantages of GLS compared to LVEF in identifying LV dysfunction The relationship between LVEF and GLS in the post-acute myocardial infarction patient group have been showed in earlier studies(35), where 25.3 % of patients had an impaired LVEF and GLS was impaired in 70% of the patients. 29

31 GLS and MAPSE s similar share of patients with pathological values, both in patients with and without impaired LVEF represents the advantage of these echocardiographic measuring techniques. The reason for inconsistency in percentage of impaired LVEF and impaired GLS or MAPSE might be that both MAPSE and GLS reflects longitudinal impaired function, whereas LVEF reflects the overall function of the left ventricle(12,20). Longitudinal fibers are mostly located in the subendocardium, which also is the part of the myocardium most susceptible to hypoperfusion and ischemia during infarction.(39). This explains why such a big portion postacute myocardial infarction patients has a normal LVEF, but impaired GLS and MAPSE values. In the post infarct patients in this study GLS was the only echocardiographic measurement, with ability to significantly predict outcome in all three endpoint variables (all-cause mortality, composite and readmission due to HF). The predictive value remained when adjusting for LVEF and ctnl. LVEF was predictive for readmission for heart failure, but not for the endpoints all-cause mortality and composite LVEF ability in predicting readmission for heart failure is expected because of a decreasing LVEF s direct connection to the failing heart(40), it also shows an accurate approach in analyzing technique, being that the analyzes were carried out by novices in the field. Worth noticing is the few events (n=9) in the readmission for HF endpoint, which makes it lack in power. The overall, relatively few events in the created endpoints, in combination with a high portion patients with a normal LVEF and overall few patients in the cohort, could explain why LVEF was lacking predictive significance. Even though MAPSE similar to GLS reflects longitudinal LVfunction, it showed no predictive value for prognostic outcome in every tested model. This could reflect MAPSE s lower accuracy compared to GLS. Levels of ctnl was higher in the group with impaired LVEF, which is reasonable since this patient group probably suffered from a greater ischemic injury to the myocardium, hence releasing greater levels of ctnl and lowering the LVEF. ctnl had no significant predictive value in any of the endpoint variables, which may seem a bit troubling. The change of ctn units could be the source of error in this case. The mean levels galectin-3 were not significantly higher in the group with impaired LVEF. GDF- 15 had predictive ability in both all-cause mortality and the composite variable and Galectin-3 only in all-cause mortality. When adjusting GLS for either GDF-15 or galectin-3 it is no longer predictive in any of the endpoints. Galectin- 3 and GDF-15 s connection to cardiac disease have 30

32 earlier been proposed. The biomarkers are not just related to myocardial fibrosis and inflammation and can increase because of renal disease, stress and hypoxia to other organs as well (31,32). Both GDF-15 and GLS were predictive for outcome in univariate analysis, but not when used together in multivariate model, suggesting that these variables can be correlated and mediate each other. In this case a stratified analysis should be performed, which was beyond the scope of this project. GLS has been shown to have independent value in assessing the prognosis in patients with mild left ventricular impairment and is likely to be superior to what is provided by LVEF (41). The advantages of GLS has been shown when evaluating myocardial changes from cancer therapy, where a reduction in GLS occurred prior to change in LVEF. An early reduction in myocardial deformation appears to forecast the development of subsequent cardiotoxicity and GLS therefore plays an important role monitoring these patients (42). A study similar to ours evaluated the predictive value of GLS on clinical outcome in patients diagnosed with STEMI and with preserved systolic function. With similar endpoints this study followed patients up till 30 days after index STEMI and found that GLS better than LVEF predicted 30 day outcome in this patient group (43), similar to what is shown in our study. Three quarters of the cohort had a normal LVEF and many of those with pathological and GLS and MAPSE values, showing the subclinical LV dysfunction The only parameter able to predict outcome in all the endpoints was GLS, an ability LVEF was lacking. This study has presented possible shortcomings of LVEF as a parameter of left ventricular function and shown the prognostic advantage of GLS in the post- acute myocardial patient group with preserved LVEF. In our cohort of post MI patients, we could not see any added predictive value of conventional or newer biomarkers such as galectin-3 and GDF-15 when used together with the studied novel echo parameters, suggesting their correlation with each other. Limitationes The relative small cohort resulted in few events and which made some analyses lack in statistical power. The analyses were done by students with no earlier experience in cardiac image analysis, however after theoretical introduction and practical training, supervised by a senior echocardiographer. The recalculation of troponin is to view as a possible source of error. GDF-15 and GLS were not predictive in the multivariate model, suggesting that these variables can be 31

33 correlated and mediate each other. In this case a stratified analysis should be performed, which was beyond the scope of this project Conclusion Despite of preserved EF, in the vast majority of patients with MI, LV deformation and longitudinal function parameters are impaired. One of them, GLS showed a significant ability to predict outcome independently of LVEF and extent of myocardial damage. The role of GLS in relation to biomarkers in prognosis and treatment for this patient group needs to be determined in future studies. 32

34 Acknowledgement I would like to specially thank my supervisor Tomasz Baron for the help and support during this project. I also want to direct a thank you to Nermin Hadziosmanovic at Uppsala Clinical Research Center for the statistical guidance. 33

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