Leadless pacemaker systems are an important upcoming device in clinical rhythmology. Currently two different products are available with the Micra system (Medtronic) being the most used in the clinical setting to date. The possibility to perform magnetic resonance imaging (MRI) is an important feature of modern pacemaker devices. Even though the Micra system is suitable for MRI, little is yet known about its impact on artifacts within the images.The aim of our ex vivo study was to perform cardiac MRI to quantify the artifacts and to evaluate if artifacts limit or inhibit the assessment of the surrounding myocardium.After ex vivo implantation of the leadless pacemaker (LP) in a porcine model, hearts were filled with saline solution and fixed on wooden sticks on a plastic container. The model was examined at 1.5 T and at 3 T using conventional sequences and T2 mapping sequences. In addition, conventional X‑rays and computed tomography (CT) scans were performed.Correct implantation of the LP could be performed in all hearts. In almost all MRI sequences the right ventricle and the septal region surrounding the (LP) were altered by an artifact and therefore would sustain limited assessment; however, the rest of the myocardium remained free of artifacts and evaluable for common radiologic diagnoses. A characteristic shamrock-shaped artifact was generated which appeared to be even more intense in magnitude and brightness when using 3 T compared to 1.5 T.The use of the Micra system in cardiac MRI appeared to be feasible. In our opinion, it will still be possible to make important clinical cardiac MRI diagnoses (the detection of major ischemic areas or inflammatory processes) in patients using the Micra system. We suggest the use of 1.5 T as the preferred method in clinical practice. The implantation of a permanent cardiac pacemaker device (PM) is currently the only effective treatment option for symptomatic bradycardia, as evidenced by the reduction of symptoms, reduction of syncope and a decrease in overall mortality. According to the 2013 European Society of Cardiology (ESC) guidelines on cardiac pacing and cardiac resynchronization therapy, a class I indication for cardiac pacing is given for patients with persistent bradycardia due to atrial fibrillation or sinus node disease.Within 50 years of clinical use, pacemakers have shrunk remarkably in size, while their features have developed from simple basic functions to highly sophisticated medical high-tech products. Today, typical systems consist of two components: the first is a pacemaker with integrated electronics and battery, usually implanted into a subcutaneous pocket of the pectoral region. The electrical impulse is generated within the pacemaker and is transmitted to the inner heart via one or more pacemaker leads which are usually implanted through the veins into the right ventricle. Although these devices have been shown to be safe and effective, a significant number of patients encounter complications during treatment. Short-term complications include perioperative hematomas, pneumothorax/hemothorax, valve trauma or infections of the subcutaneous pocket. Long-term complications to be mentioned are lead dislodgement, lead breaking or infections such as endocarditis or septicemia. Furthermore, the surgical extraction of leads showing any kinds of functional loss or damage, are often challenging .Technical progress has set the stage for a new era of cardiac pacing, which no longer depends on leads, due to permanent intracardiac placement of a new generation of leadless pacemaker (LP) devices .TM  transcatheter pacing system (TPS) has recently been developed [TM TPS is a 0.8 cm3, 2.0 g capsule, 25.9 mm in length and an outer diameter of 6.7 mm that has features of a single-chamber pacemaker system. It is implanted in the right ventricle via a steerable transfemoral catheter delivery system using a 23 French introducer [The Micraeveloped , 4. The Reynolds et al. performed the first major prospective clinical trial on the Micra system and compared it with conventional systems based on historical data . In thisIn addition to the safety and efficacy shown in the clinical trial, in a limited number of clinical cases the Micra TPS has been shown to be an effective treatment option for temporary and permanent use in patients suffering from infections of conventional devices –19.http://manuals.medtronic.com/manuals/mri/de_AT/search/index), several circumstances are required to perform safe MRI imaging in humans, using either a 1.5 T or a 3 T scanner.Pacemakers compatible with magnetic resonance imaging (MRI) have been developed and are already part of daily clinical routine. In 2017 the Heart Rhythm Society published the latest consensus paper on magnetic resonance imaging and radiation exposure in patients with cardiovascular implantable electronic devices [Any abandoned leads, which might still be present from former conventional pacemaker systems, have to be removed. For patients implanted with multiple MR conditional devices, the MR labelling conditions for all implanted devices have to be satisfied. It is required that the SureScan device is operating within the projected service life. Its pacing amplitude has to be ≤4.5 V at the programmed pulse width. Any diaphragmatic stimulation has to be excluded, when “MRI SureScan” is programmed to “On”. If these circumstances are ensured, the device can be switched to “SureScan” mode. Therefore, the operator has to click through a checklist window, which features all parameters of relevance. In patients who require continuous pacing support, the asynchronous pacing mode (VOO) should be selected. Patients who do not require pacing during the MRI examination should be put to the non-pacing mode (OVO). After the MRI examination, the manufacturer recommends a return to the pre-MRI condition as soon as possible, followed by a final check of the pacing capture threshold. If the return is not done within 24 h, the device will end the “SureScan-mode” automatically.Specific recommendations on static field spatial gradient (<25 T/m), RF exposure  and gradient field (gradient slew rate <200 T/m/s per axis) have previously been published by Soejima et al. ; howeverSince a total extraction of the intracardiac device at the end of its lifetime (estimate for Micra approximately 10 years on average) is possible but expected to be challenging, the company propagates the application of a second device. The placement of a second device has already been tested in an animal model by Chen et al.  showing A total of 15 domestic pig hearts from a local abattoir were delivered to our laboratory within 2 h after slaughter. A brief visual check for obvious signs of myocardial injury that might have occurred during slaughter was done immediately. The heart as a whole and the great vessels  were left on bloc. A similar model has already been used to assess the MRI compatibility of temporary pacemaker leads . In a seFor visual analysis Agfa Impax EE  was used. All images were visually evaluated with respect to whether the LP was displayed in the image for further analysis. The evaluation was performed by a radiologist with experience in cardiac imaging procedures. Computed tomography (CT) scans (Philips 64 CT scanner) and conventional X‑ray studies were conducted.In total three separate sessions were held using MRI, CT scan and conventional X‑ray, each investigating hearts implanted with the Micra system. All images were selected and interpreted by two radiologists, both experts in cardiac imaging.This article does not contain any studies with living animals performed by any of the authors.The MR images were imported into image processing software . Image J planimetry software  was utilized to determine the extent of the artifact area. The size of the artifact area (% of left and right ventricular myocardium) was calculated as follows: the artifact area and the total area of the left and right ventricular area were traced manually in the digital images and measured automatically by the software. Artifact area, expressed as a percentage, was calculated by dividing the area of the artifact by total ventricular area.Correct implantation using the steerable device was feasible in all porcine hearts used in our ex vivo study. The experimental set-up of a porcine heart implanted with the Micra system in the apicoseptal region of the right ventricle is shown in Fig. Fig. A similar result was found for the scar sequence  Fig. a–d. The Similar findings were generated at 1.5 T. Only the perifocal hyperintense rim artifacts in the turbo-spin-echo (TSE) sequences with selective fat suppression  were visually slightly smaller (10.2% vs. 19.9%). No relevant differences were found in perfusion and T2 map sequences.In recent years, technological advances have set the stage for a completely new era of device treatment. The Micra system was the first pacemaker device with complete intracardiac placement using a femoral access. The purpose of this ex vivo study was to evaluate the suitability of the Micra pacemaker system for MRI scans, as well as to visualize the occurrence of artifacts. Within a small focal area around the device, a shamrock-shaped artifact was generated leading to severely reduced local assessability, while the rest of the myocardium remained suitable for routine radiologic evaluations.Based on the findings in our ex vivo model we expect good evaluability in major parts of the left ventricle and the lateral wall of the left ventricle, while the septal region and primarily the right ventricle might be overshadowed by focal artifacts. As far as ischemic cardiomyopathy is concerned, diagnosing a notable scar expected in the anterior/anterolateral or lateral myocardium might still be possible without major limitations caused by the device; however, myocardial damage with involvement of the right ventricle and the septum might be poorly assessable and their actual magnitude could eventually be underestimated or overestimated.In our opinion, diffuse inflammatory cardiomyopathies or myocardial storage diseases affecting large areas of the myocardium, will still be identified; however, the detection and further evaluation of regional myocardial tissue defects will depend on the myocardial location and dimensions.Pathologies affecting primarily the right ventricle, e.g. arrhythmogenic right ventricular cardiomyopathy (ARVC) might be limited in their assessment by artifacts. Intracardiac masses  in the left atrium or in the left ventricle should be possible to visualize and characterize. Since our assumptions are based on observations of a non-vital model, the effects of cardiac motion in real life cannot yet be estimated. Cardiac motion might probably lead to an enlargement of the artifact obscuring the apical region of the right ventricle. We expect no disruptive effects on cardiac valve evaluation.Compared to sequences at 1.5 T, a remarkable increase in magnitude and intensity of the shamrock-shaped artifact when using a 3 T MRI scanner, could be demonstrated. These effects could especially be seen in the late enhancement (Scar) sequences, which are of extraordinary importance in clinical practice. We would therefore predict that the 1.5 T MRI will be the preferred method of evaluation in clinical settings. In our opinion, limitation to 1.5 T MRI evaluation will not be a major disadvantage in comparison to transvenous systems, as currently conventional systems are usually only approved for 1.5 T.First clinical data from autopsies showed various forms of intracardiac endothelialization of the device. While some cases showed complete endothelialization within months –30, evenThe occurrence of ingrowth and encapsulation, might also have an impact on artifact size. Due to the fact that these processes were only seen in single cases so far, the impact on image quality in general will probably remain insignificant. Implantation of a second device, which may become necessary after years of use due to loss of battery function, will obviously lead to an increase of generated artifacts.Since the magnitude of generated artifacts usually depends more on its metallic components than on its actual size, the effects of a possible new generation device or of an additional LP on MRI remains unclear.We can presume that in all sequences the right ventricle and the septal region directly surrounding the pacemaker device will show artifacts limiting assessment in a circumscribed area. In these areas, focal signal intensity changes of the myocardium i. e. caused by edema or scar-induced gadolinium (Gd) enhancement might be missed. Focal myocardial thickening or thinning might also be masked. Important to consider is that additional artifacts caused by breathing and cardiac motion will probably further deteriorate the image quality. Considering the estimated battery life of approximately 10 years and the ongoing development of the leadless pacemaker technology, even smaller second generation devices might soon be available. Only time will show the real-life impact of an additional device. Due to the fact that the device did not show any signs of magnetic activity we postulate a safe implementation of cardiac MRI in humans as well. The findings concerning the artefact size might be similar than those in our ex vivo model, when considering the following limitations.n = 15, 3 sessions with 5 hearts each), a valuable statistical analysis could not be performed due to the study size being too small. Although the porcine heart is considered to be the most likely model of the human heart, our model obviously has several limitations. Being a non-vital myocardium without any movement, the occurring artifact size might increase when evaluating a vital heart. The impact of cardiac motion on artifacts remains unclear. Even though the experiments were performed immediately after slaughter, a direct comparison to contractile, vital human tissue is not possible. Additionally, minor differences of the myocardial thickness between the human heart and our model have to be considered as well.With a total of 15 investigated porcine hearts (In the absence of surrounding lung parenchyma, the normal anatomic setting was simulated by ambient air, which might have an impact on the quality of the images. Furthermore, the hearts were filled with saline, a non-blood-like fluid characterized by a different viscosity. Finally, the fluid remained static within the ventricle, without the flow that would be encountered in the vital setting.For the first time, we present a general survey of possible MRI artifacts generated by the intracardiac leadless Micra System. In our ex vivo model, the directly surrounding area of the device showed limited assessability, while the majority of the myocardium remained accessible for routine radiologic MRI evaluations. Since the artifacts appeared to be smaller at 1.5 T than at 3 T in our experimental setting, we suggest a higher diagnostic accuracy at lower field strength. According to this finding we expect that the use of 1.5 T will be the preferred method in clinical practice.Further clinical studies or even case series would be warranted to estimate the clinical value of MRI in LP patients. From today’s point of view, we postulate that performing a cardiac MRI in patients with a Micra implant is still expedient in selected clinical cases; however, there are limitations concerning the diagnosis of right ventricular pathologies.


Interest in the mitral valve has increased over the past few years with the development of new technologies that allow intervention in patients previously deemed too ill for treatment. This increased attention has resulted in a significant increase in publications on the mitral valve, the majority of which focus on mitral regurgitation and mitral valve surgery/intervention. The focus of this review is on publications in the past few years that offer additional insights into our understanding and management of mitral valve disease and specifically mitral regurgitation. It will discuss mitral valve anatomy, epidemiology of mitral valve disease, changes in the 2017 management guidelines, management of mitral bioprosthetic valves, transcatheter mitral valve procedures and the repair of rheumatic valves. The focus of this review is on publications in the past few years that offer additional insights into our understanding and management of mitral valve disease and specifically mitral regurgitation. It will discuss mitral valve anatomy, epidemiology of mitral valve disease, changes in the 2017 management guidelines, management of mitral bioprosthetic valves and transcatheter mitral valve procedures.Interest in the mitral valve has increased over the past few years with the development of new technologies that allow intervention in patients previously deemed too ill for treatment. This increased attention has resulted in a significant increase in publications on the mitral valve, the majority of which focus on mitral regurgitation and mitral valve surgery/intervention . AdditioInsights into mitral valve anatomy and the changes that occur from intrinsic valvular abnormalities or secondary to other cardiac pathologies continue to evolve. This is due to advancements in cardiac imaging that allows us to visualize and quantify the mitral valve in three dimensions. In particular, there have been gains in understanding the pathomorphological mitral annular and leaflet and left ventricular myocardial changes that occur with myxomatous mitral valve disease. Additionally, there has been greater appreciation of the significance of mitral clefts and cleft-like indentations during percutaneous interventions.7. Alterations to mitral annular size and function have been recognized secondary to pathologies such as myxomatous mitral valve disease and ischemic cardiomyopathies9. The mitral annulus of patients with myxomatous mitral valve disease dilates in all directions. Although it retains its dynamic changes during the cardiac cycle, it loses its regurgitation preventive mechanism through decoupling of annular and ventricular contraction10. In contrast, in patients with ischemic cardiomyopathies, the mitral annulus enlarges only in the anteroposterior diameter and is adynamic throughout the cardiac cycle. Developments over the past few years have given us a greater appreciation that mitral annular remodeling differs not only between primary and secondary mitral regurgitation but also between primary etiologies such as Barlow’s disease and fibroelastic deficiency. These pathophysiological differences involve not only mitral annular dynamics but also leaflet tissue changes  are performed 1.6 times more commonly than mitral valve operations despite a two- to three-fold higher prevalence of mitral valve disease31.There is great interest in defining the number of patients with significant mitral regurgitation who are undertreated because of the resources that are being devoted to developing costly new therapeutic interventions for mitral regurgitation. Studies have reported that up to 50% of patients with moderate to severe mitral regurgitation who are referred for surgical evaluation are denied interventionet al. addressed this knowledge gap by studying a population with easy access to diagnostic and therapeutic interventions, which allowed them to separate socioeconomic from clinical factors32. They examined a group of patients whose isolated moderate or severe mitral regurgitation was diagnosed between 2000 and 2010 in Olmsted County , the main catchment region for the Mayo Clinic32. They identified 1294 patients  with moderate or severe mitral regurgitation, of whom 538 (42%) had a left ventricular ejection fraction below 50%. Overall, these patients with moderate or severe mitral regurgitation had higher rates of mortality compared with the general population in that region and this was true even if they had few co-morbidities and normal left ventricular function. Not surprisingly, those with poor left ventricular function had poorer outcomes. Despite access to the resources of the Mayo Clinic, only 15% of the 1294 patients underwent surgical therapy. Even within the subgroup of 561 patients with a left ventricular ejection fraction of at least 50% and class 1 guideline-based indications for intervention, only 118 patients underwent surgery. Even more concerning was the finding that men, despite having more co-morbidities, were twice as likely than women to have mitral surgery.However, there are many reasons why patients may be denied intervention. These include socioeconomic factors such as poor access to care and treatment and clinical factors related to late referral for intervention and the presence of co-morbidities precluding intervention. It was unclear whether the number who would be considered undertreated would be so large if issues relating to access to care and treatment could be removed. Dziadzko34. More data are needed to understand why it occurs. Perhaps societal guidelines require cutoff values indexed to body surface area to account for sex difference or more objective testing for symptoms should be instituted.While this article confirms that there is a large group of patients who are undertreated despite adequate access to care and intervention, it also suggests that there are areas in current clinical practice that could be improved before consigning all of these patients to percutaneous procedures. It is unclear why patients with significant mitral regurgitation are not undergoing intervention as per societal guidelines. Whether this is due to patient reluctance to undergo surgery, overestimation of the risks over the benefits of mitral valve surgery by the managing physicians, or reluctance of the surgeon to operate is unclear. Also, women are significantly undertreated. Although this is not a new finding, it warrants stronger actions to improve outcomes in women1 and the European Society of Cardiology3 guidelines for managing patients with valvular heart disease were updated in 2017. Changes in these guidelines include grading of mitral regurgitation severity in primary and secondary mitral regurgitation, the use of valve replacement over repair in severe secondary mitral regurgitation, treatment of moderate secondary mitral regurgitation at the time of coronary artery bypass surgery, and an inclination to earlier intervention in asymptomatic patients with severe primary mitral regurgitation  is often unknown. Currently, for both primary and secondary mitral regurgitation, severe mitral regurgitation is defined as an effective regurgitant orifice area of at least 0.4 cm2 or a regurgitant volume of at least 60 mL. Although this simplifies clinical reporting, the intent of the original recommendation should still be remembered. It was meant to raise awareness that patients with secondary mitral regurgitation may be classified under current guidelines as moderate but have a risk of adverse events similar to those classified as severe. However, intervention on the valve in these patients has not been demonstrated to improve outcomes.With respect to the mitral valve, the American guidelines were notable for unifying cutoff values for grading mitral regurgitation severity36. Although both groups demonstrated improvements in ventricular remodeling, the repair group has higher rates of recurrent moderate or severe mitral regurgitation, heart failure and repeat cardiac hospitalizations. However, patients with durable repairs had better outcomes than those with recurrent regurgitation. Also, recurrent regurgitation after annuloplasty was often due to tethering of the posterior leaflet toward the apex, which was not addressed by the annuloplasty ring. Thus, the 2017 European guidelines still lean toward recommending repair with a restrictive annuloplasty for these patients, as some patients do benefit from repair over replacement. What is unclear is how to identify these patients and what other repair techniques should be used in addition to the annuloplasty ring to improve repair durability.For patients with secondary mitral regurgitation, the American guidelines included a new class IIa recommendation to choose chordal-sparing mitral valve replacement over annuloplasty with repair in those with chronic severe mitral regurgitation despite goal-directed medical therapy. This recommendation originates from the results of a randomized clinical trial on patients with secondary mitral regurgitation who were randomly assigned to mitral valve repair or replacement38. The European guidelines have withdrawn the indication for mitral valve surgery during coronary bypass surgery.For patients with moderate secondary mitral regurgitation undergoing coronary artery bypass surgery, the American guidelines reported uncertainty regarding whether this valve should be repaired at the time of surgery. This is due to a study that randomly assigned patients with moderate mitral regurgitation at the time of coronary artery bypass surgery to mitral valve repair plus bypass surgery or to bypass surgery aloneFor secondary mitral regurgitation, the European guidelines also included a new IIb indication for percutaneous intervention. Patients with severe ventricular dysfunction who have no indication for revascularization and are symptomatic despite optimal medical therapy may require surgery if the surgical risk is low or percutaneous intervention if the surgical risk is high and valve morphology is favorable. This recommendation depends on the patient’s left ventricular ejection fraction. For those with a left ventricular ejection fraction of not more than 30%, there is no evidence that treatment of secondary mitral regurgitation improves survival.40. In contrast, the European guidelines introduced a IIa recommendation for surgery in asymptomatic patients with severe primary mitral regurgitation in sinus rhythm with a left ventricular ejection fraction of more than 60% if the probability of repair is high, the left ventricular end-systolic diameter is between 40 and 44 mm, and one of the following criteria is met: the left atrium is dilated (≥60 mL/m2) or the cause is chordae tendineae rupture. Patients who have severe pulmonary hypertension with exercise are not included in this indication for surgery. This differs from the American recommendation which emphasizes progressive changes on serial imaging and suggests that repair be performed only if it is feasible with a high rate of success and durability.For primary regurgitation, the American guidelines include a new class IIa recommendation based on a level of evidence C-LD that mitral valve surgery is reasonable for asymptomatic patients with primary mitral regurgitation who have normal left ventricular size (left ventricular end-systolic diameter of less than 40 mm) and ejection fraction (>60%) and have progressive left ventricular enlargement or a reduction in left ventricular ejection fraction on serial imaging studies. The patient must also have low surgical risk and the chance of repair must be high. This is due to increasing evidence demonstrating improved outcomes in patients who undergo surgery prior to achieving traditional surgical triggers42. The development of risk scores may help in these situations and two such scores have been developed in the past few years to improve management of patients with mitral regurgitation from myxomatous mitral valve disease.Although the guidelines offer direction for management, the decision for referral for intervention is an individual one based on patient co-morbidities, disease severity, and the likelihood of valve repair. Such decisions are often challenging and require a mental scale to subjectively weigh the value of various considerations. This leads to uncertainly and often a conservative management approach, which may be to the patient’s detriment. An example of this is the undertreatment of patients with significant mitral regurgitation from myxomatous mitral valve disease. Physicians tend to underestimate the mortality risks from the regurgitation and overestimate the risks from the patient’s co-morbidities43. It is composed of clinical and echocardiographic parameters that are easily obtainable and includes risk factors that are associated with adverse outcomes in patients with myxomatous mitral valve disease. The score is meant to be used to determine whether a patient should continue medical therapy or undergo surgical intervention. With higher scores, there was a progressive increase in 1- and 5-year mortality in patients who were medically managed and those who underwent surgery. Compared with the EuroSCORE II, the MIDA score provided incremental prognostic predictive value. Although the score was validated, it was in a population that differed only in that it included patients with prolapse in addition to flail leaflets. It must be noted that this score did not include measurements from three-dimensional echocardiography, global longitudinal strain, the presence of fibrosis on cardiac magnetic resonance imaging, peptides, or exercise testing, all of which could improve the MIDA score.The Mitral Regurgitation International Database (MIDA) score is an integrated risk score that was developed for use at the time of diagnosis to help improve risk stratification in patients with severe regurgitation from myxomatous mitral valve disease 43. It i44. Stratification of patients by mitral valve lesion complexity may assist in directing those with complex etiologies or lesions to surgeons with greater expertise and volumes and so improve repair rates. To date, determining complexity has been based on the knowledge that anterior leaflet repair is more difficult than posterior leaflet repair and multi-segmental posterior leaflet repair is more complicated than single segment repair. A scoring system for determining complexity in patients with myxomatous mitral valve disease has been proposed ; of these patients, only 36 had a Society of Thoracic Surgeons predictors-of-mortality score greater than 4%, further limiting the number of potential candidates55. This number may change as fewer mechanical valves and annuloplasty bands are implanted to allow possible percutaneous intervention after an initial surgery58. Overall, although there may be an understandable preference for mitral valve-in-valve procedures, there are many unknowns prior to wider use and extension into native valve in healthier patients , suggesting that their disease may not have been as severe. However, mortality rates in the control arms for the two trials were similar. Lastly, residual mitral regurgitation was higher in the MITRA-FR group (17%) than in COAPT (5%). Overall, these results suggest that mitral regurgitation not only is a marker of heart failure severity but contributes to the abnormal pathophysiology in patients with heart failure. The results also suggest that there may be a population of patients with symptomatic severe secondary mitral regurgitation that will benefit from intervention. It has been postulated that this population has disproportionate secondary mitral regurgitation, where the quantified mitral regurgitation is out of keeping with the size of the left ventricle65. However, more study to better define this population echocardiographically is needed. What is also not known from these studies is what happened to the brain natriuretic protein levels in the COAPT group and how novel therapies such as sacubitril/valsartan would have affected the results of the COAPT trial. Ultimately, the results of a third trial in this population, the RESHAPE HF2 trial, may bring more clarity to this area.There has been great anticipation for the publication of two trials—MITRA-FR and COAPT—which have studied the utility of MitraClip in patients with symptomatic severe functional mitral regurgitation66. It also has a central spacer that provides addition mitral regurgitation reduction. A feasibility study in 23 patients has been published, and a multi-center trial of 120 patients is under way67. Outside of the edge-to-edge devices, there are percutaneous chordal replacement devices and devices that address mitral annular enlargement, such as coronary sinus annuloplasty, and incomplete and complete annuloplasty rings. Percutaneous chordal replacement devices are growing in popularity and several large studies are under way68. Percutaneous mitral annuloplasty devices have been implanted mainly in patients with functional or secondary mitral regurgitation and fewer than 1500 patients worldwide have received these devices compared with the 60,000 who have received the MitraClip67. Ultimately, the future may become one where combinations of these percutaneous mitral valve repair devices are used, mimicking current surgical repair techniques70. However, the costs of these devices individually are quite high and so combining their use would require either that the prices decrease or that significant benefits be demonstrated in clinical trials with very broad populations.Beyond MitraClip, other devices have been developed for percutaneous edge-to-edge repair. This includes the Edwards PASCAL device that permits better deployment with simpler left atrial navigation and independent leaflet grasping71. Compared with transcatheter aortic valve replacement, TMVR has been more challenging because of the size and anatomy of the mitral valve, the lack of calcium to act as anchors in patients with mitral regurgitation, and the risk of left ventricular outflow tract obstruction72. Additionally, there have been challenges in recruiting patients for these trials; rejection rates have been about 60% to 70%74. Of those excluded, about 20% to 50% of patients are excluded because of anatomic concerns and 20% to 40% for clinical or other issues75. Overall, patients are being carefully selected to avoid intervention failure due to treatment of those with disease to advance to improve or those who are at risk of complications due to anatomic features. But the highly selective nature of these studies raises concerns regarding the real-life applicability of these devices.Beyond developing transcatheter mitral valve repair, investigators are developing novel methods for transcatheter mitral valve replacement (TMVR)74. Although only 10 patients were studied with this approach, procedural success was high and safe. This is encouraging but it must be noted that this less invasive approach does have some limitations related to intracardiac maneuverability and sheath sizes75. With respect to anatomic features, the two most common reasons for exclusion have been left ventricular dimensions that are out of the treatable size of the device under study and possible post-procedural left ventricular outflow tract obstruction75. This latter issue was addressed with a novice device that lacerates the anterior leaflet prior to TMVR implantation76. In 30 patients, this approach was found to be safe and effective in preventing left ventricular outflow tract obstruction. However, these patients still experienced issues related to the TMVR device used. In general, TMVR is still in the very early stages of clinical use. More study will be needed with respect to patient selection, the duration of anticoagulation required, the timing and mode of valve degeneration, and the impact of left ventricular remodeling after intervention on device stability.Recent developments hold the promise of increasing the population that could be treated. One is the development of a transseptal approach77. Patients in developed nations tend to be older at the time of valve surgery and have quiescent rheumatic disease, whereas those in developing nations tend to be young with active progressive or recurrent rheumatic disease, which would require reoperation. Additionally, differences in outcomes between mitral valve repair and replacement in developed countries are minimal because of the resources available to comply with mechanical replacement. Regardless of these differences, it has been suggested that both groups would benefit from mitral valve repair77. In fact, another study demonstrated no difference in late mortality or the need for reoperation, and the risk of valve-related complication was significantly lower in the repair group78. This is despite the younger average age in the repair group who also predominantly had regurgitation and the fact that there were very few repair cases performed per year per surgeon. This is consistent with other articles reporting that durability of mitral valve repair for rheumatic disease in the current era has improved and is comparable to the outstanding durability of repairs for degenerative disease80. Although much effort has been directed toward increasing mitral valve repair with degenerative mitral valve disease, perhaps the direction should be toward an expectation of valve repair if possible for all patients.The publications on treating and managing mitral stenosis have not been as plentiful as those on mitral regurgitation and this is reflected by a lack of changes in the guidelines with respect to managing mitral stenosis. One area that is developing is the growing experience with mitral valve repair in rheumatic mitral valve disease. Literature in this field should be interpreted with the recognition that there are differences between patients with rheumatic mitral valve disease who undergo surgery in developed countries compared with less developed nationsCurrently, there are many developments in the field of mitral valve disease that offer promise in improving our understanding and management of these patients. Application of novel imaging methods is providing us greater insights into mitral valve remodeling with disease and how these could contribute to possible mechanisms for failure with valve interventions. Additionally, although there is a significant number of patients with clinically important mitral regurgitation who are undertreated, advances in interventional techniques may not necessarily be required to improve their outcomes. Greater application of the guidelines and use of risk scores may have a larger impact. Also, the promise of transcatheter procedures will increase the number of patients receiving a bioprosthetic valve, but a clear discussion should be had with patients with respect to risks of mortality, failure and reoperation. Lastly, more study is needed both in transcatheter mitral valve procedures and in surgical repair to improve long-term patient outcomes.


Future studies could be conducted to confirm these findings, and identify pathophysiological mechanisms.Although echocardiograms are often performed when peritoneal dialysis is started, associations between commonly reported findings and prospective changes in renal function remain understudied. Ninety-nine of 101 patients in the Trio Trial had transthoracic echocardiograms within 6 months of dialysis initiation, and measurements of residual renal function every six weeks for up to two years. Generalized mixed modelling linear regression in STATA was used to examine associations between left atrial size, left ventricular hypertrophy, left ventricular ejection fraction, right ventricular systolic pressure, and left valvular calcification with subsequent slopes in renal function. After echocardiography  right ventricular systolic pressure was associated with  This frequently reveals abnormalities such as left atrial enlargement, left ventricular hypertrophy, impaired left ventricular function, elevated right ventricular systolic pressures, and valvular calcification that are prospectively tied to worsened survival and cardiovascular outcomes5. Links between echocardiographic findings and subsequent changes in residual renal function (RRF), particularly in patients receiving peritoneal dialysis (PD), are less clear. Most studies examining echocardiogram findings in relation to renal function were restricted to patients not yet on dialysis or to those on hemodialysis6. Those that included patients on PD were limited by cross-sectional or retrospective designs, imprecision of RRF measurements, short durations of follow-up, or examination of only some of the commonly reported echocardiographic parameters8.Clinical guidelines and practice have led to widespread use of echocardiography in patients new to dialysis9. Given that cardiac and renal disease commonly overlap, early markers (as assessed by echocardiography) of cardiac disease might also predict progression of kidney disease. The Trio Trial was a multi-center trial in which incident patients in Toronto and Hong Kong were randomized to receive biocompatible or standard PD solutions for up to two years9. The primary outcome was slope of RRF, and all patients received transthoracic echocardiography after PD initiation according to the published study protocol. In this sub-analysis of the Trio Trial, we examined whether and how left atrial size, left ventricular hypertrophy, left ventricular ejection fraction, right ventricular systolic pressure, and left-sided valvular calcification were associated with prospective changes in RRF in patients new to peritoneal dialysis.Renal function remains very important even after PD has been initiated, and efforts to better understand factors that affect or predict its decline are warranted. Currently accepted favorable prognostic factors include use of biocompatible PD solutions as well as use of inhibitors of the renin angiotensin aldosterone systemAll patients analyzed in the Trio Trial were eligible for this sub-analysis. Patients who did not have echocardiography within six months of PD initiation were excluded.Residual renal function - defined as the mean of 24-hour urea and creatinine clearances - was measured every 6 weeks from dialysis initiation for 2 years, or until drop-out or study closure. Only values after echocardiography were considered for this sub-analysis.Left atrial size was defined as the anteroposterior linear dimension in the parasternal long axis view. Values were categorized as less than 30 mm, 30 to 44 mm, and 45 mm or greater. Information on left ventricular mass index was provided less consistently than commentary on the presence of left ventricular hypertrophy. Left ventricular hypertrophy was thus considered present if specifically reported, and absent if specifically reported as absent or if not mentioned. Left ventricular ejection fraction was calculated using the biplane Simpson’s method, and variously reported as a percentage  or grade . If reported as percentage it was converted to the corresponding grade. Right ventricular systolic pressure, a surrogate of systolic pulmonary artery pressure, was derived from the maximum pressure gradient difference between the right atrium and ventricle added to an estimate of right atrial pressure. It was categorized as less than 30 mmHg, 30 to 49 mmHg, and 50 mmHg or greater. Valvular calcification was assessed by number of left-sided heart valves (or respective annuli) noted to be calcified .The primary outcome was slope in residual renal function (mean of 24-hour urea and creatinine clearances measured every 6 weeks) after baseline echocardiography.After data preparation in Excel  all statistical analyses were conducted in STATA . Descriptive statistics were reported as frequencies (%), means (standard deviations) or medians (ranges) as appropriate. Generalized mixed linear regression modeling assuming an autoregressive (1) covariate structure was used to examine associations between RRF and baseline echocardiographic parameters. The primary outcome was assessed in a mixed model that counted time on dialysis, study site, choice of PD solution and interaction term, and history of congestive heart failure, diabetes mellitus, or coronary artery disease in addition to the five echocardiographic parameters  along with interaction terms as fixed-effects explanatory variables. Patient identification number was the only random-effect covariate included in the model. Two sensitivity analyses were conducted: the first assessed the effect of the timing of echocardiograms relative to PD initiation by adding the date of echocardiography as a fixed-effects covariate to the model. The second assessed whether similar results were obtained if urine volume was used as the primary outcome.Compliance with Ethical Standards: study procedures were conducted in accordance with the Good Clinical Practice and the Declaration of Helsinki on biomedical research involving human subjects.Written approval to conduct the Trio Trial was obtained from the ethics review boards at each of the participating hospitals - Scarborough Hospital Ethics Review Board, Credit Valley Ethics Review Board, and The Princess Margaret Hospital Ethics Review Board). The protocol was registered at controlled-trials.com/isrctn/pf/26252543 (ISRCTN26252543).All participants signed written informed consent before enrolment in the study.2 and overall unadjusted rate of decline was 0.154 ml/min per month . Mean initial glomerular filtration rate was 6.8 ± 2.9 ml/min/1.73 mWhen examined independently of the other parameters, all but left atrial size significantly associated with RRF Table . Figure The results were not altered by inclusion of the date of echocardiogram relative to dialysis initiation (data not shown), and similar results were obtained if urine volume  was the primary outcome  and renal events10. However, in defining renal events as a 50% drop in glomerular filtration rate and/or need for renal replacement therapy, the authors may have missed more subtle changes in renal function. We speculate that a rising right ventricular systolic pressure reflects progressive right ventricular diastolic dysfunction and increasing preload dependence11. If so, the universal and sometimes aggressive pursuit of ‘dry’ weights in dialysis-dependent patients with right ventricular diastolic dysfunction would be expected to lead to disproportionately larger drops in cardiac output. Rising right ventricular systolic pressure and declining renal function may also share a common underlying cause. For example, arterial vasoconstriction in the pulmonary and renal vascular beds (on the basis of disordered circulating endothelin-1 and nitrous oxide) has been reported in CKD12. Similarly, increased pulmonary and podocyte calcium-sensing receptor activity - which induces pulmonary smooth muscle cell proliferation and increased proteinuria respectively14 – presents another intriguing possibility. However, whether such activation occurs in dialysis-dependent patients has not to our knowledge been studied.In their analysis of 2959 patients with CKD in the Chronic Renal Insufficiency Cohort, Navaneethan 15. It is likely that the consequences of left ventricular dysfunction, as seen in other scenarios, may depend on the degree of dysfunction. For example, unlike patients with more moderate dysfunction, only those with sustained ejection fractions under 35% suffer high enough rates of arrhythmic deaths to warrant consideration of therapy with implantable cardiac defibrillators16.The finding that worsened left ventricular function was associated with slower rates of decline in RRF was unexpected, especially given that left ventricular function was normal in 95% and only moderately impaired in the remaining five percent of patients Table . It is pet al. found an inverse association between valvular calcification and RRF. However, the direction of association could not be ascertained, and the significance of this association was lost after adjusting for the calcium/phosphorus product and C reactive protein levels7. While it is biologically implausible that the presence of valvular calcification should delay the decline in residual renal function, these observations may be explained by the presence of variables which confound the link between valvular calcification and renal function.To our knowledge, no studies have looked for a prospective association between left valvular calcification and RRF. In their cross-sectional analysis of 230 prevalent PD patients, Wang et al. showed a positive association with left atrial size, right ventricular systolic pressure was not included in their multivariate analysis that showed an association between left atrial size and RRF8.Left ventricular hypertrophy associated with slower rates of decline in RRF only when examined in isolation of the other echocardiographic variables, and left atrial size did not associate with RRF in this cohort of patients. Previous studies did not collectively examine these five echocardiographic variables. For example, although Kim The Trio Trial was designed and powered to ascertain changes in renal function following treatment with two different PD solutions, not after echocardiography. Furthermore, the lack of data concerning prospective residual renal function changes in relation to baseline echocardiographic parameters meant that sample size and power calculations could not be performed. The timing of the echocardiograms was also not standardized, with 22 performed before dialysis initiation, and the rest up to 101 days later. While it is unlikely that the echocardiographic parameters would have changed significantly within the time-frame allowed, this was addressed by restricting the analysis to residual renal function measured after echocardiography. This reduced the planned follow-up period for some patients, but extended the findings to those receiving echocardiograms up to 3 months post dialysis initiation. Details included in the reports were not standardized, and parameters such as diastolic function, indexed left ventricular mass, or the ability to grade left ventricular hypertrophy were not available. Finally, the impact of potential unexamined confounders  cannot be excluded, and this study is unable to conclude causality between echocardiographic findings and prospective changes in residual renal function.Elevated right ventricular systolic pressure associated with faster, while reduced left ventricular ejection fraction and valvular calcification associated with slower prospective rates of decline in residual renal function in this cohort of 99 incident PD patients. If confirmed, these findings might yield further insight into the prognostic value of echocardiography and the factors that affect residual renal function in patients receiving PD.Supplement Figure 1 (a-e)


We applied multiparametric MRI to assess changes in liver composition, perfusion and blood flow in 17 patients before direct-acting antiviral (DAA) therapy and after treatment completion .We observed changes in hepatic composition indicated by a reduction in both liver longitudinal relaxation time , transverse relaxation time , and liver perfusion (28.1 ± 19.7 ml/100 g/min) which we suggest are linked to reduced pro-inflammatory milieu, including interstitial oedema, within the liver. No changes were observed in liver or spleen blood flow, splenic perfusion, or superior mesenteric artery blood flow.For the first time, our study has shown that treatment of HCV with DAAs in patients with cirrhosis leads to an acute reduction in liver T1, T2 and T2* and an increase in liver perfusion measured using MR parameters. The ability of MRI to characterise changes in the angio-architecture of patients with cirrhosis after intervention in the short term will enhance our understanding of the natural history of regression of liver disease and potentially influence clinical decision algorithms.• DAAs have revolutionised the treatment of hepatitis C and achieve sustained virological response in over 95% of patients, even with liver cirrhosis.• Currently available non-invasive measures of liver fibrosis are not accurate after HCV treatment with DAAs, this prospective single-centre study has shown that MRI can sensitively measure changes within the liver, which could reflect the reduction in inflammation with viral clearance.• The ability of MRI to characterise changes in structural and haemodynamic MRI measures in the liver after intervention will enhance our understanding of the progression/regression of liver disease and could potentially influence clinical decision algorithms. Globally, chronic hepatitis C virus (HCV) infection is estimated to affect 71 million people –4, emergp < 0.001 [p < 0.001 [p = 0.04 [Improvement in clinical outcomes following HCV eradication with treatment regimens of pegylated interferon and ribavirin is established; large cohort studies show differences in liver decompensation rates between SVR and non-SVR groups: hazard ratio (HR) 0.24 95% CI 0.14–0.42),  < 0.001 ; HR 0.26 < 0.001 ; and HR p = 0.04 . Furtherp = 0.04 –14. Alth–0.42,  <p = 0.04 . Hepaticp = 0.04 –18. TogeHowever, individual and invasive techniques for measuring fibrosis and portal hypertension respectively do not assess the complex pathophysiological changes associated with progression and regression of chronic liver injury. Furthermore, ethical and practical constraints limit serial liver biopsy sampling with DAA therapy. A multicentre prospective study, with paired invasive HVPG and non-invasive transient elastography (TE), demonstrated DAA therapy significantly reduced HVPG, but patients continued to have clinically significant portal hypertension and remained at risk of decompensation . Current1) of liver tissue is validated against inflammation/fibrosis on liver biopsy [2) in liver disease [1 and liver perfusion, predicted clinical outcomes [Non-invasive, contrast agent-free, quantitative multiparametric magnetic resonance imaging (MRI) provides the opportunity to assess liver composition  and haemodynamics  in a single scan session (< 40 min). Longitudinal relaxation time . Patients followed standard management protocols for DAA therapy and monitoring. Routine clinical information including medical history, clinical examination and laboratory values were recorded for each participant. Laboratory values were used to calculate validated scores of ALT, Fib4  and APRI3 resolution, single breath holds per orientation) to locate the liver and vessels of interest and to estimate liver volume.MRI data were acquired on a 1.5-T Philips Achieva scanner  in a single 40-min scan session using methods described in . Subject1, T2 and T2* were mapped in nine axial slices through the liver (field of view (FOV) 288 × 288 mm2, voxel size 3 × 3 × 8 mm3, 4-mm slice spacing). A modified respiratory-gated inversion recovery sequence with a fat-suppressed spin echo echo-planar imaging (SE-EPI) readout scheme was used to measure liver T1 [1 mapping sequence was acquired with slices collected in ascend and descend slice ordering to increase the dynamic range of inversion times. In total, 20 inversion times were acquired in < 3 min. A respiratory-gated SE-EPI sequence was used to map liver T2 comprising six echo times  in approximately 2 min. T2* mapping was collected using a multiecho fast field echo (mFFE) sequence comprising 12 echo times  acquired in a ~ 17-s breath hold. T2 and T2* datasets were geometrically matched to the T1 dataset.Liver Tliver T1 , 27, 28 1, T2 and T2* maps . Prior to data fitting, images affected by motion (due to missing the respiratory trigger) were discarded. To create T1 and M0 maps, data at the 20 inversion times were fit using a voxel-by-voxel two-parameter fit. For T2 and T2* mapping, a voxel-by-voxel log-linear least-squares method was used to fit the echo intensities to create T2 and T2* maps. To assess the quantitative T1, T2 and T2* maps, a region of interest covering the liver was selected and a histogram of values within computed. A Gaussian curve was fitted to the histogram to determine the mode of the T1, T2 and T2* distribution within the liver; this procedure excludes regions where vessels are visible within the liver.In-house software was used to create T3 [2), mean velocity (cm/s), and hence mean bulk flow (ml/s) over the cardiac cycle were calculated for each vessel.Phase contrast (PC)-MRI assessed blood flow through vessels in the hepatic circulation  as well as vessels critically related to portal hypertension ) with reconstructed voxel size of 1.17 × 1.17 × 6 mm3 . PC-MRI 2 field of view, 3 × 3 × 8 mm3 voxel, 3 sagittal slices, slice gap 5 mm) were collected with a balanced fast field echo (bFFE) readout in approximately 5 min. A base (M0) equilibrium scan and T1 map were also acquired for quantification of hepatic tissue perfusion using a kinetic model. In-house software was used to motion correct the images and perform automatic outlier rejection of images affected by movement prior to quantification of tissue perfusion [Respiratory-triggered flow-sensitive alternating inversion recovery arterial spin labelling (FAIR-ASL) data , while categorical variables are reported as number of patients with (proportion of patients with) the certain characteristic.Statistical analysis was performed with t test is used for comparisons between pre- and post-treatments for normally distributed data and Wilcoxon matched pairs signed-rank test when not normally distributed. All statistical analysis is Bonferroni corrected for multiple comparisons.Paired Student’s 2) had three scans, at least 1 week apart and within 4 weeks, at the same time of day and after an overnight fast to limit diurnal and dietary variability. This healthy participant study was approved by the University of Nottingham Ethics committee.To determine between session repeatability of MRI measures, the intra-subject coefficient of variation (CoV) (defined as the standard deviation/mean) of multiparametric MRI measures was assessed. A subset of ten healthy participants ; however, there was an increase in liver perfusion following DAA therapy  and haemodynamics over a short time period following clearance of HCV infection. We did not observe any changes in bulk hepatic or splanchnic blood flow in the short time frame between MRI scans.Using multiparametric MRI in patients with HCV-related cirrhosis pre- and post-DAA therapy, we have demonstrated significant changes in the liver composition  on liver diffusion, demonstrating reduced liver apparent diffusion coefficient suggested to be associated with ultrastructural changes such as cell necrosis/apoptosis and inflammatory cell infiltration . A recen1, liver perfusion and haemodynamic measures, were associated with clinical outcomes in independent cohorts of patients [1 acquisition and analysis have been shown to be highly repeatable [1, T2 and T2* respectively, considerably lower than inter-subject variability. Capturing data pre- and post-treatment enables direct intra-individual comparisons, strengthening the validity of the data, since each subject is their own control. We show that in response to DAA therapy, the reduction in T1 is more significant compared to that of T2 and T2*; this could be attributed to the smaller CoV. However, there is also variability within the literature in terms of a T2 change, with pre-clinical models of liver fibrosis shown to result in an increase as well as decrease in T2 [2 is related to hepatic inflammation associated with the development of fibrosis or the proliferation of small biliary ducts in models of bile duct ligation [The strengths of this current study are the prospective recruitment and phenotyping of the patients. The quantitative MRI parameters have previously been validated against “gold standard” measures including liver biopsy , 20 and patients , 29. Livpeatable , with anpeatable . Here, wse in T2 . It is hligation .The limitations of this study are the small sample size from a single UK centre, with some variation in patient disease severity. Due to practical constraints, we were unable to perform parallel invasive assessments of liver biopsy or HVPG. The timing of the MRI scans in close proximity to drug therapy enabled characterisation of changes at an early time point in subjects who achieve SVR at a later time point.The observation that only few specific MR parameters changed in the study time period is relevant. Notwithstanding the possibility of type 1 and type 2 errors, the lack of significant changes in liver bulk blood flow potentially indicates the natural history of “regression”. Reversal of fibrotic and vascular networks, which of course may be incomplete , is thouPegylated interferon and ribavirin ameliorate portal hypertension in patients with HCV monoinfection –18 and H1, T2 and T2* and increased liver perfusion are linked by a reduction in the pro-inflammatory milieu within the liver, including interstitial oedema, aligned with a reduction in serum ALT. We hypothesise that DAA treatment reduces necroinflammation which may improve liver function over a longer period of time [We speculate our key findings of reduced liver T of time  and can  of time , and we  of time . A reduc of time . Chronic of time , and CT  of time . This isA multimodal technique including MRI that captures how the different aspects of liver composition, perfusion and blood flow change over time could provide additional confidence for clinical decision-making. In addition, robust non-invasive tests that are specific to the liver would be valuable to drug development for antifibrotic compounds as they can be repeated at multiple time points to evaluate drug efficacy. MRI has the potential to be a key non-invasive tool to evaluate the efficacy of interventions in chronic liver disease and stratify patients according to the potential clinical outcomes.1, T2 and T2* and increase in liver perfusion measured. The ability of MRI to characterise changes in the angio-architecture of patients with cirrhosis after intervention at such short intervals will enhance our understanding of the progression/regression of chronic liver disease and potentially assist clinical decision-making. The sensitivity of these MR measures should be exploited to accelerate early phase of clinical development of novel antifibrotic agents.In summary, for the first time, our MRI study has shown that treatment of HCV with DAAs in patients with cirrhosis leads to an acute reduction in liver TIn future work, our intention is to use quantitative MRI measures to observe the long-term effects of DAA therapy on liver composition, perfusion and surrounding haemodynamics to characterise the extent of fibrosis regression, vascular remodelling and reduction in portal hypertension that may occur after DAA therapy. Furthermore, we aim to assess whether MRI changes correspond to, or are predictive of, histological regression of fibrosis, as described in long-term studies with interferon and ribavirin , 44, 45.


SCD) is not well established. We tested the performance of several biomarkers in risk assessment for SCD in patients with coronary artery disease (CAD) and preserved left ventricular function.Biomarkers have shown promising results in risk assessment of cardiovascular events. Their role in predicting the risk of sudden cardiac death  43%) enrolled in the ARTEMIS study. The study subjects underwent examinations with echocardiography and measurement of several biomarkers. The primary endpoint of the study was SCD. During the mean follow up of 76±20 months 50 patients experienced SCD. Elevated high sensitive CRP , soluble ST2 , B-type natriuretic peptide , and highly sensitive TroponinT  predicted the occurrence of SCD in univariate analysis. Using the optimal cutoff points, elevated sST2  and hs-TnT  were the strongest predictors of SCD followed by hs-CRP  and BNP  in adjusted analysis. Combination of elevated hs-TnT and sST2 resulted in adjusted HR of 6.4 .The study population consisted of 1,946 sST2 and hs-TnT predict the occurrence of SCD among patients with CAD and preserved left ventricular function. The association between sST2, hs-TnT and SCD may be explained by an ongoing myocardial apoptosis followed by fibrosis leading to vulnerability to malignant arrhythmias.Elevated  CAD) is still the most common cause of death in Western society. Even though the prevention and treatment of CAD has improved during the last three decades, the impact of sudden cardiac death (SCD) remains prominent + 0.6 g). LV mass index was calculated by dividing LV mass by body surface area. Patients with LVEF <35% who had an indication for prophylactic implantable cardioverter-defibrillator were excluded from the consecutive series. SYNTAX Score was calculated by three experienced interventional cardiologists using the Web-based calculator version 2.11 on the SYNTAX Score Web site (www.syntaxscore.com).Laboratory samples were obtained after 12-hour overnight fast using standardized methods. Subjects without known diabetes had an oral glucose tolerance test. anization. PatientARTEMIS study is SCD, including aborted cardiac arrests. The occurrence of SCD and aborted cardiac arrests was defined by an endpoint committee (HVH and MJJ) from death certificates including autopsy reports, hospital records, and contacts with next of kin. Only probable or possible sudden deaths were classified as SCDs, including witnessed sudden death within one hour after the onset of symptoms, or within 24 hours of when the victim was last seen alive without any evidence of non-cardiac cause of death at autopsy. The secondary endpoint of the study was defined as all-cause mortality (ACM).The primary endpoint of the SD), median (interquartile range) or the number of subjects (%). Two-tailed t-test for independent samples, Mann-Whitney U-test (if non-Gaussian distribution of the data) or chi-square were used to compare the survivors with the groups of SCD and ACM. Receiver operating characteristic (ROC) was used to establish the optimal cutoff value for the novel biomarkers using SCD as endpoint. The cutoff was set to the value that provided the maximum sum of sensitivity and specificity, sensitivity being at least 20% but less than 50% of patients having positive result. The prognostic significances of biomarkers were assessed according to the recommendations by Hlatky et al. [IDI) calculation. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated by univariate Cox regression analysis for each risk marker. Thereafter, the predictive value of each biomarker was assessed in multivariate Cox regression where age, sex, body mass index, Canadian Cardiovascular Society grading of angina pectoris, left ventricular ejection fraction, albumin-creatinine ratio, estimated glomerulus filtration rate (eGFR), HbA1c, and T2D were entered in the model as continuous variables when applicable. The covariates were selected based on clinical significance and relevant differences found in characteristics between the groups with and without SCD. Multimarker Cox regression models were also established for the most significant biomarkers followed by further adjustments for potential confounders. Competing risks survival analyses were also conducted using approaches of SCD vs.non-sudden cardiac death.Values are expressed as mean . Categorical and continuous net reclassification index  were also calculated[Due to the varying follow-up time, discrimination and reclassification analyses were based on individual time-dependent estimated risk for alculated. Kaplan-SCDs, including 8 aborted cardiac arrests, were observed. Non-sudden cardiac death occurred in 44 subjects, which include pump failure and heart failure deaths. The concentrations of biomarkers, except for galectin-3, were higher in the patients who suffered SCD than those without the primary endpoint , respectively  of 6.4  compared to those with both at normal level in multivariate Cox analysis  and after adjustment for the established risk markers . Univariate and adjusted HRs for the non-sudden cardiac death from the competing risks analysis were 7.5  and 2.3  for hs-TnT, and 4.0  and 2.7  for sST2, respectively.Elevated hs-TnT to the established model for SCD improved discrimination  as well as the classification by continuous  but not categorical NRI . The inclusion of sST2 in the risk model did not improve discrimination  and improved the classification of the patients only when analyzed by continuous NRI . When both elevated hs-TnT and sST2 were added to the established model, C-index improved from 0.732 (95%CI: 0.665–0.799) to 0.780 (95%CI: 0.720–0.839); the IDI being significant . Continuous , but not categorical NRI , indicated improved classification of the cases. The Kaplan-Meier curves of elevated hs-TnT, sST2, and their combination are presented in the The addition of CAD patients with T2D, abnormal hs-TnT and hs-CRP were the only variables that predicted SCD  in the multivariate analysis , whereas among those without T2D, only abnormal sST2 predicted the primary outcome . Hs-TnT, hs-CRP, BNP and sST2 were significant predictors of all-cause mortality in CAD patients with  and without T2D .In SCD risk among the patients with CAD and preserved left ventricular function. Soluble ST2 and hs-TnT were the most powerful predictors after adjustments with several clinical and laboratory variables as well as LVEF. A combination of elevated concentrations of both sST2 and hs-TnT yielded high predictive accuracy in SCD prediction in this population.This study showed that measurement of biomarkers from blood samples provides information on SCD among CAD patients with preserved left ventricular function, since the majority of SCD victims have a heart disease with normal or mildly impaired cardiac function[CHF or on those with a recent acute myocardial infarction. This has raised the question of whether any of the risk stratification methods can be improved in order to develop appropriate preventive strategies for this large number of potential victims of SCD included in the present study.The present study aimed to focus on the risk assessment of  function,18. FurtSCD risk has not been thoroughly studied. To our knowledge, BNP is the only biomarker that has been shown to predict SCD after acute myocardial infarction[sST2, hs-TnT, galectin-3 and hs-CRP, have predicted all-cause and cardiac mortality among patients with heart failure, stable CAD and even in general population[SCD in patients with CHF [SCD in patients with preserved left ventricular function. Multimarker strategy, i.e. combination of two or more risk variables, has been shown to improve the prediction of cardiovascular events in previous studies[sST2 and hs-TnT in the present population also provided the most powerful information on the risk of SCD.All biomarkers included in this study have provided prognostic information in various patient populations in prior studies, but the utility of these variables in prediction of nfarction. The othopulation,10,20,21with CHF  while nos studies. CombinaST2 and hs-TnT were the strongest predictors of SCD in the present study. Soluble ST2 is a member of the interleukin-1 receptor family and circulating sST2 concentrations are believed to reflect cardiovascular stress and cardiac fibrosis[ST2 is elevated in CHF, older age and in diabetes[sST2 concentrations in general population[Hs-TnT is a novel marker reflecting ongoing myocyte death and apoptosis without any evidence of an acute ischemic event. Elevated levels of hs-TnT have been associated with higher risk of incident coronary event, hospitalization due to heart failure, cardiac mortality, cardiovascular mortality, stroke and cancer[ARTEMIS population, we found that hs-TnT is a strong predictor of a composite endpoint of cardiac death and hospitalization for heart failure during a 2-year follow-up[Soluble  fibrosis,24. Solu diabetes. It has opulation. Hs-TnT nd cancer–8,27,28.follow-up.sST2 and hs-TnT predicted SCD remains speculative. These two biomarkers obviously reflect partly different aspects of cardiovascular stress and tissue damage leading to untoward cardiac events, either progressive heart failure or occurrence of SCD even without prior evidence of left ventricular systolic dysfunction. It can be hypothesized that elevated hs-TnT is a marker of ongoing myocyte loss and elevated sST2 reflects the consequent cardiac replacement fibrosis as a result of cell death, which eventually creates a substrate for fatal arrhythmia. Fibrotic scarring has been shown to correlate strongly with an increased incidence of arrhythmias and SCD[CAD patients who would otherwise be at low to intermediate risk of SCD can be included in a higher risk group with biomarkers of inducted replacement fibrosis accumulation. This paradigm explains partly why some patients with stable CAD and normal LV function enter a downslope in prognosis through continuous cell death and formation of replacement fibrosis. This scenario would eventually end up in decreased LV systolic function, but we do not currently often encounter CAD patients with decreasing LV function. On the other hand, the number of patients with some form of heart failure with preserved EF is increasing. Thus more patients with accumulated fibrosis are at risk of lethal arrhythmias than lethal pump failure.The mechanism why both s and SCD. Our resARTEMIS study design including a relatively large number of patients with T2D is a potential limitation of the present study. The power of the study does not allow risk prediction separately for non-diabetic patients. Therefore, it remains uncertain whether the present results are applicable only to CAD patients with T2D but not to non-diabetic patients. Further studies should focus also on non-diabetic patients with preserved left ventricular function. A larger sample size is needed for this purpose, since the incidence of SCD is much smaller in non-diabetic patients with CAD as compared to their diabetic counterparts[ICD, but the hypothesis of ongoing fibrosis accumulation in CAD patients would hopefully result in more precise examination methods and more sophisticated intervention methods in the future. Additionally, in our analysis we used low sensitivity ELISA assays which are not approved for clinical diagnostics and can be viewed as a potential limitation. Also the number of subjects in this study prevented us from dividing the population to training and test cohorts. Unfortunately we do not have sufficient interim information on EF% development in this study and thus cannot show whether the biomarker levels are specifically associated with SCD or deterioration of LV systolic function.The nterparts. It is cSCD in CAD patients with preserved left ventricular systolic function. The multimarker strategy appeared very useful in this respect. Future research should focus on preventive strategies among patients with elevated levels of biomarkers, especially both hs-TnT and sST2. Examples include angiotensin-converting enzyme inhibitors, aldosterone antagonists, nesiritide, emerging antifibrotic therapies[The present study showed that analysis of serum biomarkers can provide important information on the risk of therapies, or perhtherapies.S1 File(XLSX)Click here for additional data file.


Atrial fibrillation (AF) is associated with cognitive impairment/dementia, independently of clinical cerebrovascular events (stroke/TIA). One of the plausible mechanisms is the occurrence of AF-induced transient critical hemodynamic events; however, it is presently unknown, if ventricular response rate during AF may impact on cerebral hemodynamics. AF was simulated at different ventricular rates  by two coupled lumped parameter validated models , and compared to corresponding control normal sinus rhythm simulations (NSR). Hemodynamic outcomes and occurrence of critical events (hypoperfusions and hypertensive events) were assessed along the internal carotid artery-middle cerebral artery pathway up to the capillary-venous bed. At the distal cerebral circle level , increasing ventricular rates lead to a reduced heart rate-related dampening of hemodynamic signals compared to NSR . This response causes a significant progressive increase in critical events in the distal cerebral circle (p < 0.001) as ventricular rate increases during AF. On the other side, at the lowest ventricular response rates (HR 50 bpm), at the systemic-proximal cerebral circle level  hypoperfusions (p < 0.001) occur more commonly, compared to faster AF simulations. This computational study suggests that higher ventricular rates relate to a progressive increase in critical cerebral hemodynamic events (hypoperfusions and hypertensive events) at the distal cerebral circle. Thus, a rate control strategy aiming to around 60 bpm could be beneficial in terms on cognitive outcomes in patients with permanent AF. This growing epidemiological burden warrants answers to currently pending questions regarding AF. In particular, it has emerged that AF is associated with an increased risk of dementia and cognitive impairment, even in anticoagulated patients2 in the absence of clinical strokes4. Several mechanisms have been proposed to clarify this association7, such as silent cerebral ischemia (SCI), microbleeds, altered cerebral blood flow dynamics and pro-inflammatory conditions.During the last two decades, atrial fibrillation (AF), the most common cardiac tachyarrhythmia, has become one of the most relevant public health problems8 ultrasonography, lack the resolving power to provide insights, in terms of flow and pressure signals, on the portion downstream the three cerebral arteries . Given the paucity of clinical data, our group recently run a validated computational model to simulate cerebral hemodynamics during AF10, concluding that AF is associated, when compared to normal sinus rhythm (NSR), with an altered cerebral hemodynamics, characterized by transient hypoperfusions and hypertensive events in the deep cerebral circle.Among these possible contributors, the hypothesis of an altered cerebral blood flow dynamics during AF has been the least investigated, most likely due to the evident concerns related to a direct sampling in the cerebral circulatory system. In addition, the currently adopted non-invasive techniques in the field of cerebral hemodynamics, as transcranial doppler (TCD)per se as a contributing factor to the non-embolic cerebral events and cognitive decline related to the arrhythmia, another open clinical question refers to the ideal heart rate target to achieve during rate control strategy of patients with permanent AF. In general, clinical evidence on this topic is scarce. The RACE II clinical trial11, albeit with widely discussed limitations12, suggested that lenient (resting heart rate <110 beats per minute) and strict (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute) rate control strategies did not differ in terms of mid-term cardiovascular outcomes. However, cerebral hemodynamics, cognitive impairment and dementia were not within the studied outcomes. Interestingly, Cacciatore et al.13 demonstrated, on a small group of AF patients with cognitive impairment, that low (<50 bpm) and high (>90 bpm) mean ventricular responses related to increased progression towards dementia.If the hemodynamic consequences of AF, therefore, candidate Given these presumptions, the present study aims to investigate, based on a validated computational model, if the cerebral hemodynamic alterations induced by AF are modulated by mean ventricular response.14 and relies on a three-steps algorithm, which is sketched in Fig. a, output of the cardiovascular model is exploited as the forcing input of the subsequent cerebral model.The stochastic modelling of the AF cerebral hemodynamics has been recently proposedThe heart beating, RR [s], is defined as the temporal interval between two consecutive heart beats, while the heart rate HR [bpm] is the number of heart beats per minute. We used, both in NSR and AF conditions, artificially-built RR intervals to span the range of average HR between 50 and 130 bpm, thus avoiding the patient-specific characteristics inherited by real RR beating.15, RR extraction is carried out according to the pink noise temporal structure17. Standard deviation values, σ, are determined considering that the coefficients of determination, cv, similarly range in the same interval  for all the HR considered18. Thus, cv was kept constant and equal to 0.07 from 50 to 130 bpm.Normal RR heart beats are extracted from a Gaussian distribution, which is the typical distribution observed during sinus rhythm for RR. Since normal heart beating is correlated and represents an example of pink noise17 and is described by the superposition of two statistically independent times, RR = φ + η. φ is taken from a Gaussian distribution and the extraction is based on the correlated pink noise. η is instead drawn from an exponential distribution (with rate parameter γ) and the beating extraction relies on the uncorrelated white noise. The resulting AF beatings are thus represented by an exponentially modified Gaussian (EMG) distribution. The standard deviation values, σ, are determined keeping the coefficient of variation, cv, constant at each HR and equal to 0.24, as recommended by Tateno et al.19. The rate parameter, γ, instead is a linear function of the mean RR (γ = −9.2RR + 14.6), as proposed in a previous work20.AF distribution, instead, is for 60–65% of the cases unimodal16 and have been validated and tested over clinically measured data21, they were adopted as the most suitable and reliable RR time-series to model NSR and AF conditions. By this approach, the resulting RR extraction intrinsically contains the chronotropic effects due to the heart rate regulation, which differently act during NSR and AF.Since the RR intervals are based on beating featuresTo guarantee the statistical stationarity of the results, 5000 cardiac cycles are extracted for each configuration. The 5000 RR beats extracted in NSR and AF conditions together with the corresponding RR probability distribution functions are displayed in Fig. a). The model, proposed by Korakianitis and Shi22, was validated during AF in resting conditions over more than 30 clinical datasets23, and then exploited to study the cardiovascular response in different conditions and pathologies related to AF25. Through a network of compliances, resistances and inductances, the cardiovascular dynamics includes the systemic and venous circuits together with an active representation of the four cardiac chambers, and is expressed in terms of pressures, flow rates, volumes and valve opening angles. Both atria are imposed as passive to simulate AF conditions, while they can actively contract during NSR.Following RR extraction, the cardiovascular model was run to obtain systemic arterial pressure . As mentioned above, the chronotropic effects due to the heart rate regulation are instead implicitly taken into account by the RR extraction. Details of the governing equations and model parameters are offered in the Supplementary Information.In addition, a baroreceptor modela, was then used as forcing inputs for the forthcoming cerebral model. A schematic representation of the complete cardiovascular system is reported in Fig. a time series in NSR and AF at different HRs.By solving the cardiovascular model, the resulting systemic arterial pressures, P2 reactivity27. The model is able to reproduce several different pathological conditions characterized by heterogeneity in cerebrovascular hemodynamics and has been validated in normal conditions up to the middle cerebral circulation14, since definitive clinical data in the microvasculature are still missing. The present model was then exploited to compare the cerebral hemodynamics during NSR and AF14 at the same heart rate (75 bpm).The cerebral model is based on a lumped parameterization of the arterial and venous cerebral circulation, along with the cerebrovascular control mechanisms of autoregulation and COa and QICA,left), middle cerebral artery , middle distal district , and capillary-venous circulation (Pc and Qpv).Similarly to the cardiovascular model, a network of compliances and resistances describes the cerebral circulation from the large arteries level up to the peripheral and capillary regions. The cerebral circulation is expressed in terms of pressure, volume, and flow rate, and can be divided into three principal regions: large arteries, distal arterial circulation, and capillary/venous circulation. The left vascular pathway ICA-MCA  is here focused as representative of the blood flow and pressure distributions from large arteries to the capillary-venous circulation: left internal carotid artery  for the hemodynamic variables along the ICA-MCA pathway for 5000 cycles at different HRs during NSR and AF were computed. We also defined for each hemodynamic variable the damping factor, df, as the ratio between cv at lowest HR  and cv at a certain HR. Regression analyses on HR-related variability of the damping factor, df, were performed, comparing AF and NSR regression slopes with ANCOVA  test.10 to different HRs, so that each rare event during AF is defined in reference to the corresponding NSR at the corresponding HR. NSR outcomes were thus exploited to define the different reference thresholds for each HR, focusing on hypoperfusions and hypertensive events, the most meaningful events from the cerebral hemodynamic point of view. At a fixed HR, an hypoperfusion occurs when the average mean flow rate per beat stands below the threshold individuated by the 5th percentile in NSR at the corresponding HR. On the contrary, an hypertensive event takes place when the average pressure per beat is above the threshold individuated at the corresponding HR by the 95th percentile in NSR. Both hypoperfusions and hypertensive events can last one or more consecutive beats and this information is also retained. In Fig. Subsequently, the recurrence and distribution of critical events at different HRs was evaluated. We applied the definition of rare events during AFSetting 70 bpm as the reference simulation, Kolmogorov-Smirnov tests with 5% significance level were performed for AF simulation couples  in order to test whether mean flow rate per beat and mean pressure per beat distributions differed in a statistically significant manner.a: systemic arterial pressure; QICA,left: left internal carotid flow rate; PMCA,left: left middle cerebral artery pressure; QMCA,left: left middle cerebral artery flow rate; Pdm,left: left middle distal pressure; Qdm,left: left middle distal flow rate; Pc: cerebral capillary pressure; Qpv: proximal venous flow rate.Table ICA,left, QMCA,left, Pa, PMCA,left), cv similarly decreases during NSR and AF at all HRs computed. In fact, at the corresponding HR, cv reported similar values during both NSR and AF, with relative variations not exceeding 10%. In addition, comparing HR-related variability damping factors for QMCA and Pa, as depicted in Fig. Table dm,left, Pc, Qdm,left, Qpv), at lower HRs, AF presents cv values 1,3-1,5 times higher than NSR, while if the ventricular rate increases (from 50 to 130 bpm), AF variability becomes 1,7-2,5 times higher than NSR. If we compare HR-related variability damping factors for Qdm,left and Pc . In particular, at 130 bpm AF simulations of the cerebral capillary level, 905 hypertensive and 534 hypoperfusions events over 5000 beats occurred, showing a two-threefold increase compared to AF simulations at lower HRs.In fact, hypoperfusions and hypertensive events mainly occurred in the distal circulation , and progressively increased with HR . The Kolmogorov-Smirnov test  lesions at cerebral magnetic resonance imaging (MRI) scan30, and cerebral microbleeds31, possibly related to suboptimal oral anticoagulation therapy (OAT)34, have candidate as potential contributors to this phenomenon. Another hypothesis, however, is that AF, by RR interval variability and loss of atrial systole, may produce cerebral hemodynamic alteration, possibly leading to reduced cerebral flow, brain damage and atrophy36. Moreover, our group previously demonstrated through a computational model of the cerebral circulation that AF, per se, is associated with transient and repetitive critical hemodynamic events in the deep circle (hypoperfusion and hypertensive events)10, that could possibly relate to the genesis of a quote of non-microembolic SCIs and non-OAT related microbleeds.Several hypotheses have been proposed in the attempt of explaining the, to date unknown, correlation between AF and cognitive impairment/dementia, in patients not presenting clinical cerebrovascular events (ictus/TIA)39 and experimental40 settings. Irregular RR intervals were associated with a reduced cardiac output, increased pulmonary capillary wedge pressure and increased right atrial pressure, mainly due to beat-to-beat changes in ventricular filling, with short RR intervals decreasing cardiac output more than long RR intervals. Interestingly, Herbert39 found that the correlation between the percentage of short cycle lengths and a decrease in cardiac index was more marked for patients with an average ventricular rate >75 beats/min than for those with a slower average rate. First evidence was provided that slow ventricular response in AF can partly compensate for hemodynamic consequences of an irregular ventricular rhythm, since at low heart rates even the shortest RR intervals may be sufficiently long to allow for adequate diastolic filling of the left ventricle. Of note, long term clinical follow-up studies apparently demonstrated a reverse association, indicating that a reduced RR variability/irregularity could be associated with higher mortality in AF patients43. These studies, however, were performed in AF patients with concomitant heart failure or severe valvular heart disease, thus the reduced irregularity of RR interval was likely a biomarker of underlying autonomic dysfunction, which directly reflects the presence of a functional/structural substrate associated with increased mortality. In addition, medical therapy recommended for heart failure and/or valvular heart disease may likely impact cardiovascular mortality independent of the achieved RR variability or irregularity.Previous studies have explored the deleterious hemodynamic effect of an irregular heart rhythm, such as in AF, on systemic cardiovascular function, both in clinicalIn the present study, increasing ventricle response during AF was associated to an overall variability reduction of the computed cerebral hemodynamic variables, both in AF and in NSR, due to the signal-flattening effect induced by the shorter duration of the mean heart beat intervals. Moreover, AF presented higher variability in the signals, if compared to NSR, only in the distal cerebral circle , underlining how the baroreceptor and autoregulation mechanisms (both implemented in the present modeling approach) are able to normalize AF-induced hemodynamic perturbations only at the systemic and proximal cerebral circle level. Still, variability of the signals decreased harsher in NSR than in AF at the distal cerebral circle level, differently from the systemic-proximal cerebral circle level where the dampening effect was similar between AF and NSR. This registered effect may, therefore, indicate that, at higher HR during AF, distal cerebral circle progressively loses the ability to absorb AF-induced hemodynamic perturbations, resulting in a limited HR-related dampening of signals variability if compared to NSR.Critical episodes mainly occur in the distal cerebral circle and significantly increase in frequency with HR. Since the trend is substantially monotone with HR, this suggests that there is no optimal HR target to minimize the occurrence of hypoperfusions and hypertensive episodes at this level of the cerebral circulation;In the 50 bpm-AF simulation (the lowest simulated HR in the present study), there is the potential occurrence (3 hypoperfusions events registered over 5000 beats) of critical events at the systemic-proximal cerebral circle level, while no critical events emerge for HR ≥70 bpm.The reduced HR-related dampening of the variability of cerebral hemodynamic parameters in AF consequently leads to more frequent critical events (in terms of hypoperfusions and hypertensive events) at higher HRs. In this perspective, two aspects clearly emerge:44 - is above 50 and below 70 bpm. In fact, these results provide theoretical support to the clinical findings of Cacciatore et al.13, reporting that low (<50 bpm) and high (>90 bpm) HR in AF patients are associated with worse cognitive outcomes.Given these findings, the optimal HR to minimize deep cerebral critical events by avoiding proximal cerebral hypoperfusions - in particular in patients with reduced baroreceptor mechanisms45. However, these computational data, together with the results of Cacciatore et al.13, suggest that in permanent AF a strict rate control strategy targeting resting HR around 70 bpm may be beneficial in terms of cerebral hemodynamics, since it minimizes deep critical events without increasing the risk of proximal cerebral hypoperfusions, possibly slowing the progressive onset of cognitive dysfunction in these patients. Based on the relevant impact in terms of quality of life and social costs of cognitive impairment and dementia, further clinical studies should necessarily focus on cerebral outcomes of NSR maintenance and ventricle rate response during permanent AF.To date, available clinical trials have failed to demonstrate a superiority of rhythm control and strict rate control in terms of classical mid-term hard cardiovascular outcomesThe present computational model does not consider the impact that rate control drugs  could exert on the cardiovascular system. Second, the cerebrovascular model assumes a perfectly functioning baroreceptor and cerebral autoregulation mechanism in both NSR and AF.In the present computational study ventricular response during AF exerts an impact on cerebral hemodynamics. In particular, higher ventricular rates relate to a progressive increase in critical cerebral events (hypoperfusions and hypertensive events) at the distal level (downstream the MCA). These results possibly suggest that, while all efforts should be addressed to maintain NSR as long as possible, a strict rate control strategy could be beneficial in terms of cognitive outcomes in patients with permanent AF.Supplementary Information