Cardiac remodeling occurs in response to regular athletic training, and the degree of remodeling is associated with fitness. Understanding the myocardial structural changes in athlete’s heart is important to develop tools that differentiate athletic from cardiomyopathic change. We hypothesized that athletic left ventricular hypertrophy is a consequence of increased myocardial cellular rather than extracellular mass as measured by cardiovascular magnetic resonance.O2max <60 or>60 mL/kg per min, respectively). In athletes, indexed cellular mass was greater in high- than low-performance athletes 60.7±7.5 versus 48.6±6.3 g/m2; P<0.001), whereas extracellular mass was constant . Indexed left ventricular end-diastolic volume and mass correlated with O2max  and differed significantly by group . Extracellular volume had an inverse correlation with O2max .Forty-five males  underwent comprehensive cardiovascular magnetic resonance studies, including native and postcontrast T1 mapping for extracellular volume calculation. In addition, the 30 athletes performed a maximal exercise test to assess aerobic capacity and anaerobic threshold. Participants were grouped by athleticism: untrained, low performance, and high performance (Increasing left ventricular mass in athlete’s heart occurs because of an expansion of the cellular compartment while the extracellular volume becomes relatively smaller: a difference which becomes more marked as left ventricular mass increases. Athletic remodeling, both on a macroscopic and cellular level, is associated with the degree of an individual’s fitness. Cardiovascular magnetic resonance ECV quantification may have a future role in differentiating athlete’s heart from change secondary to cardiomyopathy. The rare but prominent cases of sudden cardiac death in elite athletes have underlined the importance of understanding the adaptation underlying athlete’s heart (AH).See Editorial by Graham-Brown and McCannSee Clinical Perspective3 The emerging CMR technique of extracellular volume (ECV) quantification allows the relative volumes of the extracellular and intracellular myocardial compartments to be quantified. This method has been used to quantify extracellular expansion (higher ECV) secondary to interstitial fibrosis in cardiomyopathy4 and conversely greater myocyte volume (lower ECV) in pathologies such as Anderson–Fabry disease.6Cardiovascular magnetic resonance (CMR) imaging is particularly well suited to investigate changes of structure and function in athletic cardiac remodeling because of its multiparametric capabilities, high spatial resolution, and lack of ionizing radiation. The excellent reproducibility of the method means that anatomic change can be quantified with greater confidence and smaller sample size than with other methods.O2max).In this study, we sought to characterize cardiac adaptation in male athletes using CMR to gain insights into the mechanisms underlying athletic remodeling. We hypothesized that in athletes, left ventricular (LV) hypertrophy occurs secondary to an increase in myocardial cellular mass rather than ECV and that changes become increasingly prominent with increasing aerobic capacity , or systemic medical illness. All athletes underwent a CMR study before a maximal exercise test, performed on the same day when logistically possible.The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee (Research and Ethics Committee reference: 14/YH/0126). All subjects gave informed written consent.7 planned using the 3 of 5 method8 briefly comprising: ECG triggered 5b(3s)3b MOLLI, flip angle 35°, voxel size of 1.98×1.98×10 mm3. LV mass and volumes were obtained from cine imaging covering the entire LV in the short axis: balanced SSFP, voxel size 1.2×1.2×10 mm3, no gap, 50 cardiac phases. Right ventricular and atrial volumes were obtained from a transaxial stack covering the entire heart: balanced SSFP, voxel size 1.7×1.5×5 mm3, no interslice gap. 0.15 mmol/kg Gadovist (Bayer Schering) was delivered by power injector  as a single bolus via a venous cannula placed in the antecubital fossa, followed by a 20 mL saline flush at 5 mL/s. Late gadolinium enhancement (LGE) imaging  was performed to image the entire LV 7 to 10 minutes after contrast administration. Post-contrast T1 maps were acquired using the same MOLLI scheme 10 minutes after contrast administration.The CMR study was performed at rest and before exercise testing in athletes. All studies were performed on a 3-Tesla Achieva TX system equipped with a 32-channel cardiac phased array receiver coil and multitransmit technology . The cardiac long and short axes were determined using standard scout views. Mid-LV native (precontrast) T1 maps were generated using a previously described MOLLI sequence9 (LV) or long-axis cine images10 . Ventricular and atrial measurements were indexed to body surface area. The presence of focal fibrosis or scar was assessed qualitatively from LGE imaging. T1 values were calculated from source images using manual motion correction, with a region of interest in the mid-inferoseptum as per Rogers et al.11 Partition coefficient (λ) and ECV were calculated using the formulae:All image analysis was performed using cmr42 software . Volumetric and mass analysis was performed in the standard manner from the short-axis stackR1=1/T1 and Hct is hematocrit.where 2.7). Indexed myocyte and extracellular mass were calculated using the formulae: indexed myocyte mass=indexed LV mass×(100−%ECV); indexed extracellular mass=indexed LV mass×%ECV.  All T1, ECV, volumetric, and mass analyses were performed by 2 observers (A. K. McDiarmid and B. Erhayiem) blinded to all subject data, including sporting discipline and aerobic capacity.CMR chamber and tissue values were indexed to body surface area and estimated lean body mass (heightO2max) and ventilatory threshold, participants undertook a ramp-incremental step-exercise test on an electronically braked cycle ergometer , which allows for confirmation of VO2max in a single test.12 Participants wore a nose clip and breathed through a low-dead space, low-resistance mouthpiece which was connected to a bidirectional pitot tube flow sensor and gas sample line assembly, allowing for breath-by-breath measurement of gas volumes and concentrations  and subsequent calculation of ventilatory and pulmonary gas exchange variables . Before each test, the pitot tube flow sensor was calibrated over a range of flow rates using a 3 L syringe, whereas the gas analysers were calibrated using precision gases that spanned the inspired and expired physiological range. A 12-lead ECG was monitored throughout, and heart rate was measured from the R-R interval. The ramp-incremental step-exercise test was preceded by a rest period (≈2 minutes) and unloaded cycling  and continued until a steady state was attained, after which work rate increased as a linear function of time at a rate of 20 to 30 W/min (depending on reported training history), with the intention of bringing participants to the limit of tolerance in ≈10 to 12 minutes.13 The ramp increment was then followed by 5 minutes of active recovery (20 W), after which a step exercise (SE) was performed at 95% of the RI work rate peak, with this SE also continued to the limit of tolerance. In both RI and SE parts of the test, the limit of tolerance was defined as the point at which cycling cadence fell below 50 rpm, despite strong verbal encouragement.Participants were instructed to arrive rested (no strenuous exercise in the preceding 24 hours) and having abstained from any alcohol (preceding 24 hours), food, and caffeine (preceding 3 hours) ingestion. To determine maximal oxygen uptake  that were considered unphysiological.14 Anaerobic threshold was then estimated using the V-slope method15 and supporting ventilatory and pulmonary gas exchange criteria . O2peak was identified in both RI and SE phases as the highest 12-breath rolling average (highest mean O2 over ≈15–20 s).12 Within subjects, the highest 12-breath rolling average from RI and SE phases were then compared using unpaired t tests, with no difference (P>0.05) between RI and SE O2peak, and thus the attainment of O2max was confirmed in each test.17Breath-by-breath data were edited using the O2max <60 mL/kg per min (low-performance group), and athletes with O2max >60 mL/kg per min (high-performance group). Unless otherwise stated, the results are presented as mean±standard deviation (SD). Normality of distribution was determined with Kolmogarov–Smirnov testing. Differences between groups were assessed using the Chi-squared test, independent t test, or 1-way analysis of variance when appropriate. Post hoc analysis was performed with Bonferroni testing. Correlation was assessed with Spearman correlation coefficient. Significance for all tests was assumed with P<0.05.Statistical analysis was performed using IBM SPSS Statistics 20.0 . Subjects were grouped as follows: untrained, athletes with P=0.54). Hematocrit was not significantly different between groups , but body mass index was significantly lower in athletes . CMR study and maximal exercise testing were separated by a median of 0 days (quartile range 1–3). Full study participant information may be seen in Table Thirty endurance athletes  and 15 untrained sedentary controls were recruited. Athletic and untrained participants were prospectively matched for age . Mean O2max and anaerobic threshold as a percentage of O2max in high-performance and low-performance athletes, respectively, were 65.5±6.2 versus 54.2±4.5 mL/kg per min (P<0.001) and 61.9±6.5% versus 59.5±7.6% (P=0.36). No significant atrial or ventricular ectopy was recorded in the exercise or recovery phase of the exercise protocol. None of resting, peak, or Δheart rate differed between groups. Maximal exercise test results are summarized in Table Athletes were divided into high- and low-performance groups at a threshold 2; P<0.001); however, extracellular mass remained constant . Although both the cellular and extracellular masses were higher in athletes than in controls , the relative expansion of the cellular compartment was greater than the increase seen of the extracellular compartment .Indexed cellular mass was greater in high-performance athletes than in low-performance athletes  and with O2max . LGE was seen in one athlete only (3%) and was in a typical myocarditis pattern. A significant inverse correlation was seen between ECV and left ventricular mass index  and hypertrophic cardiomyopathy (HCM), which may both display increased LV mass or left ventricular end-diastolic volume. The role of CMR in the detection of these myocardial diseases is established, and both DCM and HCM display characteristic morphological abnormalities on CMR. At a microscopic level, HCM is characterized by myocyte disarray and interstitial fibrosis35 with an increase of muscle mass without increase in myocyte number.36 In this study, conducted without tissue biopsy, we are unable to determine the intracellular sarcomere arrangement; however, other CMR techniques that allow myocyte size to be quantified, as investigated by Coelho-Filho et al,37 may allow this to be determined in the future.Both side-by-side sarcomere addition in concentric remodeling and end-to-end addition in eccentric remodeling result in myocardial hypertrophy,38 and 50% of veteran athletes.39 In this cohort of athletes, LGE was seen in only 3% (n=1). This difference may be as a consequence of the relatively young age of athletes studied.LGE has previously been demonstrated in ≤13% of elite20 In this study, we have demonstrated that left ventricular end-diastolic volume index and left ventricular mass index correlate with O2max, confirming that the degree of remodeling is related to fitness, and our data are consistent with the literature.The relationship between aerobic capacity and LV remodeling is known.40 Native T1 differed significantly between athletes and controls, but not athletic groups. Native T1 is increased in myocardial edema and inflammation, but also in increased extracelluar volume; consequently, these findings are consistent with ECV in this study. The reason for a lack of difference between athletic groups is not clear, however, and merits further study. Furthermore, the assumptions made regarding the mode of myocardial hypertrophy in AH in this study have not been validated by histological sample. We have not studied female athletes in this study in order to have a homogenous study sample, but it is possible that athletic adaption differs compared with men. Finally, the participants were all of white origin, and this study should be repeated in a range of ethnic origins in an effort to understand AH in all athletes because risk and remodeling may differ between ethnicities.41There was relatively little diversity in the range of athletic discipline pursued; however, this has previously been shown not to affect the phenotype of cardiac remodeling.Cardiac remodeling and LVH in AH occurs as a consequence of greater myocyte mass, with an associated relative decrease of the extracellular space. This is unlike HCM or DCM, where CMR tissue characterization detects marked expansion of the extracellular space, in the presence or absence of LVH. Athletic remodeling, both on a macroscopic and microscopic level, is associated with the degree of aerobic capacity. ECV quantification with CMR may have a future role in differentiating AH from change secondary to cardiomyopathy, especially HCM, and warrants further study.We are grateful for the support and assistance of the radiographers  assistants  during this project.Dr McDiarmid is funded by a British Heart Foundation (BHF) Project Grant (PG/14/10/30641). Dr Swoboda is funded by BHF Clinical Fellowship (FS/12/88/29474). Dr Plein is funded by BHF Senior Research Fellowship (FS/10/62/28409).Drs Greenwood and Plein received a research grant from Philips Healthcare. The other authors report no conflicts.


Echocardiography is currently a widely available imaging technique that can provide useful data in the field of sports cardiology particularly in two areas: pre-participation screening and analysis of the cardiac adaptation induced by exercise.The application of pre-participation screening and especially, the type and number of used diagnostic tests remains controversial. Echocardiography has shown though, higher sensitivity and specificity as compared to the ECG, following a protocol adapted to athletes focused on ruling out the causes of sudden death and the most common disorders in this population. It is still a subject of controversy the actual cost of adding it, but depending on the type of sport, echocardiography might be cost-effective if added in the first line of examination.Regarding the evaluation of cardiac adaptation to training in athletes,  echocardiography has proved to be useful in the differential diagnosis of diseases that can cause sudden death, analysing both the left ventricle  and the right ventricle (arrhythmogenic right ventricular cardiomyopathy).The aim of this paper is to review the current knowledge and the clinical practical implications of it on the field of echocardiography when applied in sport cardiology areas. The benefits of sport practice in improving cardiovascular health are unquestionable2, but an increase in cardiovascular events has also been demonstrated during its practice3. As a consequence, the absolute number of people at risk of sudden cardiac death (SCD) during exercise is also increasing4. Sports activity is not a cause of the increased mortality per se; rather, it might act as a trigger of cardiac arrest in athletes with structural or electrical heart abnormalities that generating malignant arrhythmias. Thus, it seems reasonable that every effort should be made for early recognition of any disease that may put the athlete at risk, keeping in mind the perspective that inadequate disqualification of individuals might also pose a risk.The number of people practicing sport has increased about five fold over the past 30 years5 has proposed an exam which emphasizes three points or steps: a) family and personal history, b) physical examination and c) 12-lead electrocardiogram (ECG). The ECG has demonstrated a 70% sensitivity to detect the most frequent causes of SCD in young athletes7. However, about a third of these athletes with an anomalous origin of coronary arteries, aortic diseases and incipient forms of cardiomyopathies will present with a normal ECG.Therefore, a pre-participation screening (PPS) protocol seems to be of interest. Consequently, the European Society of Cardiology8. Our group reported the echocardiographic findings among 2688 competitive athletes; most of the echocardiographic evaluations were normal and only 203 (7.5%) showed abnormalities9. Cessation of athletic activity was indicated in 4 athletes: 2 for hypertrophic cardiomyopathy (electrocardiography had shown changes that did not meet diagnostic criteria), 1 pectus excavatum with compression of the right ventricle, and 1 significant pulmonary valve stenosis; the other minor alterations in echocardiography  did not entail cessation of athletic activity and only indicated periodic monitoring.The echocardiogram might be a useful, non-invasive and accessible tool to increase sensitivity of screeningAlthough rare, some cardiac structural changes can be missed on physical examination and electrocardiography; in contrast, they are easily recognized with echocardiography. These findings suggest the use of echocardiography in at least the first PPS of competitive athletes to improve the effectiveness of programs aimed at preventing SCD in athletes.10 while other studies have proposed longer protocols performing a complete echocardiogram11. In our group, we carry out the standard transthoracic echocardiographic views suggested by the European Society of Echocardiography12; we consider that the long-axis parasternal, the short-axis parasternal, the apical 4-chamber views and 2-chamber views, suprasternal and parasternal right view provide a high sensitivity to diagnose the most prevalent causes of SCD  hypertrophy show pathological changes in the ECG17. In both situations an echo scan would help to achieve the correct diagnosis.Hypertrophic cardiomyopathy constitutes the leading cause of SCD in young athletes15. It was the second cause of sudden death associated with sports in the largest register of SCD in athletes13. The resting ECG of these athletes is normal, so this entity, if asymptomatic, cannot be detected in a regular PPS based on anamnesis, physical examination and ECG. It is known that an echocardiogram performed by physicians with adequate training can differentiate coronary anomalies with high sensitivity18, and therefore echo is again a key tool to unmask these asymptomatic patients.The anomalous origin of the coronary arteries was considered to be a rare cause of SCD in athletes, but nowadays it has been demonstrated that it can be related to up to half of the previously asymptomatic SCD cases17, although they seem to be a more prevalent cause of SCD in athletes19. Echocardiogram allows for the diagnosis as well as the follow up of these patients. Similarly, bicuspid aortic valve without significant functional abnormalities would not be diagnosed in a regular PPS, and again, the echocardiogram would allow for an early diagnosis and a proper follow up20.Aortic root diseases are an infrequent cause of SCD in young people21.Finally, an echo scan is recommended in congenital heart disease patients, with special focus on ventricular morphology and function, pulmonary pressure and aortic diameters before starting an exercise protocolTo evaluate the cost effectiveness of the addition of a complementary study to the standard PPS, we have to take into account three basic parameters: a) incidence of SCD related to sport practice in the population b) cost of the study; c) years of potential life saved.22 and Israel23 have reported an incidence of 2 cases of sudden death per 100,000 athletes per year, while other studies in France have documented an incidence of < 1 per 100,000 athletes4. On the other hand, the cost to perform an echocardiography is significantly different between American countries7 and Europe24. Finally, the quantification of the years of potential life lost depends on which population is considered, from school age25 or all young adults up to master athletes engaged in sports26. The weight of each of these three factors  in a given population to determine the cost-effectiveness of adding echocardiography in PPS represent the challenge that we will have to face in the upcoming years.To date, there is no consensus which is the real incidence of SCD related to sports practice, because it depends on the analyzed population. Studies in Italy27 in the USA, while in Europe this recommendation was established more than 10 years ago5 and it has been adopted by the different sport committees28 and international federations29. Several studies have demonstrated the cost-effectiveness of including an ECG in the PPS30, but to date, only a small population study in school-aged athletes has analyzed the cost-effectiveness of adding an echocardiography in the screening31; the study showed that adding echocardiography increased both the cost and the sensitivity. In our opinion, the echocardiography provides a higher sensitivity of the PPS, especially in some special populations with greater amount of cardiac disorders described such as competitive athletes9, sports with high static component32 or long distance endurance athletes33. Recommendations for PPS and use of echocardiography used by our group according to the level of sport practice and training are summarized inCurrently, it is still controversial if the inclusion of an ECG in the regular PPS is cost effectiveth century, Henschen described for the first time sport induced cardiac enlargement by auscultation and percussion34. Seventy years after the first athlete’s electrocardiographic features were described36 and a few years after the first 2-dimensional echocardiography images showed the characteristic chamber enlargement and myocardial hypertrophy of the athlete’s heart. Finally, the current advanced echocardiography techniques and magnetic resonance imaging (MRI) have begun to clarify the mechanism involved in these athlete’s heart adaptive features. The study of the athlete’s heart is thus essential, not only to understand how cardiac adaptation contributes to improved athletic performance, but also to differentiate the athlete’s heart from important disease states which may share similar morphologic features. We briefly review the physiologic and morphologic features associated with athletic training and the keys to differentiate normal adaptive athlete’s heart features from mild or initial expression forms of cardiac diseases such as hypertrophy cardiomyopathy (HCM), dilated cardiomyopathy (DCM), left ventricle non compaction (LVNC) and arrhythmogenic right ventricular cardiomyopathy (ARVC).The structural and functional adaptive changes that the heart develops in response to exercise, classically called “athlete’s heart“, has intrigued clinicians and scientists for more than a century. In the 19Different forms of exercise impose different loads on the cardiovascular system. Classically, two forms have been described according to their hemodynamic effect. Endurance exercise results in an increased cardiac output due to the rise in heart rate and stroke volume, reduced peripheral resistance and moderate increment in systemic blood pressure, leading to a volume overload. On the other hand, strength exercise is characterized by a maintained or a slightly increased cardiac output and peripheral vascular resistance, which results in increased blood pressure and thus an increased LV afterload. Cycling or running are examples of endurance exercise while weightlifting is an example of strength exercise, but there are also overlapped sports combining endurance and strength hemodynamic conditions in different proportions such as soccer or hockey. These different hemodynamic conditions will result in different cardiac adaptive structural and functional changes. Moreover, cardiac remodeling is not a continuous response to exercise; it is influenced by individual genetic factors, gender and race. Thus, a proper athlete’s evaluation should be individual and take into account these potential influencers.et al.37 is currently controversial. A meta-analysis by Pluimet al.38 initially confirmed this model; in contrast, a recent meta-analysis by Utomiet al.33 did not find this classic concentric remodeling in strength athletes and only found a slight LV dilatation and similar LV wall thickness as in endurance athletes. An increase in LV wall thickness is a typical feature of the athlete’s heart, however it is usually minimal and within normal range. In a cohort of 947 elite athletes Pellicciaet al.39 found a LV wall thickness > than 13 mm in only 1.7% of the athletes. Sharmaet al.40 in a cohort of 720 elite athletes also reported a low incidence with only 0.4% of subjects showing LV wall thickness > 12 mm among elite junior athletes. However, this small number of extreme cases of exercise-induced remodeling may be difficult to differentiate from mild forms of hypertrophic cardiomyopathy. Various studies have tried to find out the key to differentiate these two entities, but to date there is no pathognomonic sign available, and a combination of clinical and family history, electrocardiographic and echocardiographic features is recommended. The increase in LV wall thickness in athletes is an adaptation to increase stroke volume so it has to be accompanied by chamber enlargement. Thus, a LV end-diastolic diameter > 54 mm41, an increased LV volume and particularly LV volume/mass ratios by MRI42 have been proposed to differentiate athlete’s heart from disease41.Endurance exercise LV remodeling is typically described as LV chamber enlargement with increased wall thickness resulting in an eccentric LV hypertrophy, while strength remodeling is described as a thickening of the LV wall with a slight increase in the size of the LV cavity resulting in a concentric hypertrophy. This dichotomous view, first described by Morganroth43; instead, the pathological forms of LV hypertrophy are typically associated with an impaired diastolic dysfunction characterized by lower early diastolic mitral annulus velocity44. Thus, the evaluation of diastolic LV function by TDI is nowadays mandatory in the evaluation of LV hypertrophy16.Recent advances in echocardiographic techniques including Tissue Doppler Imaging (TDI) and Speckle Tracking Imaging (STI) permit an accurate assessment of the myocardial function, helping us to differentiate adaptation from disease. Numerous studies have demonstrated normal or even supranormal diastolic LV function in athleteset al.45 more than 10% of elite ultra-endurance athletes had LV cavity end-diastolic dimensions > 60 mm, simulating forms of DCM. LV systolic function is described to be in a normal range among athletes46, but again, studies including high intensity endurance athletes have revealed a slight LV systolic dysfunction with LV ejection fraction around 45–49%47. In these extreme cases, the new advanced echocardiographic techniques can also help us. Although slightly lower ejection fraction of the LV might be found, the adaptive cardiac remodeling shows normal or even supranormal values of strain and strain rate by TDI, and normal values of longitudinal strain assessed by STI48. In contrast, in DCM patients these values are reduced49. The effect of endurance training on ventricular deformation, torsion and untwisting rate needs further investigation, but promising findings report exercise-induced supranormal LV untwisting rates50, confirming again the physiological LV response to exercise.As previously described, LV cavity enlargement is part of the cardiac remodeling observed in response to exercise, but this LV dilatation is in most cases minimal and indexed LV cavity dimensions are below pathologic limits. However, in the selected population of endurance elite-athletes this LV remodeling can be extreme. In a study by Pellicciaet al.51 in a cohort of 1146 athletes studied by echocardiography, reported trabeculations in 20% of the athletes, and even more, around 8% fulfilled conventional criteria for the diagnosis of LV non-compaction cardiomyopathy; this prevalence raised to 13% when only black athletes were considered. LV non-compaction cardiomyopathy is a rare cardiomyopathy thought to be secondary to the arrest of normal myocardial development, resulting in multiple deep ventricular trabeculations52. This entity has a wide clinical expression from asymptomatic patients to advanced cases with three characteristic symptoms: heart failure, thromboembolic events and fatal arrhythmias53, and has indeed been related to exercise-related SCD in young athletes54. The mechanisms implicated in LV hypertrabeculation in athletes are still unknown, but the reported high prevalence suggests that it might be another expression of cardiac adaptation to increased preload and afterload influenced by genetic and ethnical factors51. Structural echocardiographic features that could help to differentiate cardiac adaptive remodeling from disease are: the location of trabeculations  and the evidence of late enhancement in cardiac MRI following gadolinium in LV non-compaction cardiomyopathy54. Furthermore, LV non-compaction cardiomyopathy patients may have reduced systolic and diastolic function while athletes with LV hypertrabeculation normally have no systolic or diastolic dysfunction. In the few cases with slightly low LV ejection fraction, a normal or even supranormal increase in LV systolic function with exercise could help us to distinguish pathology from physiological adaptation51.Finally, parallel to the improvement in echocardiographic techniques and image resolution, a surprising high prevalence of LV hypertrabeculation has been described in athletes. Gati55. Classically, the study of the athlete’s heart was focused on the LV; but in the last two decades, with the introduction of advanced echocardiographic techniques and MRI, the RV exercise-remodeling has started to be described. Structurally, endurance exercise has been related to RV enlargement, typically balanced with LV dilatation56. Functionally, high intensity endurance exercise has been related to lower global RV peak systolic longitudinal strain values at rest as compared to controls; the RV basal is the segment most affected in this change57. To date, whether these lower strain values are the result of myocardial damage58 or are only an adaptive response demonstrated by an increased reserve after exercise provocation59 is still controversial. So far, few studies have focused on the RV in strength athletes but such RV remodeling seems to be less pronounced60. Extreme RV remodeling cases in elite ultra-endurance athletes may be indistinguishable from arrhythmogenic right ventricular dysplasia (ARVD). ARVD is a desmosomal cardiomyopathy characterized by progressive adipose and fibrosis myocardial infiltration with potential bad prognosis and constitutes one of the most important causes of sudden death in young athletes13. Various studies have demonstrated more rapid disease progression in patients that practice moderate-high intensity exercise, making the differential diagnosis between disease and cardiac remodeling even more challenging61. As previously mentioned, endurance exercise can induce adaptive physiologic biventricular dilatation, where the ratio of LV/RV remains unchanged. On the other hand, a reduced LV/RV ratio could be a warning sign of underlying disease62. In addition, athlete’s RV remodeling has proved to be global as opposed to that observed in ARVD patients who show a disproportionate enlargement of the RV outflow tract. Functionally, no motion abnormalities have been described in athletes62 despite having a lower deformation in the basal segment of the RV; abnormal motion of the RV is essential data to fulfil the ARVD diagnostic criteria63.64. However, to date, there is no single sign available to differentiate both entities and consequently, a combination of clinical and family history, electrocardiographic and echocardiographic features are recommended.During exercise, both ventricles have to increase stroke volume in response to the increased cardiac output demanded during exercise. This workload imposes high stress to all myocardial structures, which seems to be especially important in the right ventricle (RV) that typically works at low pressures in physiological conditionsIn summary, echocardiography is a useful imaging tool to detect underlying heart disease that may imply a risk for people practicing sport and at the same time is a non-expensive and non-invasive technique to evaluate cardiac adaptation to training. The challenge remains the diagnosis and differentiation of extreme adaptation to training that very much resembles early stages of some myocardial diseases. Recently developed tools to better quantify cardiac performance have improved this issue but still more knowledge on the pathophysiology of cardiac adaptation to training is needed to optimize the identification of subjects at risk for sudden death or irreversible cardiac damage. 1-3 , aortic dimension5,6  or pulmonary dimensions and function8 were not focused in this initial article of the sports cardiology channel because  it is problematic to start with and to write a complete update with the burden of complete echocardiographic potential/possibilities. In one of his own papers he described alterations of aortic valve/pulmonary valve/mitral valve in athletes and aortic root dilatation or severe pulmonary stenosis9.Echocardiography is an informative method for examination of cardiac structures and not dispensable in examination of athletes. Dr Grazioli focused his paper on analysis of left and right ventricle and did it well. Right and left atrial dimensions10, 13 and particularly for follow up14, 15 examinations. The possibilities of strain echocardiography were discussed in the past16, 17 and we look forward to new. The global longitudinal strain has better reproducibility18, the potential of radial strain seems to be limited in examination of training effects19.  Echocardiography was recommended for screening of athletes under different circumstances20 and importance of follow-up examinations21, 22. The advantage of this sports cardiology channel is the possibility for updating papers with new literature and information and to actualize the growing knowledge in sports cardiology. I recommend indexing of this article with the option to write an update with further possibilities and importance of echocardiography in the examinations of atrial function/valve and aortic function including 3D echocardiography and the further analysis of recreational  athletesI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The paper by Grazioli and colleagues provides a comprehensive review on the current knowledge and the clinical implications of echocardiography when applied to the evaluation of athlete’s heart in the context of pre-participation screening. The paper is currently focused on right and left ventricles, is well written, and analyses not only standard echocardiography, but also the novel echocardiographic techniques applied to athlete’s heart, with a specific focus on the differential diagnosis between exercise-induced physiological remodelling and the diseases most commonly cause of sudden cardiac death.Major revisionsAlthough the clinical implications of biatrial analysis has to be understood, in my opinion a brief paragraph on the analysis of biatrial morphology and function could be potentially of interest, also considering the some authors have demonstrated its utility in the differential diagnosis between athlete’s heart and cardiomyopathies.An interesting point of using echocardiography in the context of a screening has not been analysed. Although some authors debate about the utility and the costs of echocardiography, in my opinion the fundamental question of the application of echocardiography to the pre-participation screening in athletes is WHEN performing this exam. Considering that a frequent echocardiographic evaluation is not feasible in low-risk populations and dramatically increases the cost in absence of real clinical advantages, one has to suppose that one or two exams can be performed during the career of a non-professional athlete. Although some congenital defects can be detected in the early phase of the life of an individual, some of the most common cause of sudden cardiac death are the genetic myocardial diseases, such as HCM, DCM, and ARVC, all known to have a delayed phenotype expression.  Thus, performing an echocardiogram at the beginning of the athletic career of a child could detect congenital defects, but could be misleading in excluding the cardiomyopathies most commonly associated with sudden cardiac death, with a typical expression in the II-III (or even IV) decades of life of a young athlete. I think that the authors should analyse this clinical question and should provide a personal opinion based on the current available evidences and on the experience of their Center.Minor revisionsIn table 1 I think that “aortic coartation” should be included in the section “suprasternal view”.Table 2: exercise has not proven to be a determinant of a physiological dilation of the aorta; conversely, it has been demonstrated that aortic dimensions are comparable with those of the general population. Accordingly, I suggest removing “mild aortic dilation” from table 2, section “athlete’s heart”.Atherosclerotic coronary artery disease cannot be detected by echocardiography, although indirect signs such as left ventricular wall motion abnormalities can suggest its presence. However,  considering the signs are uncommonly observed in athletes, I suggest to remove “Atherosclerotic coronary artery disease” from table 2, section “sudden cardiac death”. et al (Circulation 2014) and the work by D’Ascenzi F. et al (Int J Cardiol 2015) both explaining the physiological determinants of benign hypertrabeculation in the athletes.Left ventricular non compaction: “it might be another expression of cardiac adaptation to increased preload and afterload influenced by genetic and ethnical factor”: ref. #51 is not correct because does refer to an hypothesis rather than an explanation of the phenomenon. I suggest to cite the article by Gati S.Table 3: the definition “competitive athletes, high static and dynamic component endurance training, > 10 hours/week” is not clear: which is the opinion of the authors? Although it is clear that echocardiography is not recommended in subjects engaged in recreational sports, which are the athletes to be evaluated by echocardiography? All the competitive athletes? Athletes with abnormal findings at resting ECG or at history/physical examination? Athletes engaged in high-volume training programs?...Please specify.Table 4At the present time, LV circumferential and radial strains cannot be definitively suggested to distinguish between cardiomyopathies and athlete’s heart. LV longitudinal strain is highly sensitive for myocardial disorders and more reproducible than circumferential and radial strains . Because of the LV shortens from base to apex in systole, the fixed short-axis tracking that is required for circumferential and radial strain is more difficult than longitudinal tracking. Particularly, radial strain is intrinsically more vulnerable to measurement variability because strain assessed in these orientations represents an aggregate measure of endocardial, mesocardial and epicardial tissue motion, encompassing both myocardial fiber shortening and global LV torsion in systole. The best inter- and intra-observed reproducibility is observed for LV longitudinal strain and particularly data based on measurements of LV radial strain should be interpreted with caution . A limited reliability has been observed also for LV circumferential strain measurements. A possible explanation is that circumferential deformation twist can hardly be assessed in the same view, because the base descends to the apex. This movement makes the correct measurement in the short axis view impossible in two different time-points or even in two different days.Finally, LV longitudinal strain measurements are known to be more robust than radial ones . According to these considerations and to the fact that LV longitudinal strain is the only form of strain that is used routinely , I suggest to remove both radial and circumferential strains from table 4 and to stress in the text that future studies are needed to evaluate whether these deformation parameters could be used in the clinical practice.“motion abnormalities” -> please correct with “wall motion abnormalities”Table 4: according to the current available data on deformation analysis applied to the athlete’s heart, I suggest to describe LV GLS at rest as “normal” and not “normal or slightly reduced”.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. This review summarizes some important aspects of echocardiography as a screening tool for the screening of athletes and should therefore be of interest for sports physicians and cardiologists. The potential advantages of this method and the technical aspects are well described.I would nevertheless recommend to mention potential problems too, mainly overdiagnosis and misdiagnosis with important consequences for the career of athletes and additional costs.  In order to prevent overdiagnosis and misdiagnosis, intensive training of sports cardiologists seems to be of utmost importance.Furthermore, as research in this area often focuses on young, competitive athletes, I would recommend to discuss the potential value of echocardiography for older, non-competitive, recreational athletes.I recommend indexing after minor revision.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Heterotaxy syndrome with left ventricular non-compaction is a rare co-existence of abnormalities with unknown cause. It can be isolated with no other associations, or associated with congenital heart diseases, or it can occur with multiple other congenital abnormalities. We describe the third reported case of heterotaxy syndrome with left ventricular non-compaction presenting in an adult. Heterotaxy, also known as situs ambiguous, is defined as the abnormal and disorganised arrangement of organs and vessels within the abdominal cavity. This is in contrast to the orderly arrangement that occurs in situs inversus or situs solitus.The two major subcategories of situs ambiguous are situs ambiguous with polysplenia, and situs ambiguous with asplenia. Situs ambiguous with polysplenia,  is generally characterised by a midline position of the abdominal organs and multiple spleens/splenules.Left ventricular non-compaction is a rare congenital abnormality of the heart with unknown cause. It can be isolated with no other associations, or associated with congenital heart diseases, or it can occur in conjunction with multiple other congenital abnormalities. The entity characteristically exhibits prominent and excessive trabeculae in the left ventricular wall segment, with the deep inter-trabecular recesses being perfused from the cavity.Genetic causes associated with multiple gene mutations have been implicated in causing the arrest of normal embryogenesis within the endocardium and myocardium.We describe the third reported case of dextrocardia with left ventricular non-compaction, situs ambiguous with an interrupted inferior vena cava, and polysplenia presenting in an adult.A 47-year-old male patient presented to the cardiologist with a history of chronic atrial fibrillation and known dextrocardia on chest radiography. The main presenting symptom was dyspnoea on exertion. The patient was a smoker and had a history of high alcohol intake. On examination he was noted to be normotensive and with a normal resting heart rate with atrial fibrillation. Lung function tests showed a mild obstructive airways disease pattern.Echocardiography confirmed the dextrocardia with hypertrophy, and possibly increased trabeculations were noted in the left ventricular wall. The ejection fraction was 50%, with a mildly enlarged left atrium and a normal-calibre left ventricular cavity.On abdominal ultrasound, the liver was observed to be midline with extension into the left hypochondrium, and the patient was noted to have polysplenia with multiple splenules located in the right hypochondrium. The ultrasound also confirmed an absent inferior vena cava.The patient’s blood work showed no abnormalities, with normal liver and renal function profile. Electrocardiography performed with a stress component showed no ischaemia and confirmed atrial fibrillation with no heart block.Cardiac magnetic resonance (CMR) imaging was performed to further evaluate cardiac and great vessel structure and function Dextrocardia is a cardiac positional anomaly in which the heart is located in the right hemithorax, with its base-to-apex axis directed to the right and caudally. The malposition is intrinsic to the heart and not caused by extra-cardiac abnormalities such as right lung hypoplasia, right pneumonectomy or diaphragmatic hernia.2Heterotaxy, also known as situs ambiguous, is defined as the abnormal and disorganised arrangement of organs and vessels within the abdominal cavity. This is in contrast to the orderly arrangement that occurs in situs inversus or situs solitus. Patients with situs ambiguous and dextrocardia have associated congenital heart disease in 50 to 100% of cases, as opposed to patients with situs solitus or situs inversus and dextrocardia.3The two major subcategories of situs ambiguous are situs ambiguous with polysplenia, and situs ambiguous with asplenia. Situs ambiguous with polysplenia  is generally characterised by a midline position of the abdominal organs and multiple spleens/splenules. Affected patients have a lower prevalence of congenital heart disease (50–90%) and less severe defects than those with situs ambiguous with asplenia.4When evaluating a patient with dextrocardia on CT or MRI, a systematic and sequential approach has been suggested in order to fully evaluate abnormalities of the heart and vascular structures. The approach favoured by Maldjian and SaricSitus of the viscera and atria is almost always concordant, and the atrial sinus is easily seen on cross-sectional imaging. On chest radiograph, this is also easily assessed by the location of the liver, spleen and stomach bubble. The morphology of the bronchial tree  is more accurate in determining atrial situs than the position of abdominal viscera. On chest radiographs in most patients, an enlarged azygous vein can be an indication of polysplenia, due to the high association with azygous or hemi-azygous continuation of the inferior vena cava.4Evaluation of ventricular morphology, atrioventricular connections and relationships of the great arteries usually requires assessment by either CT angiography or MRI. The final step in analysis involves assessment of extra-cardiac abnormalities and possible syndromic associations. In patients who present as adults, the possible abnormalities are limited . Congenital heart and vascular defects that have been described include dextrocardia with situs inversus totalis (mirror image), situs solitus with normal relationship of great arteries (variation of dextroversion), situs solitus with levo- and/or dextrotransposition of the great arteries, and dextrocardia associated with polysplenia syndrome.2Dextrocardia can also be associated with the heterotaxy syndromes of asplenia and polysplenia. Of the two syndromes, polysplenia is more likely to be associated with less severe cardiac malformations and therefore more likely to be encountered in adults. Up to 50% of cases of polysplenia syndrome can have dextrocardia. In polysplenia syndrome, there tends to be non-cyanotic congenital heart defects.2Abnormalities associated with polysplenia syndrome are bilaterally symmetrical liver, bilateral bi-lobed lungs with bilateral hypo-arterial bronchi (left isomerism), bilateral superior vena cava, absence of the intrahepatic portion (interruption) of the inferior vena cava with azygous or hemi-azygous continuation, common atrium with complete absence of the atrial septum, endocardial cushion defect, hypoplasia or absence of one ventricle, valvular or subvalvular pulmonary stenosis, aortic stenosis or atresia, and double-outlet right ventricle. There is also an unexplained relationship between polysplenia and Kartagener’s syndrome.2Left ventricular non-compaction (LVNC) is a hereditary primary cardiomyopathy with characteristic features of prominent trabeculations and conspicuous inter-trabecular recesses that penetrate deeply into the left ventricular myocardium, with a thin, compacted ventricular free wall (mainly in the affected areas), and diffuse systolic dysfunction with hypokinesia.6Non-compaction of the ventricular myocardium was first described in 1932, in an autopsy on a newborn.In the normally developed heart, the left ventricle has up to three prominent trabeculations and is less trabeculated than the right ventricle. In LVNC the trabeculations are more numerous (left ventricle compared to right ventricle) and thicker with deep recesses between the trabeculae.Several diagnostic criteria have been proposed for LVNC, including a ratio of two for the wall thickness between the non-compacted trabeculated layer and the non-trabeculated compacted layer of the LVNC at end-systole, as measured along the parasternal short axis on echocardiography.The clinical presentation can vary and initially most children and adults are asymptomatic. The left ventricular function then gradually deteriorates and other presenting events may also occur, such as cardiac failure and thromboembolic events. The prognosis is poor, with patients facing the possibility of sudden death  or eventual death due to heart failure.9The systolic dysfunction is thought to occur due to a relative ischaemia of the myocardium with a mismatch of myocardial oxygen supply and demand.10The multiple prominent trabeculations cause a restriction in filling, an abnormal ventricular relaxation pattern and diastolic dysfunction, with a generally poor eventual outcome for patients. Other complications can include thrombus formation within the recesses between trabeculae and subsequent thromboembolic events.Delayed enhancement in the myocardium has been shown to increase under conditions of myocardial interstitial expansion or fibrosis.Cardiac MRI has proven very useful in identifying these areas of fibrosis for characterisation and further management .LVNC can be an isolated finding in the heart in the absence of other cardiac abnormalities. However, associations with other cardiac disorders, including coronary arterioventricular fistulae, ventricular septal defects, patent ductus arteriosus, atrial septal defects, a left coronary artery originating from the pulmonary artery, and dextrocardia have all been reported.3Non-compaction of the myocardium can be either isolated or in conjunction with other congenital heart diseases. LVNC has been identified in relatively high association in patients with Ebstein’s anomaly with a reported figure of up to 18% of patients with Ebstein’s having non-compaction.13Other associations previously reported include mitochondrial disorders, Barth syndrome, hypertrophic cardiomyopathy, muscular dystrophy type 1, 1p36 deletion, Turner syndrome, Ohtahara syndrome, distal 5q deletion, mosaic trisomy 22, trisomy 13, Di George syndrome, and 1q43 deletion with decreasing frequency, as well as Pierre-Robin syndrome.We report on only the third known case of dextrocardia, situs ambiguous with polysplenia, and left ventricular non-compaction in an adult. All the characteristic morphological features could easily be identified on imaging studies including but not limited to echocardiography, CT angiography and MRI.


More recently, both T2-mapping and apparent diffusion coefficient (ADC) mapping have emerged as quantitative techniques for characterizing edema (or iron overload) and water mobility. The purpose of this work was to develop a framework for the simultaneous recovery of both T2 and ADC from a single breath-hold acquisition.Myocardial tissue characterization with T2 relaxation, as well as the sequence's diffusion encoding b-value (b) and echo time (TE): S = S0e-bDe-TE/T2. We propose that acquisition of several signals with varying TEs and b-values permits joint reconstruction of both ADC and T2 maps.Spin echo (SE) diffusion weighted imaging (DWI) signals are principally governed by the tissue's apparent diffusion coefficient (ADC=D) and T2 (20-70ms) and ADC (0.1-2.4x10-3mm2/s) using 10 TEs (17-100 ms) and b=500 s/mm2 (TE=60-68ms) along 3 directions. Complex Gaussian noise was added to each signal such that the signal to noise ratio (SNR) of the minimum TE, b=0 signal matched that of acquired data (SNR = 38). Reconstructions were performed using linear least-squares on a subset of the simulated data  to reflect a feasible in vivo acquisition (scan time:18s). Mapping accuracy and precision were determined by the bias and standard deviation (SD) of T2 and ADC compared to programmed values.Bloch equation simulations were used to generate signals for a broad range of T2 and ADC maps were jointly reconstructed using linear least-squares from 6 TEs plus 3 DWI sets and compared to: 1) Best-Available T2-maps from all 10 TEs; 2) Best-Available ADC maps from DWI ; 3) Independent T2 maps from 6 TEs; and 4) Independent ADC maps from 3 DWI averages.Images were acquired on a 3.0 T Siemens Skyra system in an ex vivo infarcted porcine heart using single-shot SE EPI with TEs and b-values to match simulated parameters. T2 and ADC values with bias<1% and SD<10% for a broad range of tissues and even lower for healthy and infarcted myocardium .Reconstructed ADC and T2 map.Joint acquisition and estimation of T2 and ADC maps is feasible in a breath hold and improves quantitative accuracy and precision compared to independent T2 or ADC mapping. DWI acquisitions typically require multiple averages to improve SNR. Here, varying TE takes the place of signal averaging and permits the reconstruction of a perfectly registered TThis research was supported by Siemens Medical Solutions and the Department of Radiological Sciences at UCLA.


In children with structural congenital heart disease (CHD), the effects of chronicventricular pacing on diastolic function are not well known. On the other hand, thebeneficial effect of septal pacing over apical pacing is still controversial.The aim of this study was to evaluate the influence of different right ventricular(RV) pacing site on left ventricular (LV) diastolic function in children with cardiacdefects.Twenty-nine pediatric patients with complete atrioventricular block (CAVB) and CHDundergoing permanent pacing were prospectively studied. Pacing sites were RV apex (n= 16) and RV septum (n = 13). Echocardiographic assessment was performed beforepacemaker implantation and after it, during a mean follow‑up of 4.9 years.2= 0.9849, p ≤ 0.001). RV apex pacing  and TDIlateral Tei index  predicted significantly decreased LV diastolic function.Compared to RV septum, transmitral E-wave was significantly affected in RV apicalpacing . Likewise, parameters at the lateralannular tissue Doppler imaging (TDI) were significantly affected in children paced atthe RV apex. The E´ wave correlated inversely with TDI lateral myocardial performanceindex (Tei index) (ROf the two sites studied, RV septum prevents pacing-induced reduction of LV diastolicfunction. Most pediatric studies published2have focused on ventricular systolic function assessment; therefore, theeffects of chronic ventricular pacing on diastolic function are not well known, evenless in children with CHD.RV apical pacing is conventionally performed in pediatric patients with CAVB. However,ventricular pacing induces an abnormal electrical activation pattern, which causesmechanical dyssynchrony, LV structural remodeling and increased risk of heartfailure4 showing promisingresults, while a recent research did not demonstrate any superiority over RV apicalpacing in children1; none of thesestudies4reported theeffects on LV relaxation phase.Moreover, the benefit of RV septal stimulation is still controversial, with clinicalstudiesWith the hypothetical premise that there are differences between RV septal and RV apicalpacing in terms of dynamic alterations in LV filling, we performed the currentstudy.The study included all children with CHD and CAVB that underwent pacemaker implantationin a single tertiary pediatric cardiology center, paced from RV septum (n = 13) and fromRV apex (n = 16). Patients with clinical or anamnestic evidence of heart failure wereexcluded. None of the patients were older than 18 years at pacemaker implantation, had ≤95% of ventricular pacing or ≤ 1 year of permanent cardiac pacing. The study protocolwas approved by the institutional research ethics committee and parental written consentwas obtained.Two experienced observers, blinded for the ventricular pacing site, performedprospective echocardiographic evaluations (Aloka α-10) before pacemaker implantation,immediately after and regularly during a mean period of 4.9 years. Three randommeasurements were made for every patient by each observer and the average ofmeasurements was used for further analysis. For a comprehensive diastolic evaluation,the following mitral flow parameters were evaluated by pulsed wave Dopplerechocardiography: E and A waves, E/A wave ratio and E-wave deceleration time. Likewise,pulse wave TDI velocities were obtained in the apical four-chamber view, at septal andlateral mitral annulus. In each segment, peak systolic (S´), early (E´) and late (A´)peak diastolic velocities were measured. The E/E´ ratio and TDI Tei index were alsocalculated. All data were prospectively collected.t-test. Independent variablesshowing significant univariate differences related to the development of LVdysfunction were entered into a backward stepwise logistic regression analysis, wherethe Odds ratio (OR) and Wald statistics for each variable wereidentified. Significance level was set at 5%. The statistical software MedcalcVersion 12 was used for the analyses.According to the Kolmogorov-Smirnov test, the variables that showed a normaldistribution were summarized as mean ± standard deviation. The differences betweentwo groups were compared by unpaired A total of 29 patients , with mean age at firstimplantation of 9.82 ± 2.75 years were evaluated. Tetralogy of Fallot  andventricular septal defect  were the main CHD corrected beforepacemaker implantation. Anatomic surgical correction was performed in all patients andmild residual atrioventricular regurgitation was present in 10 (34.48%) children.Thirteen (44.82%) cases underwent treatment with angiotensin‑converting enzymeinhibitors at the time of implantation. Twelve children (41.37%) received asingle‑chamber pacemaker, while 11 (24.13%) patients underwent DDD/DDDR pacing. Meanpacing duration was 4.9 years.2 = 0.9849, p ≤ 0.001)  and TDI lateral Tei indexpredicted significantly decreased LV diastolic function.Compared to RV septum, transmitral E-wave was significantly affected in RV apical pacing . Likewis≤ 0.001) .At the Our study confirms that chronic stimulation from RV apex results in diastolic functionimpairment in pediatric patients with CHD and further demonstrates the superiority ofseptal stimulation in this context.5 and in the adultpopulation7. Aoyagi et al5 showed that wall motion asynchrony prolongs LV isovolumicrelaxation time (IVRT) in dogs; this impairment correlated with the degree of wallmotion asynchrony. In the research performed by Kolettis et al6, compared to RV outflow tract pacing, RV apical pacingdecreased maximum negative dp/dt and increased the IVRT. These findings were confirmedin an analysis of nine studies7,reporting a significant benefit of RV outflow tract over apical pacing. On the otherhand, few investigations9have focused on LV diastolic function in the pediatric population.Forwalt et al8 evaluated the effectsof acute ventricular pacing in children who underwent ablation therapy; the authorsobserved that RV apical pacing resulted in acute systolic dyssynchrony with preserveddiastolic synchrony. Nevertheless, Koh et al9 provided evidence of LV diastolic dysfunction after chronic RVapical stimulation, associated with the presence of LV dyssynchrony. In our study, theimpaired diastolic indices in the lateral mitral annulus could be associated with thepattern induced by RV apical pacing, characterized by early activation of the RV anddelayed activation of the LV lateral wall.The deterioration of diastolic function after RV pacing has been previously reported inanimals10; it is the mostaccurate for the detection of diastolic and combined dysfunction10. Considering that the results of ourresearch reflect the high predictive value of this parameter, it could be used as anechocardiographic tool to predict the deterioration of both systolic and diastolicfunctions in patients with chronic ventricular pacing.The Tei index has been used to assess LV function in a wide variety of diagnoses inchildrenOf the two assessed sites, RV septum showed to prevent pacing-induced reduction of LVdiastolic function.


LV) hemodynamic forces during diastolic filling are concordant with the main flow axes in normal LVs, but that this pattern would be altered in dilated and dysfunctional LVs. Therefore, we aimed to assess the LV hemodynamic filling forces in a group of healthy subjects and compare them to the results from a group of patients with dilated cardiomyopathy (DCM). Ten healthy subjects and 10 DCM patients were enrolled. Morphological short‐ (SAx) and long‐axis (LAx) images and 4D flow MRI data were acquired at 1.5T. The LV pressure gradients were computed from the 4D flow data using the Navier–Stokes equations. By integrating the pressure gradients over the LV volume at each time frame, the magnitude and direction of the global hemodynamic force was calculated over the cardiac cycle. The hemodynamic forces acting in the SAx‐ and LAx‐directions were used to calculate the “SAx‐max/LAx‐max”‐ratio for the early (E‐wave) and late (A‐wave) diastolic filling. In the LAx‐plane, the temporal progression of the hemodynamic force followed a consistent pattern in the healthy subjects. The “SAx‐max/LAx‐max”‐ratio was significantly larger at both E‐wave  and A‐wave  in the DCM patients compared to the healthy subjects. 4D flow MRI data allow quantification of LV hemodynamic forces acting on the LV myocardial wall. The LV hemodynamic filling forces showed a similar temporal progression among healthy subjects, whereas DCM patients had forces that were more heterogeneous in their direction and magnitude during diastole.We hypothesized that the direction of global left ventricular ( Heart failure represents the final stage of the continuum of cardiovascular diseases. Cardiac remodeling is a key component of heart failure that progresses from adaptive to maladaptive as the disorder worsens  is accelerated due to the pressure difference between the LA and the LV. After entering the LV, the speed is reduced. During this deceleration , the LV myocardium exerts a force to decelerate the blood, while, following Newton′s third law (the action‐reaction law), a hemodynamic force, with equal magnitude but opposite direction, is exerted by the blood on the surrounding LV myocardial walls. During LV systole, the blood is accelerated toward the LV outflow tract by the force the contracting myocardium exerts on the blood, while the blood exerts a hemodynamic force on the surrounding LV myocardium.As the hemodynamic forces are related to blood acceleration and deceleration in the LV, one may expect that during LV filling and emptying these forces would mostly be directed along the “base‐to‐apex axis”, concordant with the predominant flow directions in the normal LV  acquired by MRI enables assessment of multidimensional blood flow dynamics in the heart and great vessels  with a spectrum of LV remodeling and dysfunction were enrolled in the study. Clinical and demographical parameters are presented in Table To confirm that each subject fulfilled the inclusion criteria, they all underwent a clinical electrocardiographic and echocardiographic examination. The echocardiographic examination was conducted using a Vivid 7 scanner and a 2.0 MHz probe .All subjects underwent a cardiac MRI examination on a clinical 1.5 T scanner , where a five element cardiac SENSE coil was used as receiver and the body coil as transmitter. Morphological short‐ and long‐axis  balanced steady‐state‐free precession images as well as time‐resolved, three‐directional, three‐dimensional velocity (4D flow) data were acquired.2 and the SAx‐stack with 1.67 × 1.78 mm2. The images were reconstructed into 1.25 × 1.25 mm2. All morphological images were acquired with retrospective cardiac gating. The 4D flow data were acquired during free‐breathing, using a navigator‐gated, gradient‐echo pulse sequence with interleaved three‐directional flow‐encoding and retrospective, vector‐cardiogram controlled cardiac gating. General acquisition parameters: VENC, 100 cm/s; echo time (TE), 3.7 ms; repetition time (TR), 6.3 ms; flip angle, 8°; SENSE factor, 2; k‐space segmentation factor, 2; and spatial resolution (acquired and reconstructed), 3.0 × 3.0 × 3.0 mm3. These settings gave a temporal resolution of 50.4 ms. The mean acquisition time for a 4D flow dataset was 31 ± 8 (median: 30 range: 16–57) minutes including the navigator efficiency.Morphological data were acquired in standard LAx two‐, three‐, and four‐chamber views as well as two stacks of SAx‐images. One SAx stack was acquired before the 4D flow scan and one after, in order to provide a backup should the first SAx stack show severe mismatch to the 4D flow data. All morphological images were acquired in 30 time frames and with 8 mm slice thickness. There was no slice gap between the short‐axis images in the stack. The LAx‐images were acquired with spatial resolution of 2.19 × 1.78 mmAfter acquisition, the 4D flow data were reconstructed into 40 time frames on the MRI system. After reconstruction, the data were corrected for concomitant gradient field effects on the MRI system and exported to an offline station and postprocessed by the use of in‐house developed software written in Matlab . In the postprocessing step, data were corrected for phase wraps Xiang  and back∇p=−ρ∂v∂t−ρv∇v+μ∇2v, where v [m/s] is the velocity, ρ the density (1060 [kg/m3]) and μ the viscosity (0.004 [Ns/m2]) of blood. The blood is assumed to be a Newtonian and uncompressible fluid. By integrating the pressure gradients, ∇p, over the entire LV volume at every time frame, the 3D hemodynamic force vector was calculated for every time frame of the cardiac cycle . In this study, the LV volume was defined from the SAx‐images where the endocardial contour of the compact ventricular myocardium was outlined. In the most basal slice, as much of the LV volume as possible was included without including any LA volume. The LVOT was not included in the LV volume Fig. . The segSpeed data were extracted from two points set near the centers of the mitral valve (MV) orifice and the LV outflow tract at end diastole. The plot of the speed data over time was used to do a rough division of the cardiac cycle into subphases and to describe the timing of the cardiac cycle Fig. ; this waIn order to assess the distribution of hemodynamic force directions, the “SAx‐max/LAx‐max” force ratio was calculated at both early (E‐wave) and the late (A‐wave) diastolic filling. The ratio was calculated by dividing the maximum force along the apex‐to‐base axis in the LAx plane  with the maximum force along the anteroseptal‐to‐inferolateral axis in the SAx‐plane  Fig. . The maxTo further assess the direction of the global LV hemodynamic forces with respect to the main flow axes, the LV hemodynamic force perpendicular to the apex‐to‐base axis was assessed over the whole diastolic phase. Therefore, for each subject, the time‐averaged magnitude of the force in this direction was computed by integrating the magnitude of the force in the SAx‐plane over (1) the early filling phase and (2) the late filling phase, which was divided by the number of time frames.P‐value <0.05 was considered significant. All statistical calculations were performed in Matlab .Data are presented as mean ± 1 standard deviation (SD), unless otherwise stated. Intergroup comparisons were made for the (1) clinical parameters; (2) the “SAx‐max/LAx‐max‐force”‐ratio at E‐ and A‐wave; and (3) the mean SAx‐forces, by the use of group‐wise comparisons with unpaired t‐tests. Linear regression was used to test the relation between the “SAx‐max/LAx‐max” force ratio and sphericity index (SI). A There was no difference in age and heart rate, whereas parameters of LV characteristics such as ejection fraction, SI and end‐diastolic volume (EDV) differed between the two groups Table . Based oIn the healthy subjects, the hemodynamic forces projected on to the three‐chamber LAx plane, presented a consistent ellipsoid‐like pattern Fig.  and 4A. In the SAx‐view Fig. B. DuringAt onset of late diastolic filling, a force directed toward the atrium Figs. A as wellSimilar to the characteristics during early filling, the forces during late filling in the SAx‐view showed a less consistent pattern in terms of direction compared to the pattern in the LAx‐view Fig. B. In fouAt the onset of systole, the magnitude of the hemodynamic force is small. During the upslope of systole it increases and is oriented opposite to the outflow direction. During late systole the force decreases, while maintaining the same direction. At end‐systole, a slight shift toward the direction of outflow is observed Figs.  and 3.P < 0.0001) and late diastolic filling  in the patient group compared to healthy subjects . No intergroup difference was observed during the late filling phase .The time‐averaged magnitude of the force in the SAx‐plane was significantly higher in the patient group during the early filling phase  and late  filling using linear regression analysis.There was a weak to moderate relation between SAx‐max/LAx‐max force ratio and SI at early (n = 5) compared to the healthy subjects , whereas no difference was observed during late filling .The “SAx‐max/LAx‐max” force ratio during early filling was higher in the subgroup of patients with normal diastolic function  the LV has to overcome will be represented as a force opposing the outflow direction. Blood that has left the LV cavity will exert forces on the walls of the aortic root and the proximal ascending aorta, but this is not assessed in this study as only the data within the LV as defined in the methods section is analyzed. Consequently, the LV hemodynamic force, which is the focus of this study, will be dominated by the force due to acceleration of the blood during systole and deceleration of blood during diastole Fig. . MoreoveDuring early filling the force of the LV intracavitary blood was observed to move counter clockwise from the perspective of the LAx‐view in 8 of the 10 healthy subjects. This finding is consistent with previous studies that have shown that a substantial portion of the early inflow enters the LV along the inferolateral wall before turning toward the anterior septum . For instance, an elevated early/late velocity magnitude ratio due to a relaxation abnormality is also reflected by an elevated early/late force magnitude ratio. However, the direction of the forces appears to be less related to conventional indices of diastolic dysfunction. Interestingly, the force ratio at early filling was significantly higher in patients with normal LV filling patterns compared to healthy subjects, whereas no difference was observed during late filling. Alterations in LV inflow direction during the early filling phase that influence intracavitary flow patterns may contribute to the increased force ratio. The number of patients with different degrees of abnormal LV filling patterns defined by echo Doppler was very low and did not allow evaluation of any relationship between specific levels of diastolic dysfunction and changes in hemodynamic forces. Of note, we do not expect any correlation of specific LV filling pattern with the underlying etiology of DCM in the current patient cohort.Given that LV force is a volume integral, it is interesting to observe that while the end‐diastolic volume is significantly larger in patients compared to healthy subjects Table , there iAssessment of LV hemodynamic force may add to pathophysiological understanding of progressive global remodeling of the failing heart. The interaction between the flowing blood and the developing heart chambers stimulates a continuous positive remodeling process that creates an optimal geometry for efficient flow  the segmentation of the LV; previous 4D flow MRI studies including segmentation of the LV blood volume have shown small inter and intraobserver variability of subvolumes of LV flow  or LV wall motion patterns (pacing). Insight regarding the clinical potential of this new method may be obtained by relating the degree of force abnormality with other accepted measures of cardiac performance and decompensation, such as 6‐minute walk test or maximal oxygen consumption, awaits further study.This study demonstrates that 4D flow MRI data allow quantification of LV hemodynamic forces acting on the myocardium. The LV hemodynamic filling forces showed a similar pattern across healthy subjects, with the main hemodynamic force directed along the base‐to‐apex axis, whereas in the DCM group the distribution in direction was heterogeneous during early and late diastole. Assessment of flow‐based forces may be a marker of altered hemodynamic effects on the myocardial wall, and thus, a novel tool in the study of progressive adverse cardiac remodeling.The authors declare that they have no conflict of interest.Figure S1. Polar plots of the hemodynamic force over time projected on a plane corresponding to a standard long‐axis three‐chamber image. Ten healthy subjects (N01–N10) and 10 dilated cardiomyopathy patients (P01–P10) are included. The forces are presented in N and the cardiac cycle is colored according to: systole, green; early diastole (E‐wave), red; diastasis, yellow; and late diastole (A‐wave), blue.Click here for additional data file.Figure S2. Polar plots of the hemodynamic force over time projected on a plane corresponding to a standard basal short‐axis image. Ten healthy subjects (N01–N10) and 10 dilated cardiomyopathy patients (P01–P10) are included. The forces are presented in N and the cardiac cycle is colored according to: systole, green; early diastole (E‐wave), red; diastasis, yellow; and late diastole (A‐wave), blue.Click here for additional data file.


Right ventricular septal pacing is thought to be better than right ventricular apical pacing for shortening the QRS duration and for preserving left ventricular function. However, right ventricular septal pacing may not be effective in all cases. In this case report, we present a rare case in which right ventricular septal pacing induced thoroughly separated right and left ventricular excitation despite the presence of a relatively narrow QRS wave during atrium-only pacing.We report a case of 63-year-old Japanese man with cardiomyopathy with an implantable cardioverter defibrillator placement for ventricular tachycardia. Three years after implantation, he developed second-degree atrio-ventricular block. Therefore, atrio-ventricular sequential pacing was started; then his heart failure was much worsened. His electrocardiogram showed a dissociated biphasic QRS wave during right ventricular high-septal pacing, despite the presence of a non-fragmented QRS morphology during atrium-only pacing. An activation map during right ventricular high-septal pacing showed that right ventricular conduction started at the pacing site and ended at the right ventricular basal inferior site. Subsequently after a 10ms interval, left ventricular conduction started at the left ventricular posteroseptum and ended at the left ventricular lateral wall. These data indicate that during right ventricular high-septal pacing, the first component of the QRS wave supposedly reflects only right ventricular excitation and the second component only left ventricular excitation. Also due to the intracardiac electrograms, it was assumed that this phenomenon was caused by transversely limited severe transseptal conduction disturbance.It should be noted that even ventricular septal pacing could evoke harmful interventricular dyssynchrony due to transversely limited severe septal conduction disturbance, despite the presence of a relatively narrow QRS wave. A prolonged duration of the QRS complex on electrocardiogram is associated with adverse prognosis not only in patients with cardiac diseases,2 but alIn this report, we present a case in which RV septal pacing induced thoroughly separated RV and LV excitation and contraction.A 63-year-old Japanese man who had cardiomyopathy of unknown etiology experienced ventricular tachycardia, and an implantable cardioverter defibrillator (ICD) was thus implanted. The ventricular lead was fixed on his RV high septum, because a low-voltage area extended across his mid- to low-ventricular septum. The pacing mode of the ICD was programmed to AAI mode. The width of his own QRS wave was 120ms. His echocardiogram showed a severely dilated and diffuse hypokinetic left ventricle. His septal wall was thin and high-echoic. Cardiac sarcoidosis was suspected, but the diagnostic criteria could not be fulfilled. Three years after ICD implantation, he developed dyspnea until he experienced New York Heart Association (NYHA) class III heart failure. A Wenckebach-type second-degree atrioventricular block was observed during atrium-only pacing at 60 beats per minute  showed a low-voltage area extended across his basal to mid-ventricular septum. Activation mapping of his own QRS wave Figure A showed It was reported that RV septal pacing might induce intraventricular LV dyssynchrony causing severe LV ejection fraction deterioration and symptoms of congestive heart failure. HoweverIn a previous study on patients with left bundle-branch block, two patDuring atrium-only pacing, RV and LV excitation started and ended almost simultaneously within 166ms. During RV septal pacing, RV and LV excitation occurred sequentially; however, intraventricular conduction durations of the right and left ventricles measured by activation mapping were comparatively shorter than those during atrium-only pacing ; therefore, it seems that each intraventricular conduction uses some intact cardiac conduction system.We experienced a rare case of idiopathic cardiomyopathy that showed a dissociated biphasic wide QRS complex and completely separated RV and LV contractions during RV high-septal pacing due to transversely limited severe transseptal conduction disturbance, despite the presence of a relatively narrow QRS wave during atrium-only pacing. Although RV septal pacing can usually achieve more physiological ventricular contraction than RV apical pacing, it should be noted that even septal pacing could evoke harmful interventricular dyssynchrony.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by Editor-in-Chief of this journal.The authors declare that they have no competing interests.TY analyzed and interpreted patient data including cardiac electrophysiological mapping, and was the major contributor in writing the manuscript. HF and AC performed most medical patient care including ICD implantation and management. SU and MT contributed in electrophysiological and circulatory interpretation. SK and MY provided major diagnostic and therapeutic suggestions, especially on patient care. All authors read and approved the final manuscript.


Thus, we assessed the hypothesis that the increase in circulating angiotensin II comparable to that reported in heart failure model affects cardiac function through the central sympathoexcitation via activating AT1R in the brain. In Sprague-Dawley rats, the subcutaneous infusion of angiotensin II for 14 days increased the circulating angiotensin II level comparable to that reported in heart failure model rats after myocardial infarction. In comparison with the control, angiotensin II infusion increased 24 hours urinary norepinephrine excretion, and systolic blood pressure. Angiotensin II infusion hypertrophied left ventricular (LV) without changing chamber dimensions while increased end-diastolic pressure. The LV pressure–volume relationship indicated that angiotensin II did not impact on the end-systolic elastance, whereas significantly increased end-diastolic elastance. Chronic intracerebroventricular infusion of AT1R blocker, losartan, attenuated these angiotensin II-induced changes. In conclusion, circulating angiotensin II in heart failure is capable of inducing sympathoexcitation via in part AT1R in the brain, subsequently leading to LV diastolic dysfunction.Sympathoexcitation contributes to the progression of heart failure. Activation of brain angiotensin II type 1 receptors (AT RVLM is a vasomotor center that contains sympathetic premotor neurons and determines basal sympathetic activity  is one of the circumventricular organs lying outside the blood-brain barrier (BBB) and thus responds to the circulating angiotensin II. Angiotensinergic neurons in the SFO are projected to hypothalamic nuclei that modulate sympathetic activity  staining because the activation of AT1R/NAD (P) H oxidase mainly produces superoxide , ICV losartan (1 mg kg−1 day−1), and SC hydralazine (8 mg kg−1 day−1) were infused for 2 weeks. In a preliminary experiment, we confirmed that 100 ng kg−1 min−1 SC angiotensin II infusion for 2 weeks increased plasma angiotensin II levels comparable to those in heart failure model rats, which was consistent with previous studies  rats  weighing 220–280 g. All rats were housed in a room with controlled lighting, temperature, and humidity and fed standard chow and water ad libitum. The rats assigned to one of four groups: (1) treatment with subcutaneous (SC) vehicle infusion and intracerebroventricular (ICV) vehicle infusion (VEH group); (2) treatment with SC angiotensin II infusion and ICV vehicle infusion (AII group); (3) treatment with SC angiotensin II infusion and ICV losartan (AII + LOS group); and (4) treatment with SC angiotensin II, SC hydralazine, and ICV vehicle (AII + HYD group). The osmotic mini-pumps and ICV cannulae  were implanted for SC infusions and ICV infusions. SC angiotensin II  to measure the MAP and inject the drug at the end of the 2 weeks treatment. Systolic blood pressure (SBP) was measured by using the tail–cuff method  in each group every 2 days before and during the treatment.Blood was collected at the end of the 2 weeks treatment period. Plasma angiotensin II levels were measured by double antibody radioimmunoassay. Urine was collected from each rat for 24 h in a metabolic cage before and after treatment. Urinary norepinephrine concentration was measured by using high-performance liquid chromatography to calculate urinary norepinephrine excretion as a marker of sympathetic activity, as described in our previous studies . Echocardiography was performed after the 2 weeks treatment using an Aloka Prosound SSD 5000  with a 7.5-MHz imaging linear scan probe transducer, as described previously  and artificially ventilated (70 breaths min−1 with 95% O2). Body temperature was maintained at 37.0°C with a controlled heating pad. A microtip pressure–volume catheter  was inserted into the right carotid artery and advanced to the LV. Signals were continuously monitored at a sampling rate 1000 Hz using an Advantage pressure–volume measurement system (Scisence Inc.). We evaluated LV end-diastolic pressure (EDP), maximum rate of pressure increase (+dP/dt max), maximum rate of pressure reduction (−dP/dt max), and LV end-diastolic pressure–volume relation slope (EDPVR) , LV end-systolic diameter (LVDs), and LV wall thickness were measured, and LV percentage fractional shortening (%FS) were determined by echocardiography under light anesthesia with an intraperitoneal injection of pentobarbital sodium , then dissected and weighed. The weights of the total heart and lung were normalized to the body weight and used as an index of ventricular hypertrophy and pulmonary congestion respectively  at 37°C. After washing with PBS, DHE fluorescence was visualized by confocal microscopy using an excitation wavelength of 543 nm and a rhodamine emission filter.Brain superoxide anion levels were estimated by DHE staining based on previous studies . Histological analysis was performed in VEH, AII, and AII + LOS groups, and showed that the cardiomyocyte size was greater in AII group than that in VEH group. The ICV losartan inhibited angiotensin II-induced cardiomyocyte hypertrophy .Heart/body weight was significantly increased in AII and AII + HYD group, but was not changed in AII + LOS group, compared with VEH group Fig.. The lunophy Fig.. The degDihydroethidium staining was performed in VEH, II, and A II + LOS groups. The DHE fluorescence levels were slightly but significantly higher in the SFO of AII group than that of VEH group. This increased DHE fluorescence levels in the SFO were inhibited in AII + LOS group Fig.. In the 1R in the brain. It is widely known and recognized that angiotensin II in the brain increases sympathoexcitation, and that increased sympathoexcitation contributes to heart failure. The present new and novel finding is that increased circulating angiotensin II at similar level of myocardial infarction could directory affect brain and cause excessive sympathoexcitation in normal rats without various mechanisms of sympathoexcitation . We would like to emphasis that excess circulating angiotensin II would be one of the major sympathoexciting factors via central renin-angiotensin system in myocardial infarction-induced heart failure.The main findings from this study are that the increase in the circulating angiotensin II induced LV hypertrophy and LVEDP elevation through central sympathoexcitation via in part AT−1 min−1, of SC angiotensin II have been commonly studied to investigate LV remodeling and dysfunction. It is notable that the increased circulating angiotensin II comparable to that in heart failure caused the sympathoexcitation, LV hypertrophic remodeling and diastolic dysfunction. Interestingly, the inhibition of brain AT1R by ICV losartan treatment significantly attenuated these angiotensin II-induced LV changes through sympathoinhibition. Although the ICV losartan inhibited the angiotensin II-induced increase in blood pressure as well as LV changes, we did not consider that the inhibition of the LV changes was due to just only blood pressure reduction, because the treatment with hydralazine did not inhibit the angiotensin II-induced LV changes, despite the fact that hydralazine reduced blood pressure to a level lower than that observed in the angiotensin II-infused rats treated with ICV losartan. The results with hydralazine predominantly provided the indication that circulating angiotensin II causes sympathoexcitation and worsen heart failure via brain renin-angiotensin system independent of blood pressure. Moreover, though we did not examine in the present study, our previous study suggested that hydralazine induced sympathoexcitation with the production of oxidative stress in the brain  was not a typical heart failure and was similar to hypertensive heart failure with mild alteration of cardiac function. The LV hypertrophic remodeling was indicated by the increase in heart/body weight, LV wall thickness, and LV cardiomyocyte size in the angiotensin II-infused rats. LV hypertrophic remodeling is involved in diastolic dysfunction, in particular, the increased stiffness and the impaired relaxation  of SC angiotensin II infusion for 2 weeks led to the LV hypertrophy and diastolic dysfunction, but not the LV fibrosis, through sympathoexcitaion. Both LV hypertrophy and fibrosis induced by the same dose of SC angiotensin II for 4 weeks was previously demonstrated, although neither sympathetic activity nor LV function were investigated .We focused on the increased circulating angiotensin II resulting from heart failure as an important input from the body for leading to central sympathoexcitaion that contributes to the progression of heart failure. Heart failure can induce a variety of sympathoexcitatory inputs to the brain, such as the increased circulating aldosterone and cytokines, and the activation of the peripheral chemoreceptors, as well as the increased circulating angiotensin II Leenen . Therefo1R should be done. Third, our results of DHE staining were not sufficient, and only these results could not show the effects of ICV losartan on superoxide production in SFO and RVLM. However, in our previous studies, ICV losartan reduced oxidative stress measured by other methods in the bilateral RVLM (Hirooka et al. There are several study limitations. First, we used subcutaneous angiotensin II infusion in only single dose to increase circulating angiotensin II instead of using models with heart failure, because known various mechanisms of sympathoexcitation in myocardial infarction-induced heart failure should be excluded. However, we also recognize that further experiments using other ideal models with heart failure and/or with lower dose angiotensin II treatment should be done. Second, the results of ICV losartan could not be valid, and we also consider that site-specific knockout or deletion of ATIn conclusion, increased circulating angiotensin II in heart failure is an important input for central sympathoexcitaion, leading to LV remodeling and diastolic dysfunction. In addition, superoxide production in the brain might be involved in the circulating angiotensin II-induced sympathoexcitaion. The increased circulating angiotensin II, sympathoexcitaion, LV remodeling, and dysfunction may play a major role in the vicious cycle of heart failure.


Cx40 mRNA was significantly downregulated in the atrial septum and AVJ tissues but not in the ventricular septum. mRNA abundance for ANP, CLCN2 and Navβ1 was increased with heart failure; Nav1.1 was increased in the inferior nodal extension/compact node area. Heart failure in the rabbit leads to prolongation of the PR interval and this is accompanied by downregulation of HCN1, Cav1.3, Cx40 and Cx43 mRNAs and anatomical enlargement of the entire heart and AVJ.Heart failure is a major killer worldwide. Atrioventricular conduction block is common in heart failure; it is associated with worse outcomes and can lead to syncope and bradycardic death. We examine the effect of heart failure on anatomical and ion channel remodelling in the rabbit atrioventricular junction (AVJ). Heart failure was induced in New Zealand rabbits by disruption of the aortic valve and banding of the abdominal aorta resulting in volume and pressure overload. Laser micro-dissection and real-time polymerase chain reaction (RT-PCR) were employed to investigate the effects of heart failure on ion channel remodelling in four regions of the rabbit AVJ and in septal tissues. Investigation of the AVJ anatomy was performed using micro-computed tomography (micro-CT). Heart failure animals developed first degree heart block. Heart failure caused ventricular myocardial volume increase with a 35% elongation of the AVJ. There was downregulation of HCN1 and Cx43 mRNA transcripts across all regions and downregulation of Ca Electrical conduction abnormalities are common in heart failure and lead to cardiac arrhythmias and sudden cardiac death . The eleIf density .Reverse transcription was followed by RT-PCR of cDNA using the ABI Prism 7900HT system and SYBR Green in 10 μl reactions performed in triplicate. The endogenous control was the 28s ribosomal RNA. Primer sequences are available in RT-PCR data are presented as means±SEM. 2-way ANOVA allows the simultaneous study of within-groups variance and between-groups variance. It was used to assess the effect of heart failure across multiple regions. Comparisons between control and heart failure in an individual region were made using the Limma test, which uses a moderated t-statistic, but, unlike the Student’s t-test standard errors are moderated across several genes . Signifi−5; heart-to-body weight ratio, 3.24±0.22 g/kg vs. 4.87±0.24 g/kg, P = 1.2×10−4; n = 9; −4; −6; −4; n = 7/9; Heart weight and heart-to-body weight ratio were increased in heart failure animals . Atrioventricular bundle length was 2369±110 μm and volume 0.32±0.04 mm3 for control animals vs. 3197±226 μm and 0.60±0.11 mm3 for heart failure animals .In a separate sample of the same experimental group micro-CT allowed not only atrioventricular bundle length measurements but also three-dimensional reconstruction and volume quantification. Total ventricular myocardial volume was also measured in the same hearts . Total v−15). There was no significant increase of cell diameter in heart failure.We measured transverse cell diameter of His bundle cells. In all samples, His bundle cells were round, irregular and loosely arranged . Their mImmunolabelling for Cx43showed that protein abundance was greatest in ventricular followed by atrial myocardium . The uppIf), which is responsible for diastolic depolarization. Tbx3, NF, HCN1 and HCN4 were more abundant in the AVJ compared to atrial and ventricular tissue  while Kv1.4 carries the slow-recovering current . Kv4.2 was more highly expressed in AVJ tissues compared to ventricular and atrial myocardium , showed preferential expression in the atrial and AVJ tissues compared to the ventricle  and the β-subunit Navβ1  is activated in hypoxic conditions. It is encoded by the pore-forming Kir6.2 subunit and the ATP-binding β subunit SUR2A. Kir6.2 mRNA was significantly more prevalent in the atrial septum and transitional tissue and decreased in these areas with heart failure  were: a decrease in HCN1 (36%) and Cx43 (37%) and an increase in SUR2A (47%), CLCN2 (40%) and Navβ1 (89%).In this study we found region-specific transcriptome changes with a 59% decrease in CaCx43 expression was reduced both at the mRNA and protein levels Figs  and 7C iv1.3 could be responsible for a slowing of atrioventricular node conduction. Both channels carry inward i.e. excitatory current. Knockout of an HCN channel (HCN4) in the mouse causes atrioventricular block [v1.3 in the mouse causes atrioventricular block and reduced automaticity [v1.1 and Navβ1 (inward current channel subunits) is not expected to slow atrioventricular node conduction. We therefore hypothesise that these changes may be compensatory.We hypothesise that a decrease of HCN1 and Caar block . Knockoumaticity ,34. DownHeart failure was associated with a 9-fold upregulation of HCN4 in the ventricular septum. HCN4 channel mRNA upregulation has been described in human failing atrial and ventricular myocardium  and it mIf and ICa channels, as well as connexins. Anatomical enlargement is expected to lead to prolongation of the PR interval because of a longer path of travel. In addition, changes at the mRNA level, taken together, may also contribute to prolongation of the PR interval. PR interval prolongation may therefore be related with both heart enlargement and/or molecular remodelling. Future studies are needed to elucidate the mechanisms by which heart failure induces these changes. Developing clinical modalities for fast and high-resolution imaging of the cardiac conduction system may help guide personalised medical and device therapy for heart failure.This study adds to our understanding of the pathophysiology of atrioventricular block in heart failure by identifying anatomical enlargement of the atrioventricular conduction tissues, which is in keeping with global heart enlargement, and remodelling in We studied heart failure-induced transcriptome changes that occur in the regions in and immediately surrounding the atrioventricular node. The physiological importance of these changes is likely to differ in different regions of the heart. Unravelling the precise anatomical site of atrioventricular block requires invasive electrophysiological measurements in a future study. The phosphorylated state of gap junctions can affect their conductance. Future studies are needed to investigate the effect of heart failure on phosphorylated Cx43 in the AVJ.We did not observe higher degree atrioventricular block (second or third) in any animals. It is unknown whether rabbits are protected from progression to higher degree atrioventricular block in heart failure, thus representing a species difference to the human. The rabbit AVJ is smaller and has only one inferior (or posterior) extension. It also has the capability to conduct faster heart rates compared to the human. No animal model satisfactorily reproduces the features of human heart failure, which is a multifactorial process involving hypertension, ischaemic heart disease and diabetes. In addition, no model reproduces the long time-frame involved in the development of human heart failure. Our model of heart failure has advantages in that it is physiological, preserves native cardiac conduction and induces a gradual decline of left ventricular function over time.S1 Checklist(DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.