In summary, echocardiographic data have a high reference value in assessing cardiac function characteristics in children and adult patients with PDA and are worthy of further promotion.This study was to investigate the value of echocardiographic data in assessing changes in cardiac function before and after transcatheter closure in children and adult patients with patent ductus arteriosus (PDA). In this study, 150 patients with isolated PDA treated by cardiac catheterization and transcatheter closure were selected as the study sample. Real-time color Doppler echocardiography was used both after and after operation. The results showed that the left ventricle returned to normal in 75 patients one day after operation, with an average age of 10.95 ± 3.27 years; the left ventricle did not return to normal in 10 patients 360 days after operation, with an average age of 64.31 ± 7.05 years. Left ventricular end diastolic volume index (LVEDVI) and left ventricular end systolic volume index (LVESVI) of patients decreased significantly one day after operation and remained at 51.95 ± 9.55 mL/m Patent ductus arteriosus (PDA) is one of the common types of congenital heart disease in children, accounting for 15% of the total incidence of congenital heart disease. The passive opening of fetal ductus arteriosus is an important channel of blood circulation. After birth, functional closure occurs about 15 hours, and 80% of them are anatomically closed 3 months after birth . The cliCurrently, clinical treatment of PDA includes traditional ligation and transcatheter closure. Both methods are physical occlusion of the PDA, blocking the left-to-right abnormal shunt, and progressively restoring cardiac function, thereby improving the patient's clinical symptoms and quality of life . TraditiWhether the effect of PDA closure on cardiac function is the same in children and adults is unclear and necessary to be explored. Therefore, this study hopes to analyze the changes of cardiac function and the diagnostic value of echocardiography before and after transcatheter closure of PDA in children and adults by performing echocardiography and cardiac function assessment in 150 patients with isolated PDA treated by cardiac catheterization and transcatheter closure. This study expects to provide some reference for the diagnosis and treatment of congenital heart disease with PDA.In this study, 150 patients with isolated PDA diagnosed in Quanzhou First Hospital Affiliated to Fujian Medical University and Fujian Medical University Union Hospital from January 1, 2016, to January 5, 2021, were selected as research samples, aged 6-70 years, all of whom were successfully treated with cardiac catheterization and transcatheter closure under local anesthesia. This study was approved by medical ethics committee of hospital; patients and their families understood the study and signed informed consent.Inclusion criteria are as follows: (1) left ventricular end-diastolic diameter (LVEDD) detected by echocardiography before operation was larger than normal value, (2) left ventricular ejection fraction (LVEF) > 0.5, (3) complete case data, and (4) patients' compliance was good.Exclusion criteria are as follows: (1) patients with other congenital heart disease, (2) patients with general anesthesia, (3) patients with dilated cardiomyopathy, and (4) patients with primary valvular heart disease.In this study, the digital subtraction angiography system (DSA) was used to perform angiocardiographic examinations on patients. Local anesthesia of the patient was required before the angiogram; then, the patient's right femoral vein and artery were punctured into the left ventricle, and aortic and left ventricular pressures were measured. Angiography was performed at the descending part of the aortic arch to observe the shape and size of PDA. Then, blood oxygen saturation and chamber pressure were measured in superior and inferior vena cava, right atrium, right ventricle, pulmonary artery, and pulmonary arteriole. Fick method was used to detect cardiac output (CO) , the pulAccording to the results of angiography to select the appropriate occluder and delivery sheath, via the femoral vein to the end hole catheter to the right atrium, right ventricle, pulmonary artery, ductus arteriosus, and descending aorta, guide wire was fixed in descending aorta, and along the guide wire, the corresponding delivery sheath and dilator tube were introduced to the descending aorta. The guide wire and expansion tube were then pushed out, and the occlude was inserted into the delivery rod and placed at the PDA. Then pigtail catheter was introduced from femoral artery to descending part of aortic arch for angiography. If only a small residual shunt was observed, the occluder can be released, and various catheters were removed and bandaged.This study adopted the digital color ultrasonic (PHILIPS IE33) to perform ultrasonography on patients. First, ultrasonography needed to be carried out in the patient's quiet state, the patient was in the left lateral decubitus position, each standard section of the heart was detected with an ultrasound probe, and three consecutive complete cardiac cycles with stable heart rate sonograms were selected for storage. After that, the images were processed, and LVEDD, left ventricular end-systolic diameter (LVESD), left atrial diameter (LAD), and right ventricular diameter (RVD) were recorded. The left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI), left ventricular stroke volume (LVSV), LVEF, fractional shortening (FS), and body surface area were calculated by the traditional single-plane area-length method.Heart valve insufficiency was measured by continuous ultrasound and classified as normal (0), mild insufficiency (1), moderate insufficiency (2), and severe insufficiency (3). The severity of mitral insufficiency (MI) and tricuspid insufficiency (TI) was assessed according to color Doppler ultrasound at the site reached by the mitral and tricuspid regurgitant beams in the apical four-chamber view. The degree of aortic insufficiency (AI) and pulmonary insufficiency (PI) was evaluated according to the distance between the aortic and pulmonary artery regurgitant beams at the long axis of left ventricle and the right ventricular outflow tract near the sternum by color Doppler ultrasound, which was divided into mild insufficiency (the distance between the aortic and pulmonary artery regurgitant beams was less than 1 cm), moderate insufficiency (1-2 cm), and severe insufficiency (more than 2 cm).The patients were followed up at 1 day, 30 days, 90 days, 180 days, and 360 days after operation. If LVEDD returned to normal at 1 day after operation, the patients were followed up for 90 days to review the changes of cardiac function. If LVEDD did not return to normal 1 day after operation, the patients were followed up until the body returned to normal. The position and shape of the postoperative occluder were observed, and the relevant parameters were measured. The recovery of cardiac structure and function and pulmonary artery pressure were observed, and the influence on the valve and other complications were observed. Whether there was residual shunt and occluder affected left pulmonary artery or descending aorta should be paid attention to.P < 0.05.The data in this study were analyzed by the SPSS19.0 statistical software. The measurement data were expressed as mean ± standard deviation . RVD index is significantly higher than that before operation (P < 0.05). There is no statistically significant difference in LVT 1 day after operation compared with that before operation (P > 0.05).Among 150 patients, 75 cases of left ventricular returned to normal 1 day after operation, 33 cases of left ventricular returned to normal 30 days after operation, 15 cases of left ventricular returned to normal 90 days after operation, 1 case of left ventricular returned to normal 180 days after operation, 7 cases of left ventricular returned to normal 360 days after operation, and 10 cases of left ventricular did not return to normal 360 days after operation. .The age of patients who recovered at different time points was analyzed. It was found that the age of patients whose left ventricle recovered to normal was 10.95 ± 3.27 years at 1 day after operation, 13.85 ± 2.93 years at 30 days after operation, 19.53 ± 4.21 years at 90 days after operation, 23.59 ± 4.11 years at 180 days after operation, 40.46 ± 5.08 years at 360 days after operation, and the age of patients whose left ventricle did not recover to normal was 64.31 ± 7.05 years at 360 days after operation .2 and 20.36 ± 8.11 mL/m2, and LVEDVI and LVESVI before operation were significantly higher than those at 1, 30, 90, 180, and 360 days after operation (P < 0.05). The LVEF and LVT of patients whose left ventricle returned to normal 1 day after operation showed a trend of decreasing first and then increasing, which was not significantly different from that before operation (P > 0.05)  .2 and 57.44 ± 9.88 mL/m2. The preoperative LVEDVI and LVESVI were significantly higher than those at 1, 30, 90, 180, and 360 days after operation (P < 0.05). The LVEF and LVT of patients with left ventricle failure to return to normal 360 days after operation showed a trend of decreasing first and then increasing, and there was no significant difference between them before operation (P > 0.05)  .In general, normal fetuses are functionally closed within 10-15 hours of birth by contraction of the smooth muscle in the medial layer of the ductus arteriosus wall and permanently closed within 2-3 weeks of birth by formation of wrinkles in the endothelium of the ductus arteriosus and fibrosis of the subintimal connective tissue . If PDA P < 0.05), while RVD indexes were significantly higher than those before operation (P < 0.05), indicating that PDA closure will cause abnormal cardiac function in patients [There were significant differences in RVD, LAD, LVEDD, LVEDVI, LVESVI, LVEF, and FS indexes 1 day after operation compared with those before operation. LAD, LVEDD, LVEDVI, LVESVI, LVEF, and FS indexes were significantly lower than those before operation . LVEDVI reflects the changes when the left ventricle is increased by preload, which mainly occurs in the earlier stage of left ventricular enlargement and myocardial remodeling. LVESVI indicates the changes when the left ventricle is increased by afterload, which generally occurs in the later stage of left ventricular dilatation and myocardial remodeling. This result indicates that the patients whose left ventricle returns to normal quickly after operation have better effect of myocardial remodeling and involution. In addition, LVEDVI and LVESVI of patients whose left ventricle did not return to normal 360 days after operation were significantly decreased on postoperative first day, and then, the downward trend was stable and finally maintained at 149.09 ± 28.09 mL/m2 and 57.44 ± 9.88 mL/m2. There was still a significant difference in their levels compared with the normal body, indicating that the effect of myocardial remodeling and involution in patients whose left ventricle returned to normal slowly after operation was poor, and it is not easy that the cardiac function indicators returned to normal levels. Drug therapy to improve cardiac load and myocardial remodeling should be considered after operation.The long-term change trend of postoperative cardiac function indicators was analyzed. It was found that LVEDVI and LVESVI in patients with normal left ventricle 1 day after operation were significantly decreased on the first day after operation, and then, the decrease trend was stable, finally maintained at 51.95 ± 9.55 mL/mIn this study, 150 patients with isolated PDA who were diagnosed and underwent cardiac catheterization and transcatheter closure in the Quanzhou First Hospital, Fujian and Fujian Medical University Union Hospital from January 1, 2017, to January 5, 2021, were selected as the study sample to evaluate the age differences in cardiac function changes before and after transcatheter closure of PDA by monitoring the preoperative and postoperative cardiac real-time color Doppler echocardiography of patients. The results indicated that there was a significant difference in the prognosis of PDA closure between children and adults, the rate of postoperative left ventricular recovery in children was significantly faster than that in adults, children could return to normal within 6 months, and adult patients mostly returned to normal 1 year or even more after surgery. In addition, the effect of myocardial remodeling and invagination in adult patients was also obviously worse than that in children, and postoperative drug therapy can be considered to reduce cardiac load and improve myocardial remodeling in clinical practice. However, this study was a single-center retrospective study, and the sample size was small, which may cause bias in the results. In the future, data collection on patients of different ages will be added to further study the changes in cardiac function after PDA surgery in children and adults. In conclusion, this study confirmed the age difference in cardiac function characteristics of patients with PDA, determined the application value of echocardiography in evaluating the cardiac function characteristics of patients with PDA in different age, and provided reference value for the relevant research on the diagnosis and treatment of PDA diseases.


Even though the tricuspid valve is no longer “forgotten”, it still remains poorly understood. In this review, we focus on some controversial and still unclear aspects of tricuspid anatomy as illustrated by noninvasive imaging techniques. In particular, we discuss the anatomical architecture of the so-called tricuspid annulus with its two components , emphasizing the absence of any fibrous “ring” around the right atrioventricular junction. Then we discussed the extreme variability in number and size of leaflets (from two to six), highlighting the peculiarities of the septal leaflet as part of the septal atrioventricular junction (crux cordis). Finally, we describe the similarities and differences between the tricuspid and mitral valve, suggesting a novel terminology for tricuspid leaflets. Today, the major impact on strategic management of tricuspid valve (TV) regurgitation (TR) is still dictated still by the work of Nina Braunwald et al., which reviewed the clinical outcome of 100 patients who underwent mitral replacement in 1967 [Among them, 28 patients had clinical and hemodynamic evidence of significant TR at the time of mitral replacement for either mitral stenosis or regurgitation, but an associated surgical procedure to correct TR was performed only in three cases. The authors followed up the 24/28 survivors of the operation for a time interval of 1 to 4 years (average 30 months), and all experienced clinical improvement with a reduction in mean right atrial pressure (from 11 mm Hg to 5 mmHg) and mean systolic pulmonary pressure (from 75 mmHg to 39 mmHg). They concluded that secondary TR “will improve or disappear after mitral replacement and that TV replacement is seldom necessary”. Needless to say, nowadays this paper would undergo severe criticism: the patient population was likely rheumatic (though not explicitly stated), and only 28 patients (and 24 operative survivors) were included in the study with a short follow up time (average 30 months). Moreover, the follow up consisted only of clinical examination and the assessment of right atrial and mean systolic pulmonary pressure, without an objective tool to evaluate the residual TR and right ventricular (RV) size and function. In the discussion, the authors state that “symptomatic improvement in the later postoperative period seemed to be achieved more rapidly by patients without than those with TR”; however, they discounted this as the “impression” of the treating physicians.In those days, the study was highly regarded for several reasons; first and foremost because it gave a reason for the surgeons to avoid implanting a second prosthesis that would be deemed useless. From then onwards, the TV pathology was considered a “benign” disease and somehow “forgotten” by the cardiology community.A renewed interest on TV was elicited by a study published by Nath et al. in 2004 ,4,5,6. Ep < 0.0001). Thus, in agreement with the study published by Nath et al., greater or equal to moderate isolated TR has an elevated risk of mortality. Indeed, adjusted for age, sex, AF, ejection fraction, presence of restrictive physiology, mitral regurgitation grade, and systolic pulmonary pressure, in the Topilsky study, the risk of mortality was of 1.17 . Finally, in both above-mentioned studies, the most frequent cause of TR was functional. The prevalence of functional TR over the organic (or primary) TR has been recently confirmed by Vieitez et al. [The prevalence of TR has been poorly known for a long time. The main reason is that many proven significant TR are clinically undetectable. Thus, 2D TTE color Doppler remains the main tool for detecting TR and define its prevalence. Cahill et al.  analyzedPatients with severe TR may be asymptomatic or paucisymptomatic for a long time before facing right ventricular dysfunction. When symptomatic, medical treatment (primarily based on diuretics) may alleviate symptoms, and currently, most patients with severe TR are treated conservatively. The preference of medical therapy is due to the high morbidity and mortality risk associated with TV surgery, evaluated at 10% and 40% respectively in all major trials. ,12. MoreThe substantial failure of an effective surgical treatment for isolated TR has accelerated the development of devices and techniques for percutaneous tricuspid interventions ,19,20. PFor a successful outcome of these novel percutaneous techniques, an in-depth understanding of the peculiar tricuspid anatomy is essential. Over the last 10 years, a significant number of papers have been published describing the TV anatomy. ,27,28,29Previous studies ,31 from (a)Which is the best noninvasive imaging technique to visualize TV?(b)Does the tricuspid annulus exist?(c)How many leaflets has the valve?(d)Which are the similarities and differences between tricuspid and mitral valve?In this respect, we pose the following questions:Describing and illustrating cardiac anatomy through noninvasive imaging techniques is a novel method with considerable advantages compared to cadaveric anatomic specimens. Indeed, these techniques show a kind of “live-anatomy” which couples morphology and function admirably. CT, CMR and 2D-3D TTE/TEE are usually requested to illustrate and clarify pathological states. Thus, imaging normal anatomic structures is a sort of “beneficial collateral effect” of these techniques. The same data set that show pathological features is able to consistently show anatomical details of the other normal cardiac components. Moreover, they play an essential role before, during and after both surgical and percutaneous intervention on TV. Not all these techniques are equally able for describing the anatomy of TV. In this section, we briefly illustrate their strengths and weaknesses.Routinely, CT scan is required for evaluating coronary artery disease and pathologies of the aorta  , for selThe ability to dynamically visualize the heart without any limitations due to body habitus and the absence of ionizing radiation makes CMR an ideal imaging technique . HoweverEchocardiography remains the first-line technique in the evaluation of TV, and it is a key modality for distinguishing primary (organic) from secondary  TR. 2D TTE and 2D TEE cross sections have been described and standardized ,40,41,42It must be said that when using 3D TTE, the leaflets may appear thicker than they actually are, due to the poor lateral and azimuthal resolution, whereas using 3D TEE, the leaflets may suffer drop-out artifacts due to their thinness and oblique orientation with respect to the direction of ultrasound beams .There is much interest in the anatomical architecture of the so-called “tricuspid annulus” (TA). Indeed, the most common cause of TR is not the anatomical involvement of tricuspid leaflets, but rather the enlargement of TA . For this reason, the TA is the main therapeutic target for surgical treatment of functional TR and, more recently, for percutaneous annuloplasty. As seen from right atrium in empty cadaveric specimen the TA appears oval in configuration A,B and sThe TA can be divided into two distinct segments , a C-shaMesser et al. studied 12 human hearts from patients who died following cardiac surgery and underwent autopsy. They found no significant amount of fibrous tissue along the C-shaped mural segment . In otheSeveral thin muscular bars extend from the right ventricular wall to the ventricular aspect of the hinge line of leaflets in a crisscross fashion. These muscular bars that look like the third order chordae of mitral valve are believed to reinforce this segment of the annulus . HoweverThe septal annulus is made up only by the hinge line of the septal leaflet which is inserted on the ventricular myocardium, lining the inferior margin of the so-called atrio-ventricular septum (see below). Histologically, fibers of connective tissue may reinforce the hinge line especially in the region of the membranous septum, making this the most recognisable part of the annulus. As for the mural annulus, muscular thin bars arising from the septal ventricular wall insert at the hinge line of the leaflet. The septal leaflet is inserted apically relative to the insertion of the anterior mitral leaflet. In a normal heart, the distance between the two hinge lines does not exceed 8–9 mm . This coIn conclusion, though we continue to call the right atrioventricular junction tricuspid annulus, we must emphasize that, from an imager’s point of view but also from an anatomical perspective, an annulus, as assumed to be a complete fibrous ring surrounding the right atrio-ventricular orifice, does not exist. The TA corresponds to the circumference where leaflets are inserted. Accordingly, regardless of the imaging modality used, all the measurements of the annulus are taken using this hinge line.It is interesting to note that surgeons and interventionalists propose a different segmentation of the TA. Surgeons divide the TA in four portions: the aortic, anterior, posterior and septal segments . The aorThe anatomical relationship between the right coronary artery (RCA) and the mural annulus is significant. Encircling the mural annulus, the distance between RCA and the leaflets’ hinge line varies with a minimum of 5–10 mm at the posterior/septal leaflet commissure to the maximum of 20 mm at the anterior/septal leaflet commissure . Importa2/m2, and the TA area shortens by 35% ± 10% during the cardiac cycle [The TA has two main systolic motions: the sphincteric contraction and the excursion towards the right ventricular apex. The sphincteric contraction is prevalently due to the muscular structure of the mural annulus which follows the contraction of ventricular and atrial cavities. In the setting of a relatively fixed septal annulus, both the sphincteric action and longitudinal motion are therefore asymmetric, involving predominantly the anterior, lateral and inferior segments of the TA . The norac cycle . The excThe annular dilatation is also asymmetric involving almost exclusively the “soft” mural annulus. Currently, two mechanisms can be described for explaining dilation of TA (and consequent TR): the “atriogenic” (previously labelled as idiopathic annular dilatation) and the “ventriculogenic” mechanisms.In some patients, longstanding atrial fibrillation has been associated with annular dilation and TR despite the fact that the right ventricle has a normal size, shape and function . The incThe “ventriculogenic” mechanism of TR is more complex and mirrors that of the symmetric patterns of functional mitral regurgitation. The increase in right ventricular volume disrupts the normal spatial relationships between leaflets, chordae, and papillary muscles leading to leaflet tethering, dilatation and flattening of the TA in a deleterious vicious circle. In particular, both anterior and inferior papillary muscles (PMs) move laterally and apically. The first tethers the anterior leaflet and the anterior part of the septal leaflet, whereas the second tethers the inferior leaflet and the inferior-lateral commissure. The above-mentioned thin muscular strings arising from the base of right ventricle and inserting on the annulus may contribute to the annular dilation when the right ventricle is enlarged.In ventriculogenic TR, dilatation of the right ventricle resulting in displacement of the papillary muscles results in leaflet tethering or tenting, and apical leaflet coaptation. In the atriogenic TR, lack of leaflet coaptation is due to the annular dilation without leaflet tethering .In the classic anatomy books, the TV has been traditionally described as having very distinct three leaflets with three main indentations. Using an attitudinal-appropriate nomenclature , the leaflets can be named septal, anterior-superior and inferior. From here on, we use this nomenclature. In the classic three-leaflet configuration, the indentations  are located in anterior-septal position , in anterior-inferior position (dividing the anterior from the inferior leaflet), and inferior-septal position . Interestingly, mirroring the mitral commissures, the indentations do not reach the hinge line, leaving a strip of valvular tissue between the leaflets. Thus, from an anatomical point of view, the leaflets are formed by a continuous veil divided by three (or more) indentations. Each leaflet can be roughly divided in three zones: the basal zone near the hinge line, a thin and translucent “clear” zone (which corresponds to the body of the leaflet) and a rough zone towards the free edge, where chordae tendineae are inserted on its ventricular side. This rough zone corresponds to the atrial side as the coaptation area .Despite the name “tricuspid”, the valve shows a large variability in terms of size and number of leaflets, and publications present divergent and often confounding results. In 1971, Silver et al. studied 50 normal heart specimens, recognizing that in 70% of patients, the inferior leaflet was scalloped, containing accessory leaflets . SkwarekThe coincidence that accessory leaflets are often localized on the mural annulus  deserves further comment ,55. The The septal leaflet warrants a more in-depth description. Characteristically, much of the septal leaflet is indeed septal and shows thin chordae arising from the interventricular septum and attaching on the ventricular surface of the leaflet . HoweverRelative to the short mitral hinge line at the septum, the hinge line of the TV at the septum is longer and is inserted more apically, thus leaving a portion of septum that divides the right atrium from the left ventricle and is named the atrio-ventricular septum (AVS). This septum is a characteristic area where atria and ventricular septa join with the anterior mitral and septal tricuspid leaflets. This region, centrally located in the heart, is named “crux cordis”. This anatomical arrangement was first described by Silverman and Schiller in their seminal paper “Apex Echocardiography” . The AVSAnterior-superiorly, the septal leaflet inserts on the membranous septum (MS). By virtue of the insertion of the septal leaflet, part of this septum is located in atrioventricular position  while the remainder interposes between the ventricular cavities. When viewed from the left ventricle, the MS almost always lies at the base of the interleaflet fibrous triangle between the right and noncoronary sinuses. Inferiorly, the MS is in continuity with the crest of interventricular septum. In some hearts, the hinge line of septal leaflet is positioned so as to place one-third of the septum in atrioventricular position; in others, the MS is divided half and half between the ventricular and atrioventricular portions . ImportaAlthough exposed to much lower systolic pressure, the general anatomic architecture of the TV is surprisingly similar to that of mitral valve. Both valves are constituted by an annulus, leaflets, chordae and papillary muscles. Both annuli can be divided in two components: one straight component and one C-shaped component. In the mitral valve, the C-shaped component is named posterior annulus and sustains the posterior leaflet, while the C-shaped component of tricuspid annulus is named mural annulus and sustains the anterior-superior and inferior leaflets and/or additional scallops. Both posterior and mural annuli are made up by the convergence of four structures: the atrial and ventricular myocardium, the hinge line of leaflets and the epicardial adipose tissue ,30. The Although called bicuspid and tricuspid, the left and right architecture of atrio-ventricular leaflets is almost similar. Indeed, the septal tricuspid leaflet may correspond to the anterior mitral leaflet, while the scalloped posterior leaflet may correspond to leaflets inserted on the mural annulus. Both mitral and tricuspid leaflets have a rough zone which corresponds on the atrial side to the coaptation zone, and in both valves the commissures do not reach the hinge line, leaving a strip of valvular tissue between leaflets and similarly between scallops. Finally, both leaflets have the same three-layered microscopic structure consisting of an atrial layer containing lamellar collagen and elastin sheet, the spongiosa containing loose connective fibers and glycosaminoglycans, and the fibrosa made by robust sheets of collagen fibers. The difference consists only on the fact that in the tricuspid leaflets, layers are thinner. In this review, we discussed some controversial or still unclear aspects of tricuspid anatomy. In particular, we focused on the anatomical architecture of the so-called tricuspid annulus and on the extreme variability in number of leaflets. This latter point deserves further comment. The term “tricuspid”, referring to the right atrioventricular valve, supposes this valve should have three well-defined leaflets. This assumption does not correspond to the anatomical reality because in a significant percentage of cases, the valve has more than three leaflets. In overcoming this discord, a previous anatomic study of 100 autopsied hearts had indeed proposed that the TV is bicuspid in having a septal leaflet without clefts and a mural leaflet with multiple clefts forming several scallops.  We ackno


Background: Permanent right ventricular apical pacing may have negative effects on ventricular function and contribute to development of heart failure. We aimed to assess intra- and interventricular mechanical dyssynchrony in patients with permanent right ventricular apical pacing, and to establish electrocardiographic markers of dyssynchrony.
Methods: 84 patients  who required permanent pacing were studied. Pacing was done from right ventricular apex in all patients. We measured QRS duration and dispersion on standard 12-lead ECG. Intra- and interventricular mechanical dyssynchrony and left ventricular ejection fraction were assessed by transthoracic echocardiography. Patients were followed-up for 24 months.
Results: Six months after implantation, QRS duration increased from 128.02 ms to 132.40 ms, p≤0.05. At 24 months, QRS dispersion increased from 43.26 ms to 46.13 ms, p≤0.05. Intra- and interventricular dyssynchrony increased and left ventricular ejection fraction decreased during follow-up. A QRS dispersion of 47 ms predicted left ventricular dysfunction and long-term electromechanical dyssynchrony with a sensitivity of 80% and a specificity of 76%.
Conclusion: In patients with permanent right ventricular apical pacing there is an increased duration and dispersion of QRS related to dyssynchrony and decreased left ventricular ejection fraction. This study shows that QRS dispersion could be a better predictive variable than QRS duration for identifying left ventricular ejection fraction worsening in patients with permanent right ventricular apical pacing. The electrocardiogram is a simple tool for predicting systolic function worsening in these patients and can be used at the bedside for early diagnosis in the absence of clinical symptoms, allowing adjustments of medical treatment to prevent progression of heart failure and improve the patient's quality of life. Since 1925, Wiggers examined several epicardial pacing sites in dogs. A decreased left ventricular pressure during isovolumetric period contraction was associated with right ventricular apical pacing, whereas pacing close to His-Purkinje system did not produce deleterious hemodynamic effects. He postulated that pacing site exerted a considerable influence on left ventricular function and was probably the first that recognized His fascicle as an excellent place for permanent pacing3,4. In 1998, Van Oosterhout et al.5 characterized the morphological changes produced in the canine myocardium after pacing. The relationship between asynchrony and reduction of myocardial performance was postulated6. The greater percentage of right ventricular pacing accumulated over time is related with changes in left ventricular geometry and hemodynamic parameters. It has been widely evidenced that right ventricular apical pacing induces asymmetrical ventricular hypertrophy, ventricular dilatation, abnormal fiber arrangement, increase of cathecolamines and myocardial perfusion disturbances, among other harmful effects4,7,8.When cardiac pacing was discovered as a conduction disorder treatment, the greatest concern was the patient survival but without addressing other aspects9. It was found that, regardless of pacing mode, a high percentage of stimulated beats is a strong predictor of left ventricular dysfunction or atrial fibrillation development9,10. Heart failure secondary to right ventricular apical pacing has also been demonstrated11,12.Mode Selection Trial (MOST) study comparing dual chamber (DDD) and single chamber (VVI) pacing mode patients analyzed the relationship between the proportion of beats with ventricular pacing and hospitalization for heart failure or onset of atrial fibrillation13.In patients with chronic heart failure associated with left bundle branch block (LBBB) and reduced left ventricular ejection fraction (LVEF), QRS duration and dispersion are increased. Also, in New York Heart Association (NYHA) Class II-IV heart failure patients with severe systolic dysfunction (left ventricular ejection fraction <35%), QRS dispersion was significantly higher in deceased patients than in survivors . Moreover, patients which died suddenly had significantly higher QRS dispersion than survivors . A QRS dispersion cut-off value of 46 ms separated patients with higher risk of death in the following three years Based on the idea that the right ventricular apical pacing’s deleterious effect is associated with LBBB, generated by pacing itself, which causes electromechanical dyssynchrony, we aimed to determine the relationship between mechanical intra- and interventricular dyssynchrony, observed with echocardiography, and electrocardiographic changes in patients with permanent right ventricular apical pacing, regardless of pacing mode: dual chamber or single chamber.Patients scheduled for permanent pacemaker implantation due to complete atrio-ventricular block, atrial fibrillation with low heart rate, carotid sinus hypersensitivity, hypertrophic cardiomyopathy, sinus node dysfunction were enrolled prospectively. Ventricular pacing was performed from the right ventricular apex, either VVI or DDD mode. Exclusion criteria were: left bundle brunch block, primary dilated cardiomyopathy, known ischemic heart disease or history of coronary revascularization, history of chronic alcoholism, prior chemotherapy and/or radiotherapy, exposure to cardiotoxic substances such as heavy metals, treatment with antiretroviral drugs, history of infiltrative diseases, patients who needed cardiac resynchronization therapy or implantable automatic defibrillator, corrective congenital cardiac surgeries or significant valvular heart diseases, patients who required antiarrhythmic in the last six months. The study included 84 patients.Variables were recorded before pacing (with intrinsic cardiac rhythm), at six, twelve and twenty-four months after implant. From the standard 12-lead ECG QRS, maximum and minimum duration was manually measured by 2 independent observers, with a paper speed of 25 mm/s, amplitude of 10 mm/1 millivolts (mV). QRS was considered from the beginning of q or R wave up to J point at the beginning of the ST segment. QRS dispersion was calculated as difference between the QRS maximum and minimum value measured on the 12-lead ECG.14-16 in the four-chamber apical view, while interventricular dyssynchrony was considered according to the differences between left and right ventricle electromechanical delays . Interventricular asynchrony  was defined as an aorto-pulmonary delay ≥ 40 ms15,16.Standard transthoracic echocardiographic variables were recorded. Left ventricular ejection fraction was measured using biplane Simpson's method. All patients had left ventricular ejection fraction ≥ 50% at inclusion. For assessing left intraventricular dyssynchrony, electromechanical delay of septal-to-lateral wall was determined by means of tissue Doppler, locating the sample volume in the basal portion of the interventricular septum and lateral wall, in order to calculate the temporal difference between both, measuring from the beginning of the QRS complex until the peak systolic velocity. Echocardiographic demonstration of cardiac asynchrony was defined for values ≥ 60 msPacing percentage was taken from pacemaker programmer.2) was applied for association between variables with the same level of significance. Linear correlations were made (Spearman test). Discriminatory power of QRS duration and its dispersion were estimated using the receiver operator curve (ROC) using estimates and the 95% confidence interval (CI) and area under the curve was calculated.We used Statistical Package for Social Science (SPSS) version 21.0 for Windows. Frequency distribution tables with absolute and relative values were created. The mean was determined for the variables that required it with standard deviation as a measure of variability. For the comparison of means, the t-student statistic was used, and statistical significance was considered if p≤0.05. From the inferential point of view, the non-parametric Chi square test  and 38 females (45.24%). Age distribution showed the highest number of patients had 70 or more years (46.43%), and between 60 and 69 years (28.57%). Pacing indication is summarized in Frequency of pacing was greater than 83% in all patients. QRS dispersion showed significant and positive correlations with interventricular dyssynchrony (p = 0.015) and intraventricular dyssynchrony (p = 0.001), as well as with pacing frequency (p = 0.003) .In addition, left ventricular ejection fraction significantly decreased, correlated with QRS dispersion (p = 0.016), Pearson coefficient=-0.606. Left ventricular ejection fraction also decreased when cardiac pacing percentage was high (p = 0.000), Pearson coefficient =-0.589.The ROC curve A shows tIn this study we showed that in patients with permanent right ventricular apical pacing there is an increased mechanical dyssynchrony and a decrease in left ventricular ejection fraction. From the total number of patients studied, 15 of them (15.47%) presented a left ventricular ejection fraction less than 40% at 24 months of follow-up. A relationship was demonstrated between lower values of left ventricular ejection fraction and increased QRS duration and dispersion. In addition, inter- and intraventricular dyssynchrony observed during follow-up was related with increased values of QRS duration and dispersion. This is the first study reporting the relationship between QRS dispersion and left ventricular ejection fraction worsening in patients with permanent right ventricle apical pacing and establishing its potential value in assessing inter- and intraventricular electromechanical dyssynchrony.16 described the harmful effects of right ventricular apical pacing. During 20 months of follow-up, patients who had a higher cumulative rate of right ventricular apical pacing compared with patients who had infrequent pacing, suffered a higher incidence of heart failure, ventricular arrhythmias and mortality.Clinical effects of right ventricular apical pacing regarding precipitation of left ventricular dysfunction and heart failure are well-documented. A Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II sub-study17, which reported an increase of the prevalence of heart failure or left ventricular dysfunction in permanent pacing, corelated with pacing percentage. PACE study (Pace to Avoid Cardiac Enlargement)18, a multicenter, double-blind, randomized trial was designed to determine if biventricular pacing was superior to permanent right ventricular apical pacing for preventing structural changes of left ventricular and to avoid systolic disfunction. Patients with left ventricular ejection fraction ≥45%, with pacemaker indication due to high-grade of AV block or sinus node dysfunction were included. All patients received atrial and biventricular pacing lead, and the pacemaker could be programmed for RV or biventricular pacing. Two days after device implanting, patients were stratified according to whether diastolic dysfunction was present. In each group the patients were randomized to receive right ventricular apical pacing or biventricular pacing (1:1). At 12 months, the group with right ventricular apical pacing (n = 88) versus biventricular pacing (n = 89) had lower left ventricular ejection fraction ; 8 patients who received right ventricular apical pacing (9%) versus 1 patient who underwent biventricular pacing (1%) had a left ventricular ejection fraction less than 45%. The deleterious effects of right ventricular apical pacing occurred in both pre-specified groups, including patients with and without previous diastolic dysfunction.The deleterious effects of chronic right ventricular apical pacing were also reflected in the study by Chen S et al.19 found a QRS duration of 156 ± 22 ms in the group who underwent permanent right ventricular apical pacing, higher than in our group, perhaps due to a reduced sample of patients, only 9 of them having apical pacing. In addition, his patients being older, QRS duration could have been increased because of age-related changes of heart electrical system conduction and the cardiac architecture. Molina Mora et al.20 obtained an average QRS of 135.5 ± 26.2 ms, similar to our results, although in their group QRS duration did not significantly increased , and there were no significant changes in the left ventricular ejection fraction .Using QRS duration for estimating the degree of dyssynchrony induced by pacing is not a new concept. Lange and al.21. Right ventricular apical pacing causes the heart depolarization to be reversed . Changes in depolarization sequence will delay left ventricular depolarization on the upper septum part and the lateral regions and could explain the increased QRS duration and dispersion22. The depolarization changes the impact on the heart contraction mechanics and at the same time on the flow patterns, leading to left ventricular ejection fraction worsening23. Chavez et al.14studied 24 patients with depressed left ventricular ejection fraction secondary to right ventricular apical pacing. They demonstrated a higher QRS duration (178.12 ± 14.31 ms versus 103.17 ± 3.43 ms) and QRS dispersion (45.07 ± 4.83 ms versus 33.15 ± 2.14 ms) during right ventricular apical pacing compared to septal region pacing. Moreover, there was reverse remodeling and an increase in left ventricular ejection fraction with septal pacing.QRS dispersion is a simple electrocardiographic marker with potential value in the assessment of patients in different clinical settingsConsidering the results of the present study, we consider that depolarization delay in right ventricular apical pacing is represented by higher values of QRS dispersion and that this could identify electromechanical dyssynchrony. The ROC curve shown in Our study was performed with a relatively small sample size and with a short time of follow-up, therefore the results obtained need to be reproduced and evaluated in a larger number of patients with different characteristics and comorbidities.An elevated percentage of right ventricular apical pacing increased QRS duration and dispersion, both being related with echocardiographic mechanical dyssynchrony and left ventricular ejection fraction decrease. This study is important because it shows that QRS dispersion could be a better predictive variable than QRS duration for identifying left ventricular ejection fraction worsening in patients with permanent right ventricular apical pacing.◊Permanent right ventricular apical pacing produces an unphysiological ventricular activation sequence which could lead to systolic dysfunction and precipitate heart failure◊Right ventricular apical pacing increases QRS duration and dispersion, both being related to mechanical dyssynchrony and left ventricular ejection fraction decrease◊QRS dispersion was better than QRS duration for identufying mechanical dyssynchrony and ejection fraction worsening◊Studies should be designed to evaluate the same electrocardiographic variables investigated here, in order to establish pacing sites that maintain electromechanical synchrony. The pacing site could be the His bundle which has been studied in several worldwide implantation centers


With the continuous improvement of the respiratory care of Duchenne muscular dystrophy patients, cardiac manifestations (heart failure and arrhythmias) become the leading causes of morbidity and mortality. Early identification of cardiac muscle affection is crucial to start anti-failure drugs that reverse remodeling and improve prognosis. This study aimed to detect subtle cardiac changes in Duchenne muscular dystrophy patients and carriers using electrocardiography and echocardiography.This study included genetically diagnosed Duchenne muscular dystrophy patients  and carriers  and compared them to healthy gender-matched control groups. All study participants underwent clinical assessment, 12-lead electrocardiography, and global longitudinal strain augmented echocardiography. In the current study, Duchenne muscular dystrophy patients had higher heart rates, smaller left ventricular internal diameters, left atrial diameter, lower ejection fraction, and worse left ventricular global longitudinal strain in comparison with the control group. The global longitudinal strain inversely correlated with the age of Duchenne muscular dystrophy patients. The number of exon mutations did not affect electrocardiography and echocardiographic findings. Exon mutations 45–47 and 51–54 were significantly associated with an ejection fraction less than 60%. Duchenne muscular dystrophy carriers had smaller left ventricular wall diameters, left ventricular end-diastolic diameter, left atrial diameter, and worse left ventricular global longitudinal strain in comparison with the control group.Left ventricular global longitudinal strain could detect subtle left ventricular systolic dysfunction in Duchenne muscular dystrophy patients and carriers before the decline of left ventricular ejection fraction.The online version contains supplementary material available at 10.1186/s43044-021-00214-0. Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disorder that shows an X-linked recessive inheritance. Dystrophin gene mutations on chromosome Xp21 result in absent or deficient functional dystrophin protein in skeletal and cardiac muscles distorting their structure with subsequent fibrosis and weakness that impair their functions . Early iThis is an observational cross-sectional case–control study in which we revised the records of the neuromuscular unit in a tertiary care university hospital. Forty patients with genetically diagnosed DMD without previous cardiac history were contacted to join the study between July 2019 and July 2020. The genetic diagnosis was done using multiplex ligation-dependent probe amplification (MLPA) in Centogene laboratories, Germany using SALSA MLPA probemix P034-B2/P035-B1 provided by MRC-Holland to test for deletion or duplication exon mutations of the DMD gene (Gene parts included in the messenger ribonucleic acid (mRNA) that are translated into proteins are known as exons). If the test was negative, then amplicon-based next-generation sequencing was performed in Centogene laboratories, Germany to detect other mutations such as intron mutation (introns are gene parts that do not have protein-coding information), non-sense mutation (point mutation the results in premature stop codon), or missense mutation (point mutation that results in changed amino acid) .Among the contacted patients, only 30 patients showed interest to join the study, but 1 of them was excluded due to his marked chest wall deformity which prevented obtaining proper loops for echocardiographic examination. Another adult patient was excluded from the study as his age was above 18 years. DMD patients were enrolled in group A , while healthy gender-matched participants were enrolled in control group B  without a history of previous cardiac disease, hypertension, or diabetes mellitus. Mothers and female relatives of the patients included in group A who were genetically tested positive to be carriers of dystrophin gene mutations were enrolled in group C , while healthy gender-matched participants were enrolled in control group D . DMD carriers and controls were not hypertensive, diabetic and they did not have a previous cardiac history.All participants were subjected to detailed clinical cardiac assessment including identification of any symptoms of heart failure or arrhythmias  and clinical examination including measuring arterial blood pressure, pulse examination, detection of peripheral edema, cardiac auscultation for heart sounds, and cardiac murmurs.Three-channel 12-lead surface ECG was done for all the study participants using  machine. Heart rate and heart rhythm were identified and the following measurements were taken. (a) PR interval: from the onset of the P wave to the onset of the QRS complex. (b) QRS complex duration: from the onset of the Q wave to the end of the S wave.Standard ECG-gated trans-thoracic echocardiography was performed for all subjects using a General Electric (GE) S7 machine using an M4S matrix sector array probe having a frequency of 2.5 mega Hertz. Standard images were obtained at a depth of 16-cm (cm) in the parasternal (long- and short-axis views) and apical  views while subject in left lateral position. Standard ECG-gated 2-dimensional (2D) and color Doppler data were saved as loops. Motion (M)-mode, 2D, tissue Doppler imaging (TDI) as well as pulsed and continuous Doppler flow across the different heart valves in all the standard views were done according to the recommendations of the American Society of Echocardiography [p value was considered significant if p < 0.05.After data collection, revision and coding, it was entered into version 23 of Statistical Package for Social Science (IBM SPSS). Mean and standard deviation described parametric quantitative data while percentages and numbers were used to describe qualitative variables. Comparison between the study and control groups was done using the Chi-square test for qualitative data, and independent t-test was used for comparing quantitative data with parametric distribution between both groups. Spearman correlation coefficients were used to assess the correlation between the number of exons and different ECG and echocardiographic parameters. Also were used to assess the correlation between the age of patients and LV GLS. The setting for the confidence interval was 95% and the margin of error accepted was set to 5%, so the r = − 0.4, p = 0.027) . The number of exon mutations was not associated with any significant difference in LV diastolic  or systolic  functions, GLS (= 0.885) PR interval (p = 0.763), and QRS duration (p = 0.580).Genetic analysis of DMD patients showed that most of the patients had deletion or duplication exon mutations (25 patients with mutations involving one or more exons), 2 patients had a non-sense mutation, and 1 patient had an intron mutation. Most of these mutations were in the hot area (exon mutations 45–50) .None of the female carriers was symptomatic. On comparing ECG and echocardiographic findings between group C and D, group C had smaller LV wall diameters, LVEDD, LA diameter, and worse GLS when compared to group D Fig. . There wE/e′, p = 0.525), or systolic functions , GLS (p = 0.448), PR interval (p = 0.536), and QRS duration (p = 0.731) , 2 carriers had a non-sense mutation, and 1 carrier had an intron mutation  and inter-observer variability (0.89).Patients with inherited neuromuscular disorders have a lot of obstacles in receiving sufficient health care services in developing countries. This study aimed to early detect the decline in LV systolic functions before the decline in LV EF or the occurrence of heart failure symptoms in DMD patients or carriers who had visited the neuromuscular unit in the neurology department in a tertiary care university hospital using clinical assessment, ECG, and transthoracic echocardiography that was augmented by speckle tracking measurement of the LV GLS rather than CMR. The mean age of DMD patients was 9.14 ± 2.85 years, and 32% of patients were ≤ 7 years in which lack of co-operation might hinder undergoing CMR without anesthesia [Group A patients showed a significantly higher rate as compared to age-matched controls. This is supported by several studies that found a lack of normal age-related heart rate decline in patients with DMD and postulated that the elevated resting heart rate may be a form of abnormal heart rate variability implicating autonomic dysfunction that is associated with myocardial fibrosis .DMD patients and carriers had smaller LV dimensions as compared to controls. This may be attributed to myocardial atrophy and fibrosis of the LV in DMD patients and carriers documented by CMR using late gadolinium enhancement  and may We observed that despite normal mean LV EF in DMD patients and carriers, the mean GLS was significantly lower in DMD patients and female carriers that indicated subclinical myocardial affection. This is supported by many studies that found that the application of myocardial strain imaging in DMD patients was characterized by decreased peak systolic strain, despite normal standard echocardiographic findings –14. In mThe genetic diagnosis was mandatory for enrolling patients in this study. The most common prevalent exon mutations were from 45 to 50 that is matching with previous studies . In thisMoreover, a significant moderate inverse correlation was found between the age of DMD patients and the decline in GLS. This is supported by Nigro et al. and Cirino et al. who found that cardiac problems typically start as latent cardiomyopathy without symptoms evolving into clinically overt cardiac disease in 14% of patients under the age of 14 years, to be present in 57% of patients over 18 years of age , 22. ThiIt is a single-center study that included a relatively small number of patients and didn’t include CMR which is the gold standard for diagnosing cardiomyopathy in DMD patients and carriers.This study presented the value of early cardiac surveillance not only in DMD patients but also in female carriers even before the onset of cardiac symptoms using relatively simple techniques. The assessment of GLS was able to detect subtle LV systolic dysfunction in patients and carriers before the decline of EF.Additional file 1: Table S1. Sites of exon mutation in Group A. Table S2. Different sites of exon mutation in group C.


The risk of cardiac events at 1 year after diagnosis of myocarditis appears to be low after resumption of exercise after 3 months among patients who recover from acute myocarditis.International cardiovascular society recommendations to return to sports activities following acute myocarditis are based on expert consensus in the absence of prospective studies. We prospectively enrolled 30 patients with newly diagnosed myocarditis based on clinical parameters, laboratory measurements and cardiac magnetic resonance imaging with mildly reduced or preserved left ventricular ejection fraction (LVEF) with a follow-up of 12 months. Cessation of physical activity was recommended for 3 months. The average age was 35 (19–80) years with 73% male patients. One case of non-sustained ventricular tachycardia was recorded during 48-h-Holter electrocardiogram. Except for this case, all patients were allowed to resume physical exercise after 3 months. At 6- ( Athletes appear to be at special risk for sudden cardiac death following acute myocarditis, possibly because intense physical exercise increases viral replication and suppresses the immune system. In turn, this may lead to enhanced susceptibility for upper respiratory infections . It has To address the question of exercise following myocarditis, we prospectively evaluated the safety of early resumption of exercise 3 months following diagnosis with myocarditis in asymptomatic patients without arrhythmias on 48-h-Holter electrocardiogram (ECG) monitoring or stress testing with normal or recovered left ventricular ejection fraction (LVEF). Outcomes included adverse cardiovascular events, defined as persistent or malignant arrhythmias, worsening LVEF, hospitalizations for heart failure, and death after resumption of exercise at 3-month until 12-month follow-up.Myocarditis was defined according to ESC diagnostic criteria, including: Clinical presentation with dyspnea, chest pain, palpitations, elevated high sensitivity troponin T (TnT-hs) (> 14 ng/l), angiographic exclusion of obstructive coronary artery disease (grade of stenosis <50%), and characteristic features on cardiac magnetic resonance imaging (CMR) [At 3, 6 and 12 months follow-up subjects received a cardiovascular examination including history and physical exam, laboratory testing of C-reactive protein , TnT-hs , myoglobin , creatine kinase (CK) , N-Terminal B-type natriuretic peptide (NT-proBNP) , leukocytes , resting 12-lead ECG, 48-h-Holter ECG, exercise stress testing with ramp protocol, and echocardiography. CMR was repeated as part of the 3 months follow-up.Our population consisted of 30 patients with a median age of 35 years (range: 19–80 years) of whom 8 (27%) were women and 22 (73%) were men. Baseline characteristics are presented in Table Initially, all patients showed patchy or diffuse midwall late gadolinium enhancement (LGE) patterns. In 16 (53%) cases additional edema was present in T2 weighted images.After 3 months visually assessed extent of LGE decreased in all patients. No edema was detected on repeat CMRs and 7 (24%) patients showed complete remission of LGE.At presentation, the averaged LVEF was 58% (± 7.4). Three patients revealed a mid-range reduced LVEF. During the follow-up, one remained stable while others normalized.During follow-up stress testing, neither significant ECG changes nor pathological symptoms were provoked.After 3 months, 48-h-Holter ECG showed episodes of non-sustained ventricular tachycardia in one patient. As a consequence, physical exercise was discouraged in this case until further investigations at 6-month follow-up. This 19-year-old man initially presented with severe dyspnoea NYHA III; however, only mild angina-like symptoms were present. The LVEF was stable with elevated CRP 12 mg/l, TnT-hs 276 ng/l, Mb 41 µg/l, CK 213 U/l, and normal NT-proBNP 158 ng/l and Lc 6.95 G/l. After 6 months, all elevated biomarkers normalized and 48-h-Holter ECG as well stress testing showed no signs of arrhythmias. On CMR, initial LGE declined after 3 months and edema on T2-weighted images disappeared. Results from repeated laboratory testing are demonstrated in Table In a first attempt we evaluated early resumption of physical activity after 3 months in a small cohort of patients who recover from acute myocarditis. This allowed us to identify patients without clinical abnormalities such as increasing levels of TnT-hs, arrhythmias in resting 12-lead ECG or 48-h-Holter ECG, worsening of maximum power on exercise stress testing or worsening LVEF as potentially good candidates for early resumptions of exercise.Due to the small sample size, the statistical power of this study is limited. Given the numerous beneficial effects of physical activity, further research is necessary to determine the right timing for resumption of exercise after the onset of myocarditis.


The role of interventricular mechanics in pediatric pulmonary arterial hypertension (PAH) and its relation to right ventricular (RV) dysfunction has been largely overlooked. Here, we characterize the impact of maintained pressure overload in the RV–pulmonary artery (PA) axis on myocardial strain and left ventricular (LV) mechanics in pediatric PAH patients in comparison to a preclinical PA-banding (PAB) mouse model. We hypothesize that the PAB mouse model mimics important aspects of interventricular mechanics of pediatric PAH and may be beneficial as a surrogate model for some longitudinal and interventional studies not possible in children.es, a measure of load-independent contractility). Surgical PAB was performed on mice to induce RV pressure overload and myocardial remodeling. bSSFP-CMR, tagged CMR, and intra-cardiac catheterization were performed on 12 PAB and 9 control mice (Sham) 7 weeks after surgery with identical post-processing as in the aforementioned patient studies. RV_Ees was assessed via the single beat method.Balanced steady-state free precession (bSSFP) cardiovascular magnetic resonance (CMR) images of 18 PAH and 17 healthy (control) pediatric subjects were retrospectively analyzed using CMR feature-tracking (FT) software to compute measurements of myocardial strain. Furthermore, myocardial tagged-CMR images were also analyzed for each subject using harmonic phase flow analysis to derive LV torsion rate. Within 48 h of CMR, PAH patients underwent right heart catheterization (RHC) for measurement of PA/RV pressures, and to compute RV end-systolic elastance  and PAH subjects . In order to compare combined metrics of LV torsion rate and strain parameters principal component analysis (PCA) was used. PCA revealed grouping of PAH patients with PAB mice and control subjects with Sham mice. Similar to LV torsion rate, LV global peak circumferential, radial, and longitudinal strain were significantly (p < 0.05) reduced under hypertensive conditions in both PAB mice and children with PAH.LV torsion rate was significantly reduced under hypertensive conditions in both PAB mice (p = 0.004) and pediatric PAH patients (p < 0.001). This decrease in LV torsion rate correlated significantly with a decrease in RV_EThe PAB mouse model resembles PAH-associated myocardial mechanics and may provide a potential model to study mechanisms of RV/LV interdependency.The online version contains supplementary material available at 10.1186/s12968-021-00759-8. Cardiac index was measured using the Fick’s principle at baseline condition, with FiOes) was calculated using the single beat method described by Truong et al. [es was estimated as the ratio of the difference between “maximum theoretical pressure” and end systolic pressure to stroke volume [(Pmax – Pes)/SV] using the Takeuchi method [a)  was defined as the ratio of end systolic pressure to stroke volume [Pes/SV].For assessment of RV contractility, RV end-systolic elastance  with dedicated cardiac receiver coils appropriate for pediatric subjects. All children were awake during the study. Retrospective-gated cine imaging was performed using breath-holds during expiration for all patients. bSSFP images were acquired at baseline, with parameters of TR 2.8–3.5 ms, echo time of 1.2–1.5 ms, 25 phases, 4–10 mm slice thickness, and acquired matrix size = 192 × 192. These parameters were selected based on subject size, and temporal resolution varied slightly based on subject heart rate. Tagged CMR images were acquired through application of spatially modulated magnetization (SPAMM) to nullify signal within defined parallel lines or grids that persist through the cardiac cycle. Tag persistence throughout the entire cardiac cycle was optimized by minimizing flip angle and utilizing binomial radiofrequency pulses. Typical tagged-CMR image parameters for human subjects were TR 3.9–4.7 ms, echo time of 3.7 ms, voxel size of 1.875 × 1.875 × 8 mm, 6–8 mm slice thickness, flip angle 15°, matrix 144 × 256, with a tag spacing of 6–8 mm. Images were acquired with a minimum of 25 phases throughout the cardiac cycle in short axis view at the basal, mid, and apical levels. The short-axis basal slice was demarcated by a full circumferential view of the LV chamber as landmarked directly inferior to the mitral valve leaflet tips. The mid-chamber slice was demarcated by the region of the cavity encompassing the entire length of the papillary muscles. The short-axis apical slice was demarcated by a full circumferential view of the chamber inferior to the papillary muscles but superior to the end of the cavity.Small animal CMR was performed on a 7T scanner  with all mice under isoflurane anesthesia. After induction of anesthesia, CMR-designated electrocardiogram (ECG) electrodes were attached to their paws for retrospective ECG gating, and mice were placed on a dedicated mouse platform inside the coil. Rodents then underwent bSSFP image acquisition and subsequent SPAMM-tagged CMR with tagging persistence optimized similarly for pediatric patients. bSSFP image parameters for mice were TR 6 ms, echo time of 2.5 ms, 1 mm slice thickness, acquired matrix size = 192 × 192, with 20 phases. Tagged CMR imaging parameters for mice were 1 mm slice thickness, TR 10 ms, echo time of 3 ms, flip angle 15°, matrix 128 × 256, voxel size of 0.15 × 0.15 × 1 mm, with a tag spacing of 0.6–0.8 mm. Tagged CMR images were acquired in LV short axis view at the basal, mid, and apical levels with 20 phases throughout the cardiac cycle. These parameters were chosen to ensure consistency of spatial sampling and standardization of the FT method used between mice and human subjects.Myocardial strain is a measurement of mechanical deformation—either lengthening or shortening—of myocardial tissue . Myocardapex + Rbase)/2D, where BR is the rotation of the base, AR is the rotation of the apex, Rapex and Rbase are their respective radii, and D is the length between the base and apex in systole [LV torsion rate describes the rate of twisting of the ventricle during systole or untwisting during relaxation in diastole . LV tors systole . LV radi systole . This waAll statistical analyses were performed in MatLab  and utilized an alpha of 0.05 for significance, with a 95% confidence interval. Mean and standard deviation were calculated—for control subjects, PAH patients, Sham, and PAB—for metrics of LV torsion rate and global radial, circumferential, and longitudinal peak strain. Metrics derived were tested for normal distribution using the Lilliefors test. Unless otherwise stated, values reported were determined to be normally distributed. An unpaired, two-tailed Student t-test was used to compare mean values of these metrics between control and PAH subjects and between Sham and PAB. To compare non-normally distributed variables we performed the Mann–Whitney test. ANOVA analysis was performed to compare means of LV torsion rate, global radial, circumferential, and longitudinal peak strain between the four groups. Univariate linear regression was used to assess relationships between LV torsion rate and RV contractility for PAH subjects and PAB.Principle component analysis (PCA) was performed on the combined dataset of z-score normalized myocardial mechanics to determine if segregation between PH groups (PAH patients and PAB mice) and control groups (control subjects and Sham mice) was seen after a transformation along the first three principal components. Results are shown using biplots with a vector for each variable superimposed.Intra-, inter-observer agreement and reproducibility for harmonic phase flow analysis—and the processing algorithm used—have been verified by us in a previous study . IntraobDemographics of the PAH pediatric sample are summarized in Table RVEF is shown in Fig. es by single beat) for both PAH  patients and PAB . LV apical rotation, basal rotation, and torsion are shown in Fig. Mean LV torsion rate and standard deviation for each group are shown in Fig. The intraobserver study results for CMR-FT derived myocardial strain in 8 mice yielded good agreement with analysis performed 2 weeks apart . Similarly, interobserver study results revealed good agreement as well . These results are shown in Additional file PCA was performed on the combined dataset of myocardial strains to further determine if grouping occurred between PAB mice and PAH patients, and between Sham mice and control subjects see Fig. . HyperteGlobal peak radial, circumferential, and longitudinal strains for each cohort are shown in Fig. In this pilot study we characterized and compared key indices of LV and RV mechanics by CMR imaging in pediatric PAH patients and a cohort of PAB mice. We demonstrate that (1) a decrease in LV torsion rate in PAH patients is also observed in RV pressure-overload in mice with a decreased RV contractility in both species; and (2) the response in global strain metrics to RV pressure overload are largely consistent between species. To our knowledge, this is the first characterization and comparison of myocardial mechanics in a pediatric PAH population with a preclinical rodent model of RV pressure overload via tagged-CMR and CMR-FT. These data suggest that PA-banded mice share the ventricular mechanics observed in the pediatric PAH population and that the PAB mouse model, therefore, could be beneficial for future mechanistic studies of inter-ventricular dependency that relate to pediatric PAH.To assess RV function, RVEF and RV systolic pressure were analyzed between groups. RVEF is an important prognostic metric for survival in PAH and is often used as a metric of RV function , 23, whiDamiano et al  along wiMultiple studies show that RV free wall remodeling -commonly seen under pressure overload—can mechanically decrease LV torsion , 43. It es. This could perhaps be attributed to the difference in progression of the disease, in which PAB 7 weeks post-surgery represents an acute and more severe insult compared to the gradual worsening of PAH over time for human subjects. Furthermore, given that we are studying the pediatric population, age could have an impact on LV torsion, which slightly increases until adulthood [Of note, the reported units of LV torsion rate (°/τ) were normalized throughout the systolic phase of the cardiac cycle, rather than in the time domain, in order to compare values of vastly different heart rates between species. Interestingly, as reported by Henson et al., end systolic LV torsion, once normalized to ventricular length, is comparable between healthy humans and mice and is argued to be a potential uniform measurement of normal ventricular ejection . Averagedulthood . Indeed,dulthood  and falldulthood , childredulthood . Thus, wComposite LV and RV strain parameters were comparable between PAB mice and PAH patients, and between Sham and control subjects. This demonstrates that studies interested in bi-ventricular mechanics in PAH can utilize the pre-clinical PAB mouse model as surrogate, despite such extreme differences in size and scale between the species. A recent study performed by Lapinskas et al. has demonstrated the validity and reproducibility of CMR-FT in small animals , and to LV global peak circumferential strain was reduced in both PAH patients and PAB mice compared to the control healthy/Sham groups. The decrease in LV circumferential strain is concomitant with a reduction in LV torsion rate. However, it is unknown whether one metric is secondary to the other. Combined, this data shows there is an overall decrease in LV circumferential motion and twisting capacity in the pressure overloaded RV. Increased pressure and volume within the RV causes a shift in the interventricular septum to flatten and encroach on the LV chamber, resulting in distortion of the shape of the LV and smaller LV volume , 42, thuVarious animal models exist for PAH research. However, there is no model that perfectly recapitulates the critical features of PAH in humans . We chosSome have also argued that increased pressure alone does not fully induce right heart failure in PAH . MonocroOur study has several limitations. First, our chosen rodent model does not identically mimic human PAH as the pulmonary vasculature remains unaltered. However, as stated in the previous section, the PAB mouse is arguably a useful model for study of ventricular mechanics in the setting of acute mechanical insult. Second, we acknowledge that the mean age difference of the pediatric populations for PAH and control subjects could be a cause for concern in which the variation in duration of RV overload could result in a difference in RV remodeling and adaptation between individual subjects. Third, the possibility of higher variance within feature-tracking measurements on mice due to the inherent lower resolution of CMR images should be considered. However, our agreement studies validate our analyses and demonstrate that our experimental data is well outside our confidence intervals of both interobserver and intraobserver variance. Fourth, we did not consider longitudinal analysis or causality, as this was a pilot study in validating tagged-CMR and CMR-FT in our rodent model. Future studies will include CMR at multiple time points from time of surgery to seven weeks post-surgery to fully document the transformation of myocardial mechanics in progression of PAH. Our future research will also explore the causal effect of the LV–RV mechanical relationship and its influence on RV functional decline in development of PAH through alterations of contractile protein expression.Our pilot study demonstrates preliminary evidence that myocardial strain and torsion derived by tagged-CMR and CMR-FT in a rodent model of RV pressure overload may be a suitable model of ventricular mechanics in pediatric PAH. LV torsion rate and myocardial strain are reduced in PA-banded mice and in children with PAH and are associated with reduced RV contractility in both species. This study further highlights the critical role of interventricular mechanical dependency and its association with RV functional decline in PAH.Additional file 1:Figure S1. Intraobserver and Interobserver agreement for CMR-FT myocardial strains. Bland-Altman plots for (a) Intraobserver agreement of LV global peak circumferential strain , and (b) Interobserver agreement of LV global peak circumferential strain .


Left bundle branch pacing (LBBP) is a physiological pacing technique that captures the left bundle branch (LBB) directly, causing the left ventricle (LV) to be excited earlier than the right ventricle (RV), resulting in a “iatrogenic” right bundle branch block (RBBB) pacing pattern. Several studies have recently shown that permanent LBBP can completely or partially narrow the wide QRS duration of the intrinsic RBBB in most patients with bradycardia, although the mechanisms by which this occurs has not been thoroughly investigated. This article presents a review of the LBBP in patients with intrinsic RBBB mentioned in current case reports and clinical studies, discussing the technique, possible mechanisms, future clinical explorations, and the feasibility of eliminating the interventricular dyssynchronization accompanied with LBBP. For decades, right ventricular pacing (RVP) has been the standard treatment for patients with symptomatic bradyarrhythmia caused by sinus node dysfunction or atrioventricular conduction disease. RVP, however, has been established to cause electrical and mechanical dyssynchronization, which increases the risk of cardiac dysfunction, heart failure hospitalization, atrial fibrillation, and a higher mortality rate –3. ThereLeft bundle branch pacing (LBBP) is a novel physiological pacing technique in which a Select Secure lead  delivered through the Select Site preshaped sheath  is deeply rotated via a transventricular septal approach to capture the left bundle branch (LBB), including the trunk and its proximal branches. When compared to HBP, LBBP has been shown to be effective, feasible, and safe for correcting LBB block and maintaining physiological left ventricle (LV) activation, with a greater success rate and more stable lead parameters –16. But The presence of a paced RBBB pattern is a required but insufficient criterion for confirmation of LBB capture with a sensitivity of 100% . When thAlthough the excitation sequence of LBBP in RBBB patients is comparable to that of the original, the morphology of paced RBBB differs dramatically from that of intrinsic RBBB. Gao et al.  comparedThe His-Purkinje system is composed predominantly of longitudinally oriented Purkinje cells, which have a conduction velocity of 2.3 m/s and are specialized for rapid conduction, whereas the ventricular muscle is composed of working myocardial cells with typical intercalated discs and has a conduction velocity is only 0.75 m/s , 29. HisThe LBB is a broad ribbon-like structure that emerges beneath the endocardium of the non-coronary cusp of the aortic valve and divides into a thin left anterior fascicle (LAF) and a broad left posterior fascicle (LPF) , 31, 32.Longitudinal dissociation theory, that is, LBB and RBB were predominantly separated longitudinally inside the HB by collagen sheaths , 34, butSLBBP is characterized by the isoelectric interval between the pacing artifact and the V wave in the intracardiac electrocardiogram, which indicates that only left conduction system is captured, resulting a typical RBBB pattern , 21. In Li et al.  believedThe paced QRS complex with BTP is differs from that with UTP, probably due to anodal capture during bipolar pacing . RV anodShimeno et al.  observedThe location of RBBB is quite crucial. The existence of two types of RBBB has been confirmed: proximal RBBB, in which conduction interruption occurs at the main right branch of HB, and distal RBBB, in which conduction delay occurs at the terminal part of the RBB . AccordiThe precise mechanisms underlying the paced QRS narrowing during LBBP in RBBB patients remain unclear and are likely multifactorial. The possible mechanism is that high output unipolar pacing overcomes the resistivity of fibrous sheaths of longitudinal dissociation and captures RBB by bypassing the blockage through transverse interconnection, or excites a part of the right septal myocardium by anodal capture of bipolar pacing to compensate for RV delay under the prerequisite that pacing lead of LBBP is placed beyond the block site of RBBB.RBBB is the electrocardiographic reflection of RV excitation delay caused by RBB sclerosis, fibrosis, or necrosis, and it is associated with an elevated risk of all-cause mortality in patients with cardiac and pulmonary disease. The intrinsic RBBB may be corrected with traditional RVP by adjusting the atrioventricular interval to achieve optimal fusion with the intact LBB, maintaining the physiological LV excitation while correcting the delayed RV excitation. However, many RBBB patients who require a pacemaker may develop complete AVB that is unable to achieve fusion and necessitates 100% RVP. Furthermore, during exercise, atrioventricular conduction may shorten, reducing optimal fusion to some extent. HBP has been reported as a viable alternative for cardiac resynchronization therapy in RBBB patients with advanced heart failure, reduced LV ejection fraction and wide QRS duration –9. HowevKZ: conceptualization and writing—original draft preparation. YS: writing—original draft preparation. ML, YD, LL, GL, JL, and XW: contribute to our revised draft and provide useful comments. DC and QL: supervision and writing—reviewing and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The Fontan circulation provides definite palliation for children born with a single anatomical or functional ventricle by diverting systemic venous blood directly to the pulmonary arteries, effectively rendering systemic venous return into portal vessels to the lung. Although this restores pulmonary blood flow and avoids the mixture of oxygenated and deoxygenated blood, it also results in elevated systemic venous pressures and low cardiac output. These are the two hallmarks of any Fontan circulation and the cause of Fontan circulatory failure later in life. We highlight the determinants of systemic venous return, its changed relationship with the pulmonary circulation, how it affects preload, and the changed role of the heart . By critically evaluating the components of the Fontan circulation, we hope to give some clues in how to optimize the Fontan circulation and avenues for future research. Francois Fontan and Eugene Baudet's pioneering work on the surgical treatment of patients with tricuspid atresia eventually led to the development of the Fontan operation . The surWhile the Fontan operation became the final palliation for thousands of patients with a single anatomical or functional ventricle worldwide, pediatric and adult congenital cardiologists are increasingly confronted with the limitations posed by the circulation created many years ago –5. ThereThe extent of the definition of “Fontan circulatory failure” recently proposed in ESC Heart Failure also underscores our lack of knowledge with regards to Fontan physiology and likely also translates into a lack of effective treatment options for Fontan circulatory failure . As FontDe Leval's observations paved the way for the modern version of a Fontan circuit: the total cavopulmonary connection . In the From the beginning, it was clear that not all Fontan circulations would be created equal. For example, a patient starting off with slightly higher pulmonary vascular resistance, pulmonary artery hypoplasia, distortion of the pulmonary arteries, AV valve regurgitation, or ventricular dysfunction will likely have worse Fontan physiology after palliation. Maybe more significantly, this also stresses the importance of a carefully and considerate construction of the Fontan circulation and especially its most limiting building block: pulmonary circulation. Allowing sufficient growth of the pulmonary arteries prior to referring for a Glenn may be crucial if one considers the implications of small changes in pulmonary vascular resistance on cardiac output and systemic venous pressure in a Fontan patient as outlined below –10.What is in essence an extra-cardiac operation nevertheless has dramatic consequences for the cardiovascular system. The Fontan circuit consists of the surgical venous connection and the graft, the pulmonary arteries, the pulmonary capillaries, and pulmonary veins and renders the systemic venous return into portal vessels to the lung . Since sIt remains remarkable that venous pressure in the Fontan portal system is sufficient to generate pulmonary blood flow. In ideal circumstances, a mean pulmonary arterial pressure of (at least) 15 mmHg is required to keep the pulmonary vasculature patent  . In a FoSecond, since the superior caval vein (±30% of venous return), inferior caval vein (±45% of venous return), and hepatic veins (±25% of venous return) now function as portal vessels to the lungs, factors determining systemic venous return will determine filling of the systemic ventricle and eventually cardiac output. Macé et al. described that such a circulation results in a downward shift of the venous return curve . As thisThird, there is a shift of the mean circulatory filling pressure, which is usually located at the level of peripheral small veins and venules to the pulmonary vasculature. With the atrial pressure as back pressure, the venous resistance is now similar to pulmonary vascular resistance. This shift illustrates the importance of the pulmonary circulation and how it functions as a dam causing congestion upstream and low flow downstream, the two hallmarks of Fontan physiology . From thExercise capacity is determined by the ability of the cardiorespiratory system to deliver oxygenated blood to the working muscles, thereby providing substrate for energy generation. Normally the main factor determining oxygen delivery is the cardiac output (CO) generated by the hydraulic power of each ventricle . In a noIt is well-known that ventricular and stroke volumes oscillate with respiration. In a normal biventricular physiology this results in peak right and left ventricular volumes (and stroke volume) at peak inspiration and expiration, respectively, a differential effect which is maintained throughout exercise . In a FoThe paragraphs above delineate the importance of systemic venous return for a well-functioning Fontan circulation. They also suggest considering the place of the pulmonary circulation which renders superior and inferior caval vein as well as hepatic veins into portal vessels toward the pulmonary circulation with its advantages (pulmonary blood flow) and disadvantages . In doing so, preload to the ventricle which is usually abundant, becomes limited and systemic venous return through the pulmonary circulation becomes the main determinant in the regulation of pulmonary blood flow and hence exercise capacity.Understanding the importance of the Fontan portal circuit for a well-functioning Fontan circulation may also give us some clues in how to optimize the Fontan circulation.Power loss in the TCPC has been a point of intensive research since pressure gradients across surgical connections, uneven distribution of pulmonary flow to the lungs, and collision of flow is disadvantageous for the Fontan circulation , 30. OffMost cardiac lesions and most cardiac patients are characterized by cardiac dysfunction due to pressure and/or volume overload of the systemic or subpulmonary ventricle. But there is remarkably little evidence evaluating the effect of chronic volume deprivation on the ventricle . The parThe staged Fontan palliation is associated with significant changes in volume load to the ventricle which evolves from being volume overloaded (prior to the Glenn) to preload deprived (after Glenn and Fontan completion) . This anWhen creating a Fontan circulation, the pediatric cardiologist and congenital cardiac surgeon have made tremendous advances, especially when balancing adequate pulmonary artery growth whilst preventing excessive volume load to the ventricle , 8, 10. In Fontan patients the sinus node may be dysfunctional, either congenitally or damaged during multiple surgeries. Although chronotropic limitation has been extensively described in Fontan patients, prior studies have demonstrated that atrial pacing at rest does not augment CO, that at comparable exercise levels Fontan patients already have a faster heart rate, and that pacing beyond maximal heart rates does not improve exercise capacity –56. WherA more aggressive rhythm control management strategy  is warranted in Fontan patients. Not only would they not tolerate faster heart rates , preservThe atrioventricular valve(s) are often structurally abnormal in patients with a Fontan circulation, but functional atrioventricular valve regurgitation due to ventricular and/or annular dilatation, prior volume, and/or pressure overload has been described as well . AtrioveAlthough we as clinicians feel that the interventions and altered Fontan circulatory hemodynamics trump all else, there is convincing evidence of neurohormonal activation in virtually all patients with a Fontan circulation (including asymptomatic patients) . SimilarDeterioration of the Fontan circulation also often coincides with an increased risk for thrombosis and thromboembolic events, which are frequent in Fontan patients, occurring in up to 33% of patients, and are often serious (mode of death in 25% of patients) –67. SeveWith limited patient numbers and insufficient power to perform adequate randomized controlled trials in Fontan patients, it may seem hopeless to even invest in similar research in Fontan patients. However, one could argue that a Fontan patient represents a prime example of a patient in a thrombo-inflammatory state with increased neurohormonal activation destined to develop diastolic dysfunction. A better understanding of the underlying pathomechanisms with identification of therapeutic targets may not only serve the Fontan patient, but the underserved HFpEF patient as well.Further elaboration on the influence of arterio-venous and veno-venous collateral flow, the development of Fontan-associated liver disease, and abnormal lymphatics on Fontan hemodynamics is beyond the scope of this review, but should be considered in any patient with Fontan circulatory failure.The Fontan circulation provides a unique solution for patients with a single functional or anatomical ventricle, expanding life expectancy and quality of life. However, every Fontan circulation carries within itself the seeds of its own decay . IncreasAV: writing manuscript. GC and TS: critical review manuscript. MG: writing and critical review manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.