Avian embryos have been used for centuries to study development due to the ease of access. Because the embryos are sheltered inside the eggshell, a small window in the shell is ideal for visualizing the embryos and performing different interventions. The window can then be covered, and the embryo returned to the incubator for the desired amount of time, and observed during further development. Up to about 4 days of chicken development (out of 21 days of incubation), when the egg is opened the embryo is on top of the yolk, and its heart is on top of its body. This allows easy imaging of heart formation and heart development using non-invasive techniques, including regular optical microscopy. After day 4, the embryo starts sinking into the yolk, but still imaging technologies, such as ultrasound, can tomographically image the embryo and its heart in vivo. Importantly, because like the human heart the avian heart develops into a four-chambered heart with valves, heart malformations and pathologies that human babies suffer can be replicated in avian embryos, allowing a unique developmental window into human congenital heart disease. Here, we review avian heart formation and provide comparisons to the mammalian heart. Birds have been diversifying to inhabit nearly every conceivable habitat on the earth’s surface since the Cretaceous period. With this diversity, birds can flourish in numerous harsh environments, such as flying atop hypoxic Himalayan mountain ranges, swimming deeply in frigid Antarctic waters, and running across hot Mojave Desert sands . To liveMh) scales with respect to body mass (Mh) as Mh = 0.014 Mb0.91 [Mh = 0.0058 Mb0.98 [Mh = 0.025 Mb0.95 [High aerobic activities  in endotherms  require an efficient CVS that is afforded by four-chambered hearts, high systolic pressure and high resting metabolism ,5. Both 8 Mb0.98 ,11. This5 Mb0.95 , possibl2 and acquires O2 via the lung capillaries. The newly oxygenated blood returns to the left atrium through four large pulmonary veins, as in mammals. The oxygenated blood moves to the left ventricle, where it is pressurized for systemic circulation. Both avian and mammalian hearts are surrounded by a thin, fibrous pericardial sac that is filled with serous fluid that lubricates the motions resulting from cardiac contractions and also confines the heart so it does not rattle around the thoracic cavity or overfill with blood.The avian and mammalian heart transports blood to the lungs and body in a similar manner . Birds a2) in their flight muscles than those of species that do not migrate or migrate only short distances (1604 capillaries per mm2) [2 in their flight muscles [As birds increase their activity level with flight, they must also increase oxygen delivery and thus blood supply to tissues involved with flight. The two main flight muscles, the pectoralis and supracoracoideus, originate in the sternum and insert onto the base of the humerus. Blood to the flight muscles and wings is delivered by the subclavian arteries, which branch into the pectoral (flight muscle) and brachial (wing) arteries. Flight demands lead to an increase in the number of capillary beds in the flight muscles, increasing capillary density. The greater the capillary density, the greater the surface area for gas exchange, at the expense of an increased resistance to blood flow. This requires the heart to pump harder to push the blood through all the blood vessels. Birds that migrate long distances have a greater capillary density (1935 capillaries per mmper mm2) . For an  muscles .The ventricles of the bird heart have more muscle mass and less chamber space than those of the human heart. The left ventricle in a bird’s heart is by far the largest heart chamber, powered by a thick cardiac muscle to pressurize the blood for transport throughout the body, and must work especially hard in birds during flapping flight. The right side of the heart only delivers blood to the lungs and the resistance of this circuit is low, thus its smaller size. Externally, the avian ventricles appear trimmer and more pointed than those of the human heart . InternaIn both birds and mammals, up to six aortic arches develop in the embryo, but only three remain in the newborn animal. In birds, the left systemic arch does not develop, and all functions are carried out by the right systemic arch. The blood vessels to the forelimb (subclavian arteries) develop from the anterior arteries supplying the head . In mammals, the left systemic arch develops, and the right does not. The blood vessels to the forelimbs (subclavian arteries) develop from the dorsal aorta and left systemic arch.Studies on avian embryos date back to Aristotle, and even further back, to the Egyptians. Historically, the avian model has played an important role in establishing the foundations in circulation research. Chicken eggs were easy to obtain and could be incubated in ovens  to obserAvian models have unique characteristics that make them invaluable for embryonic developmental studies and, in particular, heart development research. First of all, like mammals, chickens and quails are amniotes, animals whose embryos develop within an amnion and chorion, and developmental processes are highly conserved among amniotes . SpecifiLimitations to avian model systems include the difficulties to perform high-throughput chemical mutagenesis screening, and the lack of stem cell technology that allows for efficient generation of genetically modified avian species. Nevertheless, the genomes of chickens and quails have been sequenced at deep coverage levels ,55,56,57The Hamburger and Hamilton (HH) avian staging system, originally published in 1951 and based on the chicken embryo, is the most widely used table of normal bird development . It diviAfter Hamburger and Hamilton  establisDevelopmental biologists have long used the ability to biochemically distinguish between chicken and quail tissues to study developmental questions ,83. QuaiThe heart is the first functional organ in the body. The first manifestation of the heart is a linear tubular structure, termed the heart tube, that soon starts contracting. To form the heart tube, two movements of cells bring CPCs to the ventral midline, where the heart tube is formed. In the first cellular movement, heart mesoderm ingresses through the anterior primitive streak (PS) during gastrulation to form the cardiac crescent in the lateral plate mesoderm ,87,88. TThe proper fusion of the heart primordia fields and later cardiac looping requires CPC-ECM interactions ,97,98. AThe heart tube is composed of an inner endothelial  layer and an outer myocardial layer that is separated by an ECM called cardiac jelly . The myo2 and CO2 at thin capillary beds. The yolk sac blood islands have long been recognized as the first site for blood cell emergence during embryonic development [Gallus gallus) [Coturnix japonica) [A functioning heart propels red blood cells  throughout the lungs and body to pick up and release Oelopment ,119,120.elopment ,123,124.elopment . Avian belopment . Avian eelopment ,128,129.elopment . The fulelopment . The mea gallus) ,132 and aponica) ). In conaponica)  (~120 daaponica) .The heart begins to function while it is forming (around HH10) and pumps blood throughout the body as it continues to morph into its adult shape. The heart intrinsically generates and transmits the electrical impulse that is required to initiate synchronized cardiomyocyte contractions that propel blood throughout the body. In chick embryos, sinoatrial node cells originate in a small population of progenitor cells within the right lateral plate mesoderm posterior to the Nkx2-5+ (primary) heart field in HH5 embryos . PacemakThe primitive heart tube gives rise to the definitive left ventricle and atrioventricular canal (AVC) ,94. The The fast conduction system of the ventricles is the final part of the pacemaking and conduction system to differentiate. In chickens, this maturation step is evidenced by the reversal in the sequence of ventricular activation . The iniRightward heart looping is the first obvious sign of left–right asymmetry in avian species and mammals within the developing embryo  see Fig. In day Endocardial cushions, which are local thickenings of the cardiac wall, form in the atrio-ventricular canal (AVC) and outflow tract of the tubular heart. Upon myocardial contraction, the cushions come into contact with each other, completely closing the lumen and limiting reverse flow ,168,169.Cardiac cushions in the heart tube give rise to valves and septa. They are initially composed mainly of ECM, also referred to as cardiac jelly, sandwiched between the endocardium and myocardium layers. During the tubular stages of heart development, prior to valve formation and septation, cardiac cushions undergo an endocardial-mesenchymal transition (EndoMT). During EndoMT, endocardial cells delaminate from the endocardium and migrate into the cushion tissue where they proliferate and secrete ECM proteins, populating and expanding the cushions. EndoMT starts in the AVC cushions, which later give rise to the atrio-ventricular valves and septum; and later occurs in the outflow tract cushions, which gives rise to semilunar valves and a portion of the interventricular septum. The avian model has played a fundamental role in deciphering EndoMT and cardiac valve formation ,175. PioConcommitant with the development of cushion, the heart becomes more efficient at pumping blood. From HH13 to HH18 (approximately 2 to 3 days of incubation), maximum centerline velocity in the heart outflow tract portion increased initially and then reached a plateau A. NevertUsing avian embryos, and due to their ease of access for imaging, studies have quantified early embryonic heart form and function under diverse conditions. For example, some studies quantified the changes in blood flow dynamics that occur due to early exposure to ethanol , trichloStarting at HH25, the tubular heart enters the septation phase. During septation, the initially tubular heart will transform into a four-chamber heart with valves . In the Once fully formed, the avian heart resembles the human heart, with four chambers and valves. However, the inner walls of the atria and ventricles are smoother in birds than in humans, and the avian valves are simpler than their human counterparts. The atrioventricular (AV) valves in a bird heart are different to the AV valves in humans . The rigOne of the great advantages of using avian embryos is that early interventions can be easily followed longitudinally, and heart formation assessed. These early interventions can be, for example, transient increases or decreases in diverse bioagents, achieved by injecting or dropping compounds into the embryos, e.g., ,189,192.Avian and mammalian hearts have a coronary vessel system that supplies the heart tissues with oxygenated blood. The coronary system consists of arteries and veins. The arterial coronary system originates from the ascending aorta , and then the venous coronary system returns blood to the right atrium (just inferior to the opening of the vena cava). In both avians and mammals, the coronary system runs through the surface of the heart, in the epicardium, but branches into the myocardium forming capillary networks, so that each myocardial cell is in close contact with the capillary bed . The patA fundamental difference between avian hearts and mammalian hearts is their proliferative ability after birth or hatching. In mammals, cardiomyocytes (the heart muscle cells) lose their ability to proliferate shortly after birth. During fetal stages, cardiomyocytes are mononucleated and proliferate, leading to heart growth by hyperplasia. But around the time of birth and shortly after birth, cardiomyocytes become binucleated and lose their ability to proliferate. Thereafter growth of the heart is through an increase in cardiomyocyte volume, or hypertrophy . The carDuring fetal stages, when the lungs are not functional, blood is shunted from the right (pulmonary) circulation to the left (systemic) circulation. In mammals this is accomplished by the ductus arteriosus, which connects the pulmonary arteries to the aorta. In avians, in contrast, there are instead two ductus arteriosi, the left ductus arteriosus and the right ductus arteriosus . Both ciA summary of similarities and differences between avian and mammalian hearts, as presented in this review, follows .Imaging has played a fundamental role in studies of avian  heart development. Time-lapse imaging has been repeatedly used  to understand heart tube formation. However, time-lapse imaging is particularly challenging in the developing and functioning heart (after HH10). Tissue growth and movements relatively slowly alter heart morphology compared to the rapid shape changes induced by the heartbeat. This is compounded by limitations in imaging systems, which are generally not fast enough to capture images of the 3D heart beating motion, also known as 4D images (3D images over time). One way to address this difficulty is to slow or stop the beating heart through cooling  or pharmGiven the ease of access of avian embryos in ovo or ex ovo, diverse imaging modalities are employed for longitudinal studies. In avian embryos, cardiac looping can be longitudinally imaged with optical microscopy, laser microscopy , and OCT  can be employed. The resolution of research echocardiography systems, about 30 μm, is enough for imaging the embryonic heart at HH24 and beyond. It is worth mentioning that it is also possible to use echocardiography to image the hearts of mammal models, including mice, in utero, at the latest stages of development, when the embryos are big enough for echocardiography to resolve the heart structure. Ultrasound imaging allows us to visualize and measure the heart dynamics in long and short axes, enabling quantifications of stroke volume, area shortening fraction, as well as wall contraction velocities. Doppler ultrasound can be employed to quantify blood flow velocities over the cardiac cycle and compute volume flow rate, as well as determine rates of strain in cardiac walls.To more precisely determine heart morphology, the heart can be excised and stained for histology or microCT imaging. Histological images of thin slices (spanning the whole heart) can then be reconstructed to generate the 3D morphology of the heart. Because histological sections show different aspects of tissue composition, they can be used to determine distributions of ECM components, or cell (including cell distributions and orientations within the heart). Using microCT, a 3D detailed morphological image of the heart is generated automatically, and there is no need for reconstruction. Three-dimensional microCT and histological images reveal morphological heart malformations. For example, in vivo ultrasound imaging followed by microCT imaging see  can be uAvian embryos have been a favorite animal model for centuries, due to the simplicity by which embryos can be accessed, manipulated, and longitudinally studied inside the egg. New imaging technologies have brought new insights into the development of the embryo and its heart, allowing researchers to carefully trace the fate of progenitor cells, and the consequences of missing progenitor populations. Moreover, cell trajectories can be followed in vivo, to observe how the heart and other organs are formed and how progenitor cells continue to contribute to organ formation. In the heart, cardiac function can be monitored and evaluated over developmental stages, allowing researchers to carefully map the morphological development of the heart and the changes in blood flow conditions that accompany cardiac growth and morphological heart changes. New technologies, such as CRISPR-Cas9, and TALEN-mediated gene inactivation, are further allowing researchers to genetically modify the avian embryos and test the effect of gene disruptions, which for a long time could only be done in mice and zebrafish embryos through gene knockout or knockin lines. Transgenic quail fluorescent lines allow careful in vivo monitoring of cell fate, especially over the early developmental stages, but also the visualization of heart cell populations at later stages, including using light sheet microscopy at mature stages of heart development to determine distribution of specific cells or ECM components. While avians are not mammals, and their metabolism is higher than human metabolism, much can still be learnt from studying avian development that is very applicable to human developmental health. Basic research into how the heart develops and functions in birds provides critical insight into how the human CVS can adapt to extreme conditions be altering heart form and function. While perhaps less favored nowadays due to advances in mice genetic manipulations, avian embryos should not be left out from research endeavors. Developmental processes are highly conserved among amniotes, and avian embryos offer an uncomplicated window into human development and pregnancy inside their shelter in the egg.


Autoimmune rheumatic diseases are systemic diseases frequently affecting the heart and vessels. The main cardiovascular complications are pericarditis, myocarditis, valvular disease, obstructive coronary artery disease and coronary microcirculatory dysfunction, cardiac failure and pulmonary hypertension. Echocardiography, including transthoracic two and three-dimensional echocardiography, Doppler imaging, myocardial deformation and transesophageal echo, is an established and widely available imaging technique for the identification of cardiovascular manifestations that are crucial for prognosis in rheumatic diseases. Echocardiography is also important for monitoring the impact of drug treatment on cardiac function, coronary microcirculatory function, valvular function and pulmonary artery pressures. In this article we summarize established and evolving knowledge on the role of echocardiography for diagnosis and prognosis of cardiovascular abnormalities in rheumatic diseases. Autoimmune rheumatic diseases (ARD) are immune-mediated diseases targeting the connective tissues. Cardiovascular complications are frequent and almost all cardiac structures may be affected. The main cardiovascular manifestations in ARD are (a) pericardial, myocardial and vascular inflammation, (b) coronary artery disease (CAD) and dysfunction of the coronary microcirculation, (c) structural and functional abnormalities of the heart valves and (d) elevated pulmonary artery pressures ,2.Anti-inflammatory treatment reduces inflammation and disease-associated morbidity and mortality. However, the incidence of cardiovascular (CV) events is higher in ARD patients in comparison with the general population resulting in worse prognosis ; thus, tEchocardiography is an established and widely available imaging technique for the detection of cardiovascular involvement and for monitoring the effects of treatment on cardiac and vascular structure and function in ARD patients. In this article, we aim to review the role of echocardiography for diagnosis and prognosis in ARD associated with increased incidence of cardiovascular complications and higher cardiovascular risk  includinCardiovascular complications are common including (a) pericardial involvement (in 30–50% of RA patients) , (b) myoSystemic Lupus Erythematosus is mostly complicated by (a) valvular heart disease in 13–100%) [3–100% 1, (b) perIn Systemic Sclerosis (SSc) the main cardiovascular complications are (a) pulmonary artery hypertension (PAH) ,20 and (Psoriasis and psoriatic arthritis are characterized by (a) accelerated atherosclerosis and increased CV risk because of linked causative pathways with CAD including inflammation and oxidative stress  (in psorThe main cardiovascular manifestations in AS include (a) aortitis with aortic and mitral valve involvement ,27 and  and Doppler imaging ,29. Swin2 and tricuspid regurgitation maximum velocity >2.8 m/s are findings consistent with elevated filling pressures [As some studies have indicated that the systolic function of the LV may be moderately reduced in RA patients suggesting progression to heart failure , assessmressures . Myocardressures ,34.Although extensively validated and used in daily practice, left ventricular ejection fraction (LVEF) is not the ideal marker for the evaluation of myocardial function because a reduction in LVEF is indicative of a relatively advanced myocardial dysfunction. Speckle tracking deformation analysis is considered a more sensitive technique for the identification of subclinical alterations in myocardial contractility, providing a more comprehensive study of myocardial function .It has been demonstrated that subclinical myocardial dysfunction may be present in very early RA patients without CV risk factors. Impaired values of global longitudinal and circumferential strain were observed in RA patients with preserved ejection fraction and high disease activity compared with healthy controls ,37.Inflammatory cytokines including tumor necrosis-α (TNFα), interleukin-1 (IL-1) and interleukin-6 (IL-6) have a pivotal role in RA and may induce myocardial and vascular dysfunction and promote LV remodeling and fibrosis ,39,40.Speckle tracking deformation analysis can be applied in ARD patients with unexplained dyspnea and a preserved ejection fraction. Impaired global longitudinal strain (GLS) values in combination with echocardiography findings of elevated filling pressures in the absence of valvular disease or pulmonary abnormalities are consistent with heart failure with preserved ejection fraction ,35. SpecTreatment with an interleukin-1 (IL-1) inhibitor (anakinra) resulted in improved LV global longitudinal strain .LV twisting-untwisting in RA patients, in parallel with a reduction in oxidative stress markers and interleukin-6, particularly in patients with coexisting CAD ,41,42,43The impairment of circumferential systolic and diastolic strain has been associated with disease activity and the degree of inflammation and diffuse fibrosis as expressed by expansion of extracellular volume by cardiac magnetic resonance (CMR) T1 mapping ,46.Finally, LV hypertrophy is associated with an increased prevalence of cardiovascular events in the general population and in RA patients. TNFα seems to be a significant determinant of LV remodeling . It has Patients with SLE myocarditis may have global or segmental wall motion abnormalities by 2D echo and low systolic Tissue Doppler imaging velocities of the mitral annulus ,49. ImpaTransthoracic 2D echo is a valuable tool for the assessment of heart function in SSc, whereas 3D echo may offer additional information on ventricular volumes and EF especially in case of PAH affecting the right ventricle (RV). Structural and functional abnormalities of the LV and RV have been reported in up to 23% and 21% of SSc patients, respectively . Primaryp > 0.01)) and circumferential strain values ). In patients with SSc, impaired GLS and circumferential strain values each correlated with worse functional capacity and rhythm disturbances [Patients with SSc and preserved EF as compared with controls had impaired GLS  .Impaired myocardial strain correlated with disease activity and the amount of focal and diffuse myocardial fibrosis by CMR T1 mapping  and has It has been demonstrated that GLS is impaired in a similar degree in psoriasis and CAD patients compared with normal controls (−16.5% in psoriasis vs. −16.2% in CAD vs. −21.9% in controls). This is consistent with the presence of subclinical myocardial dysfunction in psoriasis due to a similarly elevated inflammatory and oxidative stress burden as indicated by elevated IL-6 and malondialdehyde values . TreatmeTwo and three dimensional transesophageal echocardiography is an accurate technique for the diagnosis and assessment of the severity of valvular heart disease ,7,63. RhValvular heart disease may be identified in 30–50% with transthoracic and 60–70% with transesophageal echocardiography in SLE patients . ValvulaLibman–Sacks vegetations are detected in 10% by transthoracic and 30–40% by transesophageal echocardiography in SLE patients. Libman–Sacks vegetations are typically located on the tips of the left heart valves as inflammatory formations of >2 mm in diameter, or thrombotic or firm masses that may resolve or relapse . Thus, pAortitis is a frequent and serious complication of AS, occurring late in the course of the disease. The inflammatory process begins from the aortic root wall and may expand to the aortic cusps causing thickening and fibrosis . Mitral RA is characterized by a higher incidence of CAD and cardiovascular events compared with the general population due to systemic inflammation and the high prevalence of traditional CV risk factors ,68. PatiThe detection of carotid atherosclerosis has been shown to reclassify patients with RA into a higher risk group . In ARD Coronary flow reserve can be calculated non-invasively by Doppler echocardiography of the left anterior descending artery as the ratio of peak diastolic velocity after adenosine infusion to peak diastolic velocity at rest . CoronarDecreasing CFR values correlated with elevated values of symmetric dimethylarginine, a marker of endothelial dysfunction that acts as an endogenous inhibitor of nitric oxide synthase . Treatment with an interleukin-1 (IL-1) inhibitor (anakinra) resulted in improved CFR in RA patients, particularly when CAD coexisted, indicating a beneficial effect of the anti-inflammatory treatment on coronary microcirculatory function in RA ,41,42,43The calculation of CV risk based on the traditional risk scores is inaccurate in SLE . SystemiCoronary flow reserve was similarly impaired in psoriasis and CAD patients after adjustment for atherosclerotic risk factors in parallel with elevated markers of inflammation and oxidative stress . MoreoveSeveral studies have indicated an increased CV risk and accelerated atherosclerosis in AS ,87. A meInflammatory cytokines, oxidative stress, traditional CV risk factors and the toxic effects of non-steroid inflammatory drugs have been considered to cause aggravation of the atherosclerotic process in AS ,90,91. ETransthoracic echocardiography is a first line modality for PAH screening and for the detection of RV dysfunction because RV remodeling has a major role in the prognosis of PAH patients . ContinuMoreover, poor contractile reserve and impaired GLS during exercise stress echo in SSc patients has been associated with reduced functional capacity and higher values of pulmonary artery systolic pressures .Due to the complex triangular-crescent shape of the RV, a structural and functional assessment of the RV by 2D echo is based on geometrical assumptions . 3D echoPatients with ARD can have excess CV risk and increased incidence of CV complications. Echocardiography is the first line imaging technique for the detection of cardiovascular involvement and for monitoring the effects of treatment in ARD. Additionally, 3D echo may have an added value in volumetric evaluation especially of the right ventricle, whereas speckle tracking may accurately identify subclinical cardiac dysfunction. It remains to be elucidated in future studies whether the improvement of echo markers of myocardial deformation and microcirculatory function by reduction of the inflammatory burden will reduce adverse cardiac events and improve the prognosis of ARD patients.


Background and objectives: Plasma arginine vasopressin (P-AVP) is regulated by the non-osmotic pathway in patients with heart failure (HF) and reduced ejection fraction. However, the regulation of P-AVP in patients with severe aortic stenosis (AS) remains unknown. Materials and Methods: Consecutive patients with severe AS who received trans-catheter aortic valve implantation (TAVI) between Apr 2016 and Apr 2019 were enrolled in this prospective study. Clinical data including P-AVP were obtained just before TAVI, and the correlation between P-AVP and other variables was investigated. Results: In total, 159 patients with severe AS  were enrolled. P-AVP was 1.45 ± 1.13 ng/mL and cardiac index was relatively preserved (2.76 ± 0.54 L/min/m2). There was no significant correlation between cardiac index and P-AVP (p > 0.05), whereas plasma osmolality had a moderate positive correlation with P-AVP , predominantly due to blood urea nitrogen . Patients with diuretics had significantly higher P-AVP than those without diuretics . Two-year survivals free from HF readmission were statistically comparable irrespective of the level of pre-procedural P-AVP (p = 0.44). Conclusion: In patients with severe high-gradient AS who received TAVI, the P-AVP level was dominantly regulated by plasma osmolality instead of arterial underfilling. The clinical implication of elevated P-AVP in the TAVI candidates is the next concern. Arginine vasopressin (AVP) is a central hormone to maintain homeostasis, regulating water and osmolality balance . AVP is One of the major receptors that AVP binds to is V2, which is located on the collecting duct in the kidney. When AVP stimulates the V2 receptor, free water is reabsorbed via aquaporin-2, followed by concentrated urine and diluted plasma .In a healthy population, AVP secretion is relatively suppressed and is triggered by increased plasma osmolality (osmotic pathway) . On the Given the recent introduction of less invasive trans-catheter aortic valve implantation (TAVI) with non-inferior outcomes with the surgery , the phyIn this study, we investigated the association of AVP with other clinical parameters to clarify the regulation of AVP in patients with severe AS, as well as the impact of pre-procedural plasma AVP (P-AVP) level on post-TAVI outcomes. 2, were prospectively enrolled [Consecutive patients who underwent TAVI between Apr 2016 and Apr 2019 for their symptomatic severe AS, defined as aortic valve area <1.0 cmenrolled . Candidaenrolled ,13. PatiAll procedures were performed with a balloon-expandable valve  or self-expandable valve  via trans-femoral approach or alternative approach under general or local anesthesia. Following the procedure, all patients received guideline-directed medical therapy. Informed consent was obtained beforehand, and this study was approved by the local institutional review board on Aug 13, 2018 (IRB 30-416). General hemodynamic data were obtained by right heart catheterization within one month before the procedure. Standard echocardiographic data were also obtained within one month before the procedure. The aortic valve area was calculated by a continuity equation . Within Following TAVI, the heart failure readmission that required IV diuretics under careful in-hospital observation and all-cause death were counted during the two-year observational period. Within two weeks following TAVI, the above-described clinical data were obtained. p-values < 0.05 were considered statistically significant. Continuous variables were expressed as mean and standard deviation and compared between the groups by unpaired t-test or Mann–Whitney U test considering their distributions. Categorical variables were presented as a number with percentage and were compared by Fisher’s exact test. Correlations of P-AVP with other clinical variables were assessed by Pearson’s correlation coefficient. Clinical variables before and after TAVI were compared by paired t-test or Wilcoxon signed-rank test as appropriate. Impact of baseline P-AVP on two-year freedom from death or heart failure readmissions were compared between the two groups stratified by the median P-AVP levels by the log-rank test.Statistics were performed with JMP pro ver14.2 (SAS Institute Inc). Two-sided 2, mean pressure gradient through aortic valve 50.0 ± 17.2 mmHg, and peal velocity of aortic valve flow 4.51 ± 0.73 m/sec.In total, 155 patients with severe AS who received TAVI were enrolled. Baseline characteristics are summarized in 2. Urine osmolality and aquaporin-2 concentration were also relatively preserved. Left ventricular diastolic diameter was 45.8 ± 6.6 mm and ejection fraction was 62.9% ± 11.7%. Hemodynamics were relatively preserved, with right atrial pressure of 5.4 ± 2.7 mmHg, pulmonary artery wedge pressure of 12.3 ± 5.0 mmHg, and cardiac index of 2.76 ± 0.54 L/min/mSociety of Thoracic Surgeons score was 6.7% ± 3.4%, and most of the patients (96%) had heart failure symptoms with New York Heart Association functional class II or III, and plasma B-type natriuretic peptide level was 377.6 ± 370.0 pg/mL.P-AVP averaged 1.45 ± 1.13 pg/mL. The distribution of P-AVP is shown in p > 0.05 for all; p > 0.05 for all). In a sub-analysis of the patients with cardiac index below 2.2 L/min/m2 (N = 19), there was again no significant association between P-AVP level and cardiac index (p = 0.74). P-AVP had no statistically significant correlations with hemodynamic parameters, including right atrial pressure and cardiac index (p < 0.01), dominantly due to blood urea nitrogen , instead of sodium and glucose (p > 0.05 for both) (p < 0.01).On the contrary, P-AVP had a statistically significant correlation with plasma osmolality  . Elevatep = 0.02; Eighty-three patients received diuretics, whereas 72 did not. Patients with diuretics had significantly higher P-AVP compared to those without diuretics . P-AVP decreased statistically significantly from 1.45 ± 1.13 to 1.29 ± 0.93 pg/mL (p < 0.01), although the absolute value was clinically trivial. Similarly to the pre-TAVI analyses, post-TAVI P-AVP had a statistically significant correlation with plasma osmolality  but had no significant correlation with cardiac index . Echocardiographic parameters associated with the severity of AS, as well as B-type natriuretic peptide levels, improved significantly following TAVI . Post-TAVI use of diuretics at index discharge (39%) also did not have any prognostic impact (p = 0.43). During the two-year follow-up period following TAVI, 10 patients died  and 9 experienced heart failure readmissions. Patients were stratified into two groups by the median baseline P-AVP of 1.20 pg/mL. Survival free from heart failure readmission was not statistically stratified by the median baseline P-AVP  AVP secretion was relatively suppressed in patients with severe AS; (2) peri-procedural P-AVP had no significant association with severity of heart failure or AS (non-osmotic pathway) but was associated with plasma osmolality dominantly due to blood urea nitrogen (osmotic pathway); (3) peri-procedural P-AVP had no significant impact on post-TAVI outcome. In general, P-AVP is inappropriately elevated in heart failure patients despite low plasma osmolality . P-AVP hIn our cohort, despite relatively worse heart failure symptoms and elevated intra-cardiac load, indicating severe heart failure, P-AVP was relatively lower and “appropriate” for their normal plasma osmolality. Despite the severe heart failure they had as symptoms, P-AVP had no association with hemodynamics (non-osmotic pathway) but instead with plasma osmolality (osmotic pathway). 2). Following TAVI, although statistically significant, the absolute value of changes in P-AVP was trivial. Post-TAVI P-AVP was consistently correlated with plasma osmolality instead of cardiac output. Given that hemodynamics was already well-preserved before TAVI, TAVI might not have any significant impact on P-AVP. The major reason why P-AVP was regulated by the osmotic pathway would come from the relatively preserved cardiac output in our cohort  compared with other studies. The implication of P-AVP among those with more elevated P-AVP, which might be observed in those with low-flow and low-gradient AS, remain a future concern. The changes in P-AVP following TAVI and its clinical implications are also future concerns. The sample size is moderate, but we collected comprehensive clinical data, although further data including frailty would have improved our findings. Our findings should be validated in larger-scale studies. Our study lacked the longitudinal follow-up of P-AVP. We should pay special attention that our findings can be adopted only for those with severe symptomatic aortic valve stenosis, mostly left ventricular hypertrophy, and also mostly preserved ejection fraction. Our findings cannot simply be adopted into those with reduced ejection fraction , mild aortic valve stenosis, and left ventricular hypertrophy due to other etiologies. Furthermore, the association between arginine vasopressin and plasma osmolality following surgical aortic valve replacement remains unknown.P-AVP did not have prognostic implications on post-TAVI mortality and heart failure readmission, but the impact of P-AVP on other clinical outcomes, including exercise capacity, quality of life, and other comorbidities, remains a future concern. In such studies, other clinically significant factors should be adjusted for.In elderly patients with severe AS receiving TAVI, cardiac output was relatively preserved, the P-AVP level was not associated with the severity of AS and post-TAVI clinical outcomes, and P-AVP might not be a good marker for them. The implication of elevated P-AVP and any intervention for the elevated P-AVP in the TAVI candidates are the next concerns.


According to the ROC curve analysis, an LVEF ≥ 58% indicated that the LV could maintain the IFLSAF. We concluded that the loss of IFLSAF, which could reflect even slight impairment in LV contractile performance, was a reliable indicator for new-onset HF in patients with LVEF ≥ 40%. LVEF ≥ 58% could be taken as a surrogate for the IFLSAF maintenance; this threshold could be useful for risk stratification of new-onset HF in patients with preserved LVEF.Heart failure (HF) with mid-range left ventricular ejection fraction (LVEF) (HFmrEF) is considered a new category of HF and LVEF < 50%, which is the upper threshold of LVEF for HFmrEF, is thought to represent a mild decrease in LV contractile performance. We aimed to consider an LVEF threshold value to be taken as a surrogate for impairment of LV contractile performance, resulting in new-onset HF. We enrolled 398 patients with LVEF ≥ 40% that underwent cardiac catheterization. Using the LV pressure recording with a catheter-tipped micromanometer, we calculated the inertia force of late systolic aortic flow (IFLSAF), which was sensitive to the slight impairment in LV contractile performance. We evaluated the utility of the IFLSAF for predicting future cardiovascular death or hospitalization for HF. We performed a receiver operating characteristic (ROC) curve analysis to determine the best LVEF threshold value for distinguishing whether the LV maintained the IFLSAF. A multivariate Cox proportional-hazards model revealed that the loss of IFLSAF was significantly associated with the future adverse events (HR: 7.798, 95%CI 2.174–27.969,  American and European classifications of heart failure (HF) are based on left ventricular (LV) ejection fraction (LVEF) measurements. The criteria for HF with preserved LVEF (HFpEF) are HF symptomology and LVEF ≥ 50%, which indicates LV diastolic dysfunction, despite normal LV systolic functionl , 2. In aLVEF represents global LV function, and it is commonly used to indicate LV contractile performance in clinical practises. However, LVEF values are influenced by several factors extrinsic to the LV, such as the preload, afterload, and heart rate, in addition to the intrinsic contractile factor and LV dilatation , 4. TherWe hypothesized that, among patients with LVEF ≥ 50%, some might have slightly impaired LV contractile performance that could not be detected based on LVEF values. We further hypothesized that these patients might be identified with a sophisticated cardiac function parameter that could detect marginally reduced LV contractile performance. Moreover, we hypothesized that these patients also had a potential risk of future HF development. We previously reported that the inertia force of late systolic aortic flow (IFLSAF) could be calculated from LV pressure recordings with a catheter-tipped micromanometer. We demonstrated that the IFLSAF displayed a masterful ability to detect slight impairment in LV contractile performance, and this could be used as a prognostic marker of poor outcome in patients with LVEF ≥ 50% as well as those with coronary artery disease –11. In tThis study retrospectively recruited 523 consecutive patients that underwent diagnostic cardiac catheterization with a catheter-tipped micromanometer to evaluate coronary artery disease, from April 2001 to December 2010. Of these patients, we enrolled 398 eligible patients that met our inclusion and exclusion criteria. The inclusion criteria included age, 20 years or older; status, no experience of hospitalization due to symptomatic HF; or no change in baseline drug therapy during the 1 month prior to enrolment. The exclusion criteria included LVEF, less than 40%; serum creatinine > 2.5 mg/dL or on haemodialysis; acute coronary syndrome requiring urgent revascularization or severe coronary artery stenosis needing early revascularization within 30 days; pacing controlled by factors other than sinus rhythm, including a pacemaker rhythm; haemodynamically significant aortic or mitral valve disease; hypertrophic cardiomyopathy; acute myocardial infarction within the past 3 months; percutaneous coronary intervention or open-heart surgery within the past 3 months; or any serious non-cardiovascular disease, including malignancy. At the time patients underwent cardiac catheterization for this study, we collected data on demographics, laboratory values, cardiac function parameters, and medications. The study endpoint was a composite of unplanned hospital admission for acute decompensated HF, and cardiovascular death. The indication for hospitalization due to acute decompensated HF was dependent on the discretion of each outpatient doctor. No one of such doctors participated in the analysis of obtained data or writing the current paper. Cardiovascular death was defined as death from congestive HF deterioration, coronary artery disease, cardiac arrest, cardiac arrhythmia, myocardial infarction, stroke, or sudden death.Tp). Then, we derived the IFLSAF from the LV pressure and dP/dt relationship (phase loop plot), based on the assumptions and procedures previously described by Sugawara et al. [Tp was defined as the negative inverse slope of the line with the best linear fit to the LV pressure and dP/dt relationship, in the phase between the peak -dP/dt and the minimum LV pressure from which the first several data points after peak -dP/dt and those before the minimum LV pressure were excluded. In the Sugawara method, the best linear-fit line was determined with the least squares method and expressed as: -kP + C . Thus, the Tp was given by 1/k. Sugawara et al. hypothesized that the Tp might be more independent on the LV contraction phase and it might be more sensitive to the deterioration of LV relaxation than the time constant proposed by Weiss et al. [0, 0) and point X is equal to the amount of pressure decay augmented by the effect of the momentum of blood  diameter was adopted as the parameter representing LA size. LV mass was calculated by the Devereux formula  and normp value < 0.05 was considered statistically significant. We defined the day of the cardiac catheterization study as the time of patient enrolment in the study. The duration of observation in our prognosis study started at the time of enrolment and ended either at the occurrence of a terminal endpoint or at the last censoring, when the remaining patients had survived the follow-up period without any adverse events. Besides, when the study patients had no experience of concomitant HF but needed percutaneous coronary revascularization or surgical coronary artery bypass grafting, these patients were defined as censored cases at the time of coronary revascularization and the duration between the enrollment and the time of coronary interventions was adopted as the observation period for them. Furthermore, to clarify the extent of the predictive power of the IFLSAF for the endpoint, we performed a time-dependent receiver operating characteristic (ROC) curve analysis, as proposed by Heagerty et al. [Tp, and the effective arterial elastance, to clarify the clinical features of the IFLSAF.Continuous data are presented as the mean ± SD, and categorical variables are summarized as the frequency and percentage. We used Cox proportional-hazards models and a stepwise procedure to evaluate the contributions of clinical variables, including cardiac function parameters, to the relative hazard of experiencing the composite endpoint of this study. We adopted two types of models to assess the contribution of IFLSAF: In model 1, all clinical variables were included; in model 2, the pressure parameters and brain natriuretic peptide (BNP) levels were excluded from the variables used in model 1. We used the model 2 to focus on the IFLSAF and other cardiac function parameters. A y et al. , to deteAll statistical analyses were performed with SPSS version 23.0 software . This study was conducted in full accordance with the Declaration of Helsinki, and it received approval from the Institutional Review Boards and Ethics Committees of the Nagoya City University Graduate School of Medical Sciences, Japan.Of the 523 consecutive patients that underwent diagnostic cardiac catheterization, 125 patients were excluded from the present study, for the reasons described in the method. . In model 2, which lacked the BNP level, intracardiac pressure data, and the aortic pressure value, we identified two significant predictors of adverse events; the loss of IFLSAF  and the LVMI .In the current study, 14 cardiovascular deaths and 17 hospitalizations for HF were documented during the follow-up period . We analysed the contribution of each parameter to the end point with two multivariate Cox proportional-hazards models . In contrast, the hemoglobin level, the peak + dP/dt, and the effective arterial elastance showed significant, but relatively poor correlations with the IFLSAF . We found no significant correlation between the IFLSAF and the cardiac index, Tp, or the cardiac pressure parameters.We performed correlation analyses to examine the association between the IFLSAF and age, hemoglobin levels, BNP levels, the effective arterial elastance, the cardiac pressure parameters, as well as other cardiac function parameters shown in Table The present study had four major findings. First, we found that mild decrease in LV contractile performance, which was reflected by a loss of the IFLSAF, was an important predictor of new-onset HF in patients with normal or slightly decreased LVEF (≥ 40%). Second, we found that, among patients with LVEF that ranged from 48 to 67%, a loss of the IFLSAF could strongly predict poor prognosis. Third, we demonstrated that the LVEF cut-off value of 58% could serve as a surrogate for determining whether the LV maintained the IFLSAF in patients with LVEF ≥ 40%. Finally, the IFLSAF was correlated with the LVMI, the LVEF, the peak -dP/dt, and the BNP level.The LVEF has been widely used as a parameter of LV contractile performance for predicting the development of heart failure and cardiovascular death in the general population, in patients with asymptomatic reductions in LVEF, and in patients with symptomatic HF , 17. In HFmrEF was recently recognized as a new general category of HF, different from both HF with reduced LVEF (HFrEF) and HFpEF. However, the pathophysiological mechanisms underlying HFmrEF and the threshold LVEF values for differentiating among the three general categories of HF have not been elucidated. Our main findings suggested that mildly decreased LV contractile performance was associated with HF development in patients with LVEF ≥ 40%. Our findings also suggested that the extent of pathophysiological effects of the decrease in LV contractile performance on HF occurrence could be shown in patients with the LVEF from 48 to 67% who had not experienced hospitalization for HF previously. When patients have mild decrease in LV contractile performance that could lead to HF development, the condition might be classified as HFmrEF. In addition, when the classification of a normal LVEF is defined as no reduction in LV contractile performance, based on the maintenance of IFLSAF, the patients who have LVEF of around 67% or greater are considered with normal contractile performance.Currently, the only promising medical treatments for patients with HF are for patients with decreased LV contractile performance (LVEF < 35 ~ 40%). When we reconsider the HF classification from the viewpoint of responses to medical treatments for HF, the classifications may not be based on the already established LVEF value, but on LV contractile performance, irrespective of whether or not the LVEF is ≥ 40%. A sub-analysis, reported by Solomon et al. in the TOPCAT trial , demonstIn this study, we performed a ROC curve analysis to assess the best threshold LVEF value for determining whether the LV was with the IFLSAF. We demonstrated that LVEF values < 58% could predict a loss of the IFLSAF with high sensitivity (85.4%) in patients with LVEF ≥ 40%. This finding indicated that patients with LVEF < 58% had a potential risk of decrease in LV contractile performance that could lead to the development of HF in the future, despite a LVEF > 40%. Therefore, taking decrease in LV contractile performance as a risk factor for new-onset HF, we propose that the upper LVEF cut-off value between HFmrEF and HFpEF should be around 58%. Several previous reports have supported the notion that the LVEF threshold for defining HFpEF should be raised above the 50% threshold commonly used. Some community-based cohort studies demonstrated that the persons with LVEF 55 to 60% had greater risk for morbidity and mortality compared to those with LVEF 60% –26. In aThis study had several limitations. First, the study design was retrospective, and we analysed data from a single institution. We recruited study patients from those who underwent diagnostic cardiac catheterization for the evaluation of coronary artery disease concomitantly with a sophisticated measurement of LV pressure with a catheter-tipped micromanometer. It may be associated with lower proportion of female in the study patients. Second, all patients had some HFpEF risk factors, such as hypertension and diabetes mellitus, but no history of hospitalization for HF. Because this study focused on the potential risk of the impairment of LV contractile performance in patients with LVEF ≥ 40% for new-onset HF, the patients with a history of hospitalization for HF were excluded. When we discuss a threshold LVEF value for distinguishing between HFpEF and HFmrEF, we should give consideration to the distinction in the mechanism underlaying HF between new-onset and recurrence HF in patients with LVEF ≥ 40%. In addition, all our patients were in sinus rhythm. Thus, a future prospective study is needed to strengthen our conclusions, with a larger study cohort that includes more patients with a history of hospitalization for HF and atrial fibrillation. Third, we focused on the IFLSAF as a marker of LV contractile performance. Although, compared to LVEF, the IFLSAF could detect small reductions in LV contractile performance, the IFLSAF measurement was somewhat complicated and invasive, because it required LV pressure recordings with a catheter-tipped micromanometer. This procedure is not practical for the bed-side management of patients with HF. Consequently, a more practical parameter for representing LV contractile performance, which could be measured by non-invasive approach such as echocardiography or cardiac magnetic resonance imaging, might be necessary. Finally, we did not address changes in LV contractile performance over the course of HF, nor did we investigate the association between changes in LV contractile performance and prognosis.In conclusion, we demonstrated that mild reduction in LV contractile performance, indicated by a loss of the IFLSAF, was one of the prognostic indicators for new-onset HF in patients with LVEF ≥ 40%. We showed that an LVEF ≥ 58% could be taken as a surrogate for the IFLSAF maintenance. Moreover, medical treatments that are efficacious for HFrEF might be applicable for the patients with their LVEF < 58%.


Studies on the management of functional tricuspid regurgitation (TR) during mitral valve operations have drawn inconsistent conclusions. This study was designed to compare the treatment strategy of concomitant tricuspid annuloplasty (TAP) against isolated mitral valve replacement (MVR) in rheumatic mitral valve disease patients, and to assess the effect of concomitant TAP on postoperative right ventricular (RV) remodeling and function.n = 124) and non-TAP group (n = 46). Clinical and echocardiographic data were collected preoperatively and at 1-year follow-up. Three-dimensional echocardiographic indices of RV geometry and function were analyzed.One hundred-seventy patients with rheumatic mitral valve disease receiving MVR were categorized into TAP group (P <  0.001). At 1-year follow-up, TAP group had improved RV geometry and function. While adverse changes were observed in non-TAP group. In analysis of variance, the above indices demonstrated significant interaction with different treatment group . In multivariate regression analysis, independent of age and Maze procedure, concomitant TAP was associated with postoperative RV volume reduction (P <  0.001), improvement of RV ejection fraction (P <  0.001), and relieved postoperative functional TR severity (P = 0.025).At baseline, concomitant TAP group had larger RV end-diastolic volume, more decreased RV ejection fraction and RV longitudinal strain than non-TAP group (all Our results suggest that concomitant TAP could improve RV remodeling and function for rheumatic mitral valve disease patients, while those with mild preoperative functional TR who had isolated MVR might experience RV dilation and deterioration of RV function at follow-up. Concomitant surgery for functional TR could be considered for patients undergoing MVR with rheumatic mitral valve disease.The online version contains supplementary material available at 10.1186/s12947-021-00245-2. Concomitant tricuspid annuloplasty (TAP) at the time of mitral surgery has gained growing acceptance recently. Despite surgical repair for severe tricuspid regurgitation (TR) at the time of left-sided valve surgery is a Class I recommendation under the current guidelines, the optimal management for moderate and mild functional TR depends more on whether the patient had dilated tricuspid annulus and/or right heart failure , 2. BesiAs RV is a crescent-shaped structure located in close proximity to the sternum, two-dimensional (2D) echocardiographic measurements of RV structure and function are often challenging. Especially for post-cardiac surgery patients, 2D-based assessment of longitudinal function may not be reflective of global RV function . Three-dThis research protocol was compliant to the ethical guidelines of the 1975 Declaration of Helsinki, and was approved by the institutional review board of West China hospital. Between March 2016 to June 2017, 211 patients with rheumatic mitral valve disease scheduled for MVR provided their willingness to participate in this study and signed informed consent. The diagnosis of rheumatic heart disease was according to the 2012 World Heart Federation criteria . Patient2), atrial fibrillation, pulmonary hypertension and right heart failure were the main risk factors when considering whether less-than-moderate functional TR patients needed prophylactic TAP. However, some surgeons at our center would take rheumatic heart disease as a risk factor and perform prophylactic TAP for those with rheumatic mitral valve disease and less-than-moderate functional TR, irrespective of tricuspid annular dimension or pulmonary artery systolic pressure.All patients in this study underwent MVR, the use of mechanical mitral valve or bioprosthetic valve was according to patients’ age and anticoagulant plan, and the addition of Maze procedure for patients with atrial fibrillation was according to each patient’s informed preferences and the attending surgeon’s discretion. All patients with moderate and severe TR had concomitant TAP. If TR grade was less than moderate, the implementation of TAP was at the attending surgeon’s discretion. Tricuspid annular dilation  with a 2-MHz to 4-MHz matrix-array transthoracic transducer, which could display both 2D and 3D full-volume images. Four consecutive cardiac cycles were recorded in patients with sinus rhythm and 6 cycles in atrial fibrillation. For patients with sinus rhythm, 3D full volume data set were obtained from 4 to 6 consecutive cardiac cycles during held respiration (frame rate ≥ 18 Hz). In patients with atrial fibrillation, high volume rate quantification mode was applied in the reconstruction of 3D full volume data. All the echocardiographic parameters were measure in 3 successive beats and then averaged.2), mild , moderate (3 mm ≤ vena contracta < 7 mm), and severe (vena contracta ≥7 mm).LV volume and ejection fraction were calculated using Simpson’s biplane method from 2D imaging. Left and right atrial volume were calculated by the disk summation technique from apical 4-chamber view. The tricuspid annulus diameter was measured from RV-modified apical 4-chamber view in end-diastolic and was indexed to body surface area. 2D RV systolic function was assessed by tricuspid annular plane systolic excursion (TAPSE), RV fraction area change and tissue Doppler of the tricuspid annulus. Systolic RV pressure gradient was calculated by the modified Bernoulli equation and then pulmonary artery systolic pressure (PASP) was derived. According to current guidelines , 10, TR The 3D full volume images from RV-modified apical 4-chamber view were analyzed by the software of Tomtec Image Arena 4.0 on off-line Imaging workstation . After manual initialization of the RV endocardium at 8 points on the long axis and short axis views Fig. , a, the At baseline and during 1-year follow-up, symptoms were recorded and functional New York Heart Association (NYHA) class was assessed. Physical examination and electrocardiogram were performed before each echocardiographic assessment. Cardiopulmonary bypass time and other data of surgical procedure were extracted from medical records.2 or Fisher’s exact test for categorical variables as appropriate. Cumulative incidence rates of survival were estimated by the Kaplan–Meier method and compared using the log-rank test. To compare the effect of with and without concomitant TAP on cardiac remodeling between groups across the preoperative and 1-year follow-up periods, 2-factor analysis of variance with repeated measures were conducted. Within groups, changes of each continuous variable at follow-up time were analyzed by Wilcoxon signed rank test, and changes of dichotomous variables were analyzed by McNemar test. A sensitive analysis was performed in patients with less-than-moderate functional TR who received concomitant TAP, we compared their pre- and post-operative data with patient who had less-than-moderate functional TR and isolated MVR.Continuous variables were expressed as median and interquartile range, categorical variables were expressed as numbers and percentages. Comparison between 2 groups were performed by Mann-Whitney U test for continuous variables, and χTo evaluate whether post-operative TR severity, RV remodeling and function were affected by multiple factors , multivariate ordinal logistic regression was used to assess the risk factors for the severity of TR grade at 1-year follow-up, and multivariate linear regression was used to test the association between the abovementioned characteristics and percent change of postoperative RV EDV, RVEF, and RVLS.P value < 0.05 was considered statistically significant.Interobserver and intraobserver agreement for RV EDV, RVEF, RVLS of free wall and septal wall measurement were tested by Bland-Altman analysis (mean difference and standard deviation). Two independent blinded observers performed the offline analysis on 2 different days for 34 randomly selected images. Statistical analyses were conducted using the Statistical Package for Social Sciences release 25.0 . All tests were 2-tailed, a P = 0.57). Finally, 170 patients with complete 1-year postoperative clinical records and echocardiographic data were assessed . One hundred thirty-three patients had mechanical mitral valve and 37 had bioprosthetic valve. Concomitant tricuspid repair by DeVega annuloplasty was performed in 28 patients, and ring annuloplasty in 96 patients . Table P <  0.001). While patients in the isolated MVR group all had less-than-moderate TR. Cardiopulmonary bypass time were longer in TAP group than the non-TAP group, and Maze procedure was more frequently performed in the TAP group.Among the 176 patients enrolled in this study, 6 patients were deceased within 6 months after the surgery, with 5 patients in the TAP group , and 1 patient in the non-TAP group . No significant difference in all-cause mortality between the two groups was found (log-rank P <  0.001). Longitudinal changes of the 3D RV parameters were also demonstrated in Fig. P = 0.01).Changes of clinical and echocardiographic data at 1-year follow-up were summarized in Table n = 32), the other 59% received isolated MVR (n = 46). Additional Table The results of sensitive analysis were presented in Fig. P = 0.025). Predictors of longitudinal changes of RV volume and function by multivariate linear regression were demonstrated in Table 2 = 0.41, Standardized β = − 0.557, P <  0.001). TAP was also the independent predictor for RVEF increment , as well as for improvement of RVLS of the free wall  and septal wall . In general, TAP was closely related to the RV reverse remodeling and functional improvement at 1-year follow-up. Meanwhile, concomitant Maze procedure was the independent predictor of the postoperative RVEF and RV strain improvement, but no significant correlation was found between Maze procedure and change of RV EDV at 1-year follow-up.Table Inter-observer reproducibility by Bland-Altman analysis demonstrated good agreement: mean difference (standard deviation) was − 0.06 (±1.59) for RV end-diastolic volume, − 0.21 (±1.59) for RVEF, 0.35 (±1.34) and 0.16 (±1.94) for RVLS of the free and septal wall. Also good agreement was seen in intra-observer reproducibility: 0.01 (±1.22) for RV end-diastolic volume, 0.18 (±1.05) for RVEF, 0.24 (±0.79) and 0.21 (±0.85) for RVLS of the free and septal wall.The major findings of the present study were the following: (1) Routine TAP at the time of MVR in rheumatic mitral valve patients could relieve residual functional TR, promote RV reverse remodeling and improve RV function in patients with worse baseline characteristics; (2) RV dilation and functional deterioration were observed in patients with isolated MVR at 1-year follow-up. These findings support the approach to perform TAP concomitant with MVR in rheumatic mitral valve disease patients. Prophylactic TAP could prevent RV dilation and functional deterioration postoperatively.Patients with mitral valve disease often have functional TR, concomitant TAP with left heart operation is an effective treatment to reduce TR grade and improve RV function. Since increasing TR severity was reported to be independently associated with worse long-term survival, and functional TR could progress even after left heart valve surgery , 12, to The postoperative deterioration of RV volume and function in patients with isolated MVR is a concern for surgeon to perform prophylactic TAP for less-than-moderate functional TR. Sakata et al. had reported that in patients with moderate and mild TR who had no concomitant TAP, worsening of RV systolic function and dilation of RV diameter were prominent at 6-month to 1-year follow-up, while RV diastolic function was preserved , 19. SimWhether adding TAP to left heart surgery for mild or trace TR could improve postoperative survival remains to be clarified. Kim et al. found that, in rheumatic mitral valve patients, risk of death and congestive heart failure were similar between TAP and non-TAP group for mild-to-moderate TR . In anotThere were several limitations in our study. First, as its observational nature, patients were treated by several surgeons in whom different standards for operation and different surgical technique existed, some patients with less-than-moderate TR in our study had no guideline-recommended indication of concomitant TAP, for whom prophylactic TAP was based on the attending surgeon’s discretion. This selection bias and the potential confounder brought by different surgeons was inevitable. Second, the power of tests could be affected as the sample size was limited. Due to the limited sample size of patients with less-than-moderate TR, propensity score matching could not achieve sufficient pairs of patients from concomitant TAP and non-TAP group, and the comparison was underpowered. The effect of concomitant TAP in rheumatic valvular disease patients with less-than-moderate TR need to be tested by randomized control trial or large observational cohort. Third, there was no analysis of the RV geometry and function immediately postoperative, thus the trends of RV remodeling after the surgery were incomplete. Another limitation was that, due to the short-term follow-up of 1 year, we were not able to detect the long-term clinical outcome of concomitant TAP, or whether postoperative RV reverse remodeling could reduce valve-related adverse cardiac events. Further studies with large sample size and long-term follow-up is required.In this study focused exclusively on rheumatic mitral valve disease patients, we found that concomitant TAP with MVR had positive effect on postoperative RV geometry and function, independent of concomitant Maze procedure. Whereas patients with isolated MVR had RV dilation and deterioration of RV function at 1-year follow-up. Our results support that rheumatic mitral valve patients undergoing MVR could benefit from concomitant surgery for functional TR.Additional file 1: Additional Table 1. Preoperative characteristics of patients with less-than-moderate functional tricuspid regurgitation. Additional Table 2. Follow-up data in patients with less-than-moderate functional tricuspid regurgitation


Univariate analysis showed that low MBF was a significant predictor of events (hazard ratio (HR): 3.4; 95% confidence interval (CI): 1.2 to 12.0; p = 0.02). This relationship maintained significant after adjusted for the presence of ischemia and cardiac risk factors . In conclusion, MBF value ≤1.15 ml/min/g derived from dynamic CTP in remote myocardium is significantly related with poor outcome and this relationship was independent of myocardial ischemia and cardiac risk factors.The objective of this study was to investigate the incremental prognostic value for adverse events of myocardial blood flow (MBF) derived from stress computed tomography perfusion (CTP) at remote myocardium over cardiac risk factors and ischemia. We prospectively analyzed 242 patients who underwent dynamic CTP and CT angiography. Adverse events were defined as a composite of all-cause mortality, non-fatal myocardial infarction, unstable angina, heart failure requiring hospitalization, peripheral artery disease, and stroke. MBF value was calculated in each myocardial segment and ischemia was defined as mild decrease in MBF in two consecutive segments or moderate decrease in a single segment accompanied with a coronary stenosis ≥50%. The mean MBF of the non-ischemic segments was defined as remote MBF. We divided the patients into two groups by median MBF value of 1.15 ml/min/g. During a median follow-up of 18 months, 18 patients had adverse events. Annual event rate showed a significant difference between patients with low (≤1.15 ml/min/g) and high (>1.15 ml/min/g) MBF (6.1% vs 1.8%,  Although the sensitivity to diagnose ischemia-causing stenosis of coronary CT angiography is very high, the low specificity ranging from 60 to 70% is a major shortcoming3. Recent meta-analyses showed that myocardial CTP could improve the specificity to 80% without significantly reducing the sensitivity3.Myocardial computed tomography perfusion (CTP) is an emerging technique to assess ischemia-causing stenosis using CT4. Static CTP evaluates relative ischemia by determining hypoperfusion at first-pass of contrast medium. Dynamic CTP could further evaluate the absolute myocardial blood flow (MBF)6. Quantitative evaluation of myocardial ischemia could be performed using MBF of stenosis-related myocardium. Conversely, microvascular function of the myocardium could be evaluated using MBF of the remote myocardium, which is myocardium without coronary stenosis. Previous studies using positron emission tomography (PET) showed that reduced coronary flow reserve (CFR) was associated with increased risk of cardiovascular events8. Recent studies using CTP showed that ischemia detected by CTP was related to incremental predictive value in assessing future events over clinical risk factors and coronary stenosis10. However, the prognostic value of MBF at the remote myocardium is not fully assessed. Therefore, the purpose of the present study was to investigate the incremental prognostic value for adverse events of MBF at the remote myocardium over cardiac risk factors and ischemia.The evaluation of CTP can be achieved either by static or dynamic acquisitions2) were invited at the outpatient department  entered in a prospective registry under the Protocol Registration System of the University hospital Medical Information Network Clinical Trials Registry (UMIN000024245). The inclusion criteria were history of type 2 diabetes, regardless of symptoms, suspected coronary artery disease due to multiple risk factors, or evaluation of coronary stenosis after percutaneous coronary intervention and/or coronary artery bypass grafting. Patients who met the inclusion criteria without severe renal dysfunction . We trained each patient before the scan to keep the end-inspiratory position at the same position. We used iopamidol 370 mg iodine/ml  when the body weight was <70 kg, otherwise iomeprol 350 mg iodine/ml . We used iomeprol in obese patients because the amount of contrast medium included was 135 ml for iomeprol but was 100 ml for iopamidol. We adjusted the amount of contrast medium by body weight to maintain the signal-to-noise ratio in obese patients.All patients underwent cardiac CT using a single-source CT  with a collimation of 64×0.6 mm and flying-focal spot, resulting in 128 slicesMyocardial CTP started 3 min after administration of adenosine triphosphate  at 140 μg/kg/min. When the heart rate increase was <10 beats/min or blood pressure decrease <10 mmHg, we increased the injection rate of adenosine up to 200 μg/kg/min. The scanning parameters were as follows: tube voltage, 100 kVp; reference mAs, 190 mAs; scan coverage 68.5 mm; acquisition window, 30‒40% of the R-R interval. A total of 38‒60 ml of contrast medium was injected for 12 s, followed by a saline chaser. The scan initiation timing after the contrast medium injection was optimized with the stress heart rate: 6, 8, and 10 s when >90, 65-90, and <65 beats/min, respectively. During the data acquisition of 25 s, 5 sets of 2-slab prospective electrocardiogram-gated axial scans were performed. The time interval between each slab was ≈1 s, and the interval was ≈3 s between each set. Adenosine triphosphate infusion was discontinued after the acquisition was completed. Half-reconstruction images were acquired with a slice thickness of 0.75 mm, and an increment of 0.4 mm using a cardiac kernel (I36f) with sinogram-affirmed iterative reconstruction (SAFIRE) strength 2.11. No side-effects were reported using beta-blockers including vasospasm. All patients received 0.3 mg sublingual nitroglycerin . Half-reconstruction was performed with a slice thickness of 0.75 mm and an increment of 0.4 mm using a cardiac kernel (I36f) with SAFIRE strength 2.Coronary CT angiography was performed by prospective electrocardiogram-gated axial scan. When the tube current-time product of the CTP scan exceeded 150 mAs, the tube potential and the reference mAs was set as 120 kVp and 250 mAs, otherwise these were set as 100 kVp and 350 mAs. The acquisition window initiated at 60‒75% of the R-R interval when the heart rate was below 65 beats/min, otherwise initiated at 30‒75%. A total of 37‒85 ml of contrast medium was injected for 14 s, followed by a saline flush. Bolus tracking method was performed to determine the scan timing. The scan started 6 s after the descending aorta reached 60 Hounsfield units (HU) above the initial value. If the heart rate was over 65 beats/min, a maximum dose of 12.5 mg of landiolol  was given intravenouslyFor processing, images were transferred to a workstation . The effective radiation dose was derived by multiplying the dose-length product with the constant k (k = 0.014).Two experienced cardiovascular interpreters evaluated the presence of significant stenosis (≥50% stenosis) on a per-vessel basis. When the evaluation differed between the two readers, the final stenosis grade was determined by consensus.6. The input function was sampled in the left ventricle at every table position and combined into one arterial input function that had twice the sampling rate of the tissue time-attenuation-curve. Regional MBF was measured using the standard American College of Cardiology/American Heart Association 17-segment model12. The software automatically calculated the MBF of each myocardial segment . To increase the precision of the fit, double sampling of the arterial input function was performed14. Unstable angina was defined as new-onset, worsening, or angina at rest that required hospital admission. We also analyzed all-cause mortality as hard events.Follow-up information was obtained by clinical visits at 3-month intervals up to March 2019. All reported events were checked by hospital records or, if possible, by direct contacts with the primary physician. The primary endpoint was a composite of all-cause mortality, non-fatal myocardial infarction, unstable angina, heart failure requiring hospitalization, peripheral artery disease, and stroke. All revascularization procedures were ischemia driven. We did not determine early revascularization within 3 months after CT as an event and did not exclude these patients for analysis. The diagnosis of non-fatal myocardial infarction was based on the presence of typical chest pain, elevated cardiac enzymes, and typical electrocardiogram changest test was used to compare continuous variables. The chi-square test or Fisher’s exact test was used to compare categorical variables. We divided the patients into two groups according to MBF value: low MBF group as MBF ≤ 1.15 ml/min/g and high MBF group as MBF > 1.15 ml/min/g. We chose this value because 1.15 ml/min/g was the median MBF in this cohort.Continuous variables were shown as means ± SD and categorical variables as number unless otherwise described. Student’s Kaplan-Meier survival analysis was used to assess the distribution of time to events in different groups. Differences in time-to-event curves were compared with the log-rank statistic. The effect of the variables on the primary endpoint was evaluated using the univariate Cox proportional hazards models. Adjusted Cox proportional hazards models were used to evaluate whether the predictive value of MBF was independent of the presence of ischemia and cardiac risk factors: Model 1, MBF ≤ 1.15 and presence of ischemia; Model 2, parameters in model 1 and sex, age >65 y, cardiac risk factors ; Model 3, parameters in model 2 and known cardiovascular disease, performance of early revascularization.15. We assumed that the mean event rate would be around 2%, and the event rate of the high and low MBF group would be 4% and 0.5%, respectively. To indicate a difference between the different MBF groups, the minimum sample size was calculated as 498 patients (249 patients in each group) at 0.80 power. Sample size calculations were based on a type 2 error (α = 0.05). However, patient recruitment became impossible because of the change in the affiliation of the primary investigator in May 2019. We therefore included 286 patients for analysis.Sample size was calculated based on the results of the FACTOR-64 trialp < 0.05 was adopted to indicate statistical significance.Statistical analyses were performed using JMP software . In all analysis, Records of 286 patients in the registry were initially examined Fig. . We exclp = 0.02), otherwise, no statistically significant difference was observed in the remaining patient characteristics between the groups.Male patients accounted for 70% and the mean age was 65.9 ± 11.3 y . Twenty-seven patients (11%) underwent early intervention, which we did not determine as an event. A total of 18 patients had adverse events: cardiac death (n = 1), non-cardiac death (n = 1), non-fatal myocardial infarction (n = 1), unstable angina (n = 6), heart failure (n = 2), peripheral artery disease (n = 3), and stroke (n = 4). One patient with stroke died due to complications from a stroke.p = 0.02). The event rates did not differ between patients with or without ischemia, known cardiovascular disease, and early revascularization  was a significant predictor of adverse events  (hazard ratio (HR): 3.4; 95% confidence interval (CI): 1.2 to 12.0; p = 0.02). Even when adjusted for sex, age, and cardiac risk factors (Model 2), low MBF remained a significant predictor of adverse events . Furthermore, when adjusted for known cardiovascular disease and early revascularization (Model 3), low MBF remained an independent predictor of adverse events , and male was also an independent predictor .Multivariate analyses were performed to evaluate whether MBF was an independent predictor of adverse events Table . When adp = 0.53)  Fig. .Figure 415. The annual event rate was higher in this study than the FACTOR-64 trial, because we included patients with known previous cardiovascular disease. The present study emphasized the importance of evaluating microvascular function and managing microvascular disease might improve the prognosis of patients with diabetes mellitus.The present study showed that decreased MBF of the remote myocardium was a significant predictor of adverse events independent of myocardial ischemia and conventional cardiac risk factors. The annualized event rate for adverse events increased from 1.8% to 6.1% in patients with a MBF value of ≤1.15 ml/min/g than the remaining patients. Most patients in the present study had diabetes mellitus without symptoms and the results of FACTOR-64 trial were against to screen these patients by coronary CT angiography16. This relationship remained significant after adjusting for age, sex, and cardiac risk factors. In the study by Meinel et al.16 more than half of the events were percutaneous coronary intervention (21 out of 40 events), and all coronary revascularizations including early and late procedures were determined as events. Therefore, the results of the CTP exam could have resulted in increased coronary interventions. Another study showed that the presence of abnormal perfusion was related to an increased risk of major adverse cardiovascular events independent of significant coronary stenosis at CT angiography 9. In this study by Nakamura et al.9 early coronary interventions (within 60 days after CT) were not determined as events, but follow-up was censored at the time of intervention. We did not censor patients with early coronary interventions in the analysis and the annual event rate did not differ between patients with or without early coronary interventions. Our result is in line with the ISCEMIA trial17 which showed that cardiovascular risk of an initial invasive strategy as compared with an initial conservative strategy did not differ in patients with intermediate stenosis and proven ischemia.Presence of ischemia by dynamic CTP was not related with increased future events in the present study. This might be in conflict with a previous study which showed that patients with at least one perfusion defect at dynamic CTP were at increased risk of major adverse cardiovascular events 19. Longer diabetes duration is related to MBF reduction at stress20. Furthermore, coronary intervention procedure might decrease the regional MBF21. Several studies showed that glycemic improvement normalizes microvascular function in diabetic patients23. Medications such as statins24 or glucagon-like peptide-1 agonists25 might improve microvascular function. Nicorandil moderately improved exercise-induced myocardial ischemia in microvascular angina patients by dilating both epicardial and resistance vessels and modulating the vasomotor responses of the vessels to sympathetic stimulation26. Currently, a randomized controlled trial is ongoing to investigate the role of phosphodiesterase-5 inhibitor to reduce myocardial ischemia in female microvascular angina patients27. Improvement of microvascular function by these methods might be related to better prognosis but this is only hypothetical and needs further investigation.Microvascular function is affected by various factors. Cardiac risk factors such as hypertension and diabetes mellitus are risk factors for microvascular dysfunction2. Recently, dynamic CTP protocols with lower sampling rate have been introduced29. The mean radiation dose could be reduced to 2 to 3 mSv using these protocols. However, low sampling rate might reduce the MBF value30 and furthermore, MBF values might differ between various calculation methods31. Further study is necessary to normalize the value of MBF derived from dynamic CTP.One major shortcoming of dynamic CTP is the increase in radiation dose than static CTP protocols. A meta-analysis showed that the mean radiation dose ranged from 5.3 to 10.5 mSv per dynamic CTP examThis study had a number of limitations. First, this was a single-center study and we used only one CT scanner for the evaluation of stress MBF. Further multicenter studies using different CT scanners and various MBF calculation methods are required to validate the results of this study. Second, the difference in mortality rate did not reach significance between patients with low and high MBF. Studies with a larger cohort and longer follow-up period might solve this problem. Third, patients who underwent early revascularization were included for analysis in this study. Although no adverse events related to coronary stents were reported during follow-up, the results might change when the follow-up period is longer. Fourth, most patients in this cohort had diabetes mellitus. Validation is necessary to confirm the results of this study in patients without diabetes mellitus. Finally, we chose 1.15 ml/min/g as a cutoff for impaired microvascular function because it was a median value in the present cohort. Further study is necessary to determine the absolute value for impaired microvascular function.In conclusion, an MBF value ≤1.15 ml/min/g derived from dynamic CTP in remote myocardium is significantly related with poor outcome. The relationship was independent of myocardial ischemia and cardiac risk factors. This emphasizes the importance of evaluating the microvascular function in patients especially with diabetes mellitus.


Letrozole can significantly decrease the estrogen level, and has been administrated to prevent the incidence of early ovary hyperstimulation syndrome (OHSS). However, the effect of Letrozole on prevention of OHSS reached to controversial conclusions. The present meta-analysis aim to examine whether Letrozole could reduce the incidence of early OHSS after assisted reproductive technology (ART).An exhaustive electronic literature search was conducted on MEDLINE, Google Scholar, CNKI and WANFANG MED ONLINE, from inception until May 2018. We include clinical trials that examined the effect of Letrozole on the prevention of early OHSS. The main outcome measures were the incidence of total early OHSS, mild early OHSS, moderate early OHSS, and severe early OHSS.Eight studies included in the review. Of these, five publications evaluated the effect of Letrozolel on the prevention of total, mild, moderate, and severe OHSS, respectively. The results indicated that there was a significantly decreased incidence of total OHSS with Letrozole compared with control group, and there were no significantly differences in the incidence of mild, moderate, and severe OHSS between study group with Letrozole and control group. Eight studies reported the incidence of moderate + severe OHSS. We found a significant decrease in incidence of moderate + severe OHSS in high-risk women with Letrozole.Letrozole has no beneficial effect on the prevention of mild, moderate, and severe OHSS, individually; Letrozole should not be considered as the first-line treatment for prevention of OHSS. Further cohort studies are required to explore the effect of Letrozole on the prevention of OHSS.This study aimed to examine whether Letrozole could reduce the incidence of early OHSS after assisted reproductive technology (ART). A meta-analysis including 8 studies was conducted. There were no significantly differences in the incidence of mild, moderate, and severe OHSS between study group with Letrozole and control group. Letrozole has no beneficial effect on the prevention of mild, moderate, and severe OHSS, individually. Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic complication resulted by controlled ovarian stimulation (COS) during assisted reproductive technology (ART). It was reported that 3.1–8.0% of in vitro fertilization (IVF) cycles developed into moderate to severe OHSS, and the incidence rate has reached to 20% in women at high-risk [Vascular endothelial growth factor (VEGF) plays a crucial part in the development of OHSS , 4. BesiAs we all known, elevated serum estrogen concentrations have been correlated with a higher incidence of OHSS . LetrozoIn the present systematic review, we aim to further evaluate whether Letrozole have effect on the prevention of early OHSS during ART in high-risk women and perform a systematic review and meta-analysis of the available literatures.Electronic databases including MEDLINE, Google Scholar, CNKI and WANFANG MED ONLINE, were searched from inception until May 2018. The key words used to search relative studies were as follows: one including terms on Letrozole , one including terms on OHSS , and the last one about reproductive technologies . A subset of citations related to the present question were generated by combining these subsets with “AND”. Two authors independently evaluated the eligibility of the articles, and group discussion was needed when there was a discrepancy.Studies that administered Letrozole to prevent the OHSS in high-risk women undergoing COS were selected. The primary outcome was the incidence of total OHSS, the incidence of mild, moderate and severe OHSS. For studies to be eligible, outcome data were extracted in 2 × 2 tables. We also recorded the study type, treatment of ART, the ovary stimulation protocol, and the inclusion criteria of women. The quality of the included studies was evaluated by two authors with the Newcastle–Ottawa Quality Assessment Scales , a thirdI2 to quantify heterogeneity between studies. A fixed effect model or a random effect model was implied to calculate an overall OR and its 95% CI. Statistical analyses were carried out with RevMan 5.0 (Cochrane Collaboration). The results were considered to be statistically significant when the P value was < 0.05..The comparisons of included studies were analyzed by a standard meta-analytic method, and the combined results were expressed with the odds relatives (ORs) and its 95% confidence interval (CI). Heterogeneity of the studies was evaluated graphically using Forest plot and statistically using the 216 articles were yielded with the above search strategy. Of there, 199 were not relevant after reviewing the titles and abstracts. Of the 17 remaining studies, one were excluded because the incidence of OHSS was not reported; Two studies have no full-text available. Three studies were excluded because all their data were duplications of another three studies that have been included in our review; an additional three articles were excluded because of lack of a 2 × 2 table. , and there was good statistical heterogeneity in the results  . The random effects model was used and the combined OR was 1.21  .The effect Letrozole administration on the prevention of moderate OHSS was also evaluated. Five studies with 770 women were included outcomes. The results indicated that there was no significantly difference in incidence of moderate OHSS between study group with Letrozole administration and control group with no medication or other treatments  Fig. . The stuI2 = 67%, P = 0.02), as the Q statistic P-value was below 0.05. We implied the random effects model and the combined OR was 0.76  . The random effects model combined odds ratio (OR) was 0.47   Fig. .Fig. 6FoThe studies have got good marks with the Newcastle–Ottawa Quality Assessment Scale (not shown). The funnel plots evaluating the effect of Letrozole on the prevention of total OHSS, mild, severe, and moderate + severe OHSS suggest lack of publication bias, thanks to their symmetrical shape . When we classify the OHSS into mild, moderate, and severe OHSS according to the severity, the results indicated that all kinds of OHSS seems cannot be prevented by Letrozole administration, the pooled ORs was 1.21  for mild OHSS, 0.60  for moderate OHSS, 0.76 . The incidence of moderate and severe OHSS showed a decreased tendency, but there were no significantly difference between study group with Letrozole administration and control group with no medication or other treatments.In the clinical practice, there is no clear boundary between the moderate OHSS and the severe OHSS, and the moderate OHSS would develop into severe OHSS in a short time. So we in further evaluate whether Letrozole administration could decrease the incidence of the moderate + severe OHSS. Eight studies with 1551 women were included. The pooled OR was 0.47 with 95% CI 0.30, 0.74, indicating beneficial effect of Letrozole administration on prevention of combined moderate + severe OHSS. The difference between combined and individual analysis may be attribute to the sample size.2 [2 level on the day of HCG injection is an important indicator to predict the occurrence of OHSS [2 is more than 6000 pg/ml, the incidence rate of severe OHSS can up to 38% [2 to safe concentration, and the HCG was administrated to induce oocyte final maturation, leading to decreased incidence of OHSS in the women at a high-risk [2 level is strongly related with the incidence of OHSS.The characteristic of OHSS is multi-follicular development, enlarged ovarian, and high E2 , 42. The of OHSS . When thp to 38% . During igh-risk . This in2 level [2-dependent tumors, such as breast cancer, and was used to induce ovulation [2 level, but it is conflict whether Letrozole can decrease the incidence of OHSS.As a non-steroidal aromatase inhibitor, Letrozole can block the human aromatase, and inhibit androgens from converting to estrogens, thereby decreasing the E2 level . At firsvulation . In receIn 2008, Fatemi reported that E2 level was significantly decreased after 5.0 mg Letrozole administration during luteal phase compared with placebo group . In 20092 and VEGF to some extent in patients at high-risk for OHSS. The incidence of OHSS was slightly decreased with 2.5 mg and 5 mg Letrozole, and was significantly decreased with 7.5 mg Letrozole, indicating that 7.5 mg Letrozole may be useful to limit OHSS [Recently, some studies have tried Letrozole to prevent the occurrence of early OHSS. One study explored the effect of different doses of Letrozole on the incidence of OHSS after oocyte retrieval during IVF in patients with high-risk OHSS, and showed that 2.5 mg, 5.0 mg, and 7.5 mg daily for 5 days can decrease the level of Emit OHSS . In 2017mit OHSS .nd, 5th, and 8th days after oocyte retrieval compared with the control group, but it could not decrease the incidence of severe OHSS [However, Wang described that 5 mg of Letrozole during luteal phase can significantly decrease serum E2 levels on the 2ere OHSS . Two yeaere OHSS .At present, the guideline for “Prevention and Treatment of moderate and severe ovarian hyperstimulation syndrome” has not commended Letrozole to prevent OHSS . So it iThe possible explanations for our results were as follows: Firstly, the sample size was relative small when three kinds of OHSS were evaluated individually. Secondly, Letrozole have no effect on prevention of OHSS. As Wang have state, high E2 level could only predict the occurrence of OHSS, and is not the reason for OHSS, so decreased E2 level during luteal phase could not prevent the incidence of OHSS. Thirdly, exuberant secretion from multiple corpus luteum after superovulation can cause the high E2 levels observed during the luteal phase. From the point of pathogenesis and pathophysiology, aromatase inhibitor administration during the luteal phase cannot completely prevent OHSS.VEGF serum levels are associated with the likelihood of developing OHSS and with clinical feature , 50. AftA strength of systematic reviews is the more precision estimate with pooled ORs than the individual studies. The combined estimate indicated that Letrozole administration could decrease the incidence of total OHSS and moderate + severe OHSS, however have no effect on prevention of mild, moderate, and severe OHSS, individually. In addition, there were also some limitations. A major drawback of the present systematic review was the significant heterogeneity among these included studies’ characteristics: different study type (Prospective / Retrospective), different treatment type (IVF/ICSI/PGD), different dose of Letrozole administration (2.5 mg/5.0 mg/7.5 mg), and different treatments in control group (Aspirin/HES/Ca/Placebo). Besides, small sample size of study and lack of adjustment for meaningful confounders were the limitations of the present review. Although there were many drawbacks, the present systematic review and meta-analysis come into a valuable summary of the results of scientific publication so far.The findings of this systematic review demonstrated that Letrozole administration after oocyte retrieval in high-risk women has no beneficial effect on the prevention of mild, moderate, and severe OHSS, individually; whereas could decrease the total incidence of moderate + severe OHSS. As the number of events in some studies is relatively small and the characteristics of studies are diversity, Letrozole should not be considered as the first-line treatment for prevention of OHSS. Further cohort studies are needed to explore the effect of administration on the prevention of OHSS.Additional file 1: Figure S1. Funnel plot of analysis for the effect of letrozole administration on prevention of total early OHSS, showing the results of Eggers to assess publication bias.Additional file 2: Figure S2. Funnel plot of analysis for the effect of letrozole administration on prevention of mild early OHSS, showing the results of Eggers to assess publication bias.Additional file 3: Figure S3. Funnel plot of analysis for the effect of letrozole administration on prevention of severe early OHSS, showing the results of Eggers to assess publication bias.Additional file 4: Figure S4. Funnel plot of analysis for the effect of letrozole administration on prevention of moderate + severe early OHSS, showing the results of Eggers to assess publication bias.Additional file 5: Figure S5. Funnel plot of analysis for the effect of letrozole administration on prevention of moderate early OHSS, showing the results of Eggers to assess publication bias.