Serious adverse events associated with new vaccines targeting SARS-CoV-2 are of high interest to the public and to public health as a worldwide mass immunization campaign has been initiated to contain the ongoing COVID-19 pandemic. We describe a series of 4 individuals with signs of a myocarditis/pericarditis according to cardiac MRI results in temporal association with currently in the European Union authorized SARS-CoV-2 vaccines. We found mild abnormal MRI results independent of the type of SARS-CoV-2 vaccine. There is a need of continuing monitoring outcomes of myocarditis cases after COVID-19 vaccination as recently published cases suggest an uncomplicated short-term course whereas the long-term implications are not yet known but taking the available evidence into account the benefits of using COVID-19 vaccines still clearly outweigh the risks. Before the COVID-19 pandemic, there have only been a few reports of myocarditis and pericarditis as an adverse event following immunization with the exception of cases following live-attenuated smallpox vaccine .Serious adverse events associated with new vaccines targeting SARS-CoV-2 are of high interest to the public and to public health as a worldwide mass immunization campaign has been initiated to contain the ongoing COVID-19 pandemic.SARS-CoV-2 vaccines currently authorized for use in the European Union by the European Pharmacy Agency include the messenger RNA (mRNA) vaccine Comirnaty (Pfizer-BioNTech), Spikevax (Moderna) and the vector-based vaccines Vaxzevria (AstraZeneca), and Vaccine Janssen (Johnson and Johnson) .We describe a series of 4 individuals with signs of a myocarditis/pericarditis according to cardiac MRI results in temporal association with SARS-CoV-2 vaccination to investigate any differences regarding the phenotype.For this report we retrospectively reviewed cardiac MRI exams performed at our institution between 07/01/2021-09/06/2021 for MRI findings of cardiac inflammation such as myocarditis or pericarditis associated with SARS-CoV-2 Vaccination. We reviewed the medical records regarding the timing of COVID-19 or SARS-CoV-2 vaccination and the vaccine used. All available demographic, clinical or laboratory information were documented .The study complies with the declaration of Helsinki. Approval was obtained from the ethics committee of Charite – Unversitätsmedizin Berlin. All examinations have been clinically indicated.Cardiac MRI was performed at 1.5T/3T  and evaluated using a standardized diagnostic protocol as described previously . The proPatient 1, a healthy 21-year-old male, received his second vaccination dose of Spikevax (Moderna). The following day the patient complained about chest pain and discomfort, shortness of breath, limited physical capacity and malaise. At presentation to the hospital the electrocardiogram showed no pathological findings. The serum levels for C-reactive protein and NT-proBNP were normal. High-sensitive Troponin T was elevated up to 526 ng/l . A coronary angiography was performed with exclusion of a coronary artery disease. CT pulmonary angiography excluded a pulmonary embolism. Transthoracic echocardiography showed normal myocardial function without wall motion abnormalities or relevant valvular heart disease.Cardiac MRI at 3 Tesla showed a normal left and right ventricular size with normal left and right ventricular ejection fraction and normal values for the global longitudinal strain. T2 weighted images indicated a regional edema anterolateral/inferolateral  with corresponding elevated quantitative myocardial T2 mapping parameters up to 70 ms  . CorrespPatient 2, a healthy 42-year-old male, received the second vaccination dose of Comirnaty (Pfizer-BioNTech). Two days later, the patient presented to the emergency room of a referring hospital with chest pain and discomfort, shortness of breath and a decreased physical capacity.The electrocardiogram on admission showed no pathological findings. The serum levels for C-reactive protein  and cardiac necrosis marker were elevated with a highsensitive Troponin-I level of 4,868 pg/ml  and creatinin kinase of 581 U/l . The levels for D-Dimer and BNP were normal. A coronary angiography was performed with exclusion of a coronary artery disease. CT pulmonary angiography excluded a pulmonary embolism. Transthoracic echocardiography showed normal myocardial function without wall motion abnormalities or relevant valvular heart disease.Cardiac MRI at 3 Tesla showed a normal left and right ventricular size with normal left and right ventricular ejection fraction but reduced values for the global longitudinal strain with −17.8% . T2 weighted images indicated a regional edema inferior/inferolateral  with corresponding elevated quantitative myocardial T2 mapping parameters up to 53 ms  and corresponding subepicardial LGE in this region . The gloPatient number 3 was an 18-year-old healthy and athletic young man. The patient reported that shortly after a vaccination with Janssen (Johnson and Johnson), he initially experienced an episode of fever and limb pain. The initial symptoms subsided significantly after 3 days. However, a marked limitation of physical capacity and a feeling of chestpain and discomfort at rest and under physical stress remained. After the complaints persisted even for 2 months after vaccination, an outpatient presentation was made for further diagnostics. The electrocardiogram showed no pathological findings. Transthoracic echocardiography showed normal myocardial function without wall motion abnormalities or relevant valvular heart disease. Cardiac MRI at 1.5 Tesla showed a normal left and right ventricular size with normal left and right ventricular ejection fraction and normal values for global longitudinal strain. The images showed a mild pericardial effusion in the area of the free RV wall and the basal posterior LV wall up to a maximum of 4 mm with evidence of inflammatory changes of the pericardium in the T2 weighted images and the LGE images in the area of the lateral LV wall. The global T2 relaxation time  and T1 relaxation time  were normal. Assuming a discrete pericarditis of the LV-lateral area, a native MRI follow-up after 3 months was recommended.Patient number 4, a healthy 18-year-old male received the first dose of Vaxzevria (AstraZeneca) at the end of June 2021. The patient reported new episodes of chestpain and discomfort and exercise limitation ~10 days after the vaccination. Initially, no medical presentation was made in the expectation that the symptoms would disappear. After a clear increase of the symptoms in the course of time, the patient presented to the emergency department of a referring hospital. The electrocardiogram on admission showed ST segment elevation in the inferior leads . A coronary angiography was performed with exclusion of a coronary artery disease. The serum levels for C-reactive Protein  and highsensitive Troponin-I  were normal. Creatinin kinase was increased with a serum level of 255 U/l . Transthoracic echocardiography showed normal myocardial function without wall motion abnormalities or relevant valvular heart disease.Cardiac MRI at 1.5 Tesla showed a normal left and right ventricular size with normal left and right ventricular ejection fraction and normal values for global longitudinal strain. The examination showed a mild to moderate pericardial effusion up to 11 mm in the mid-posterior wall of the LV. There was no evidence of acute cardiac inflammation in the T2 weighted and LGE images. The global T2 relaxation time  and T1 relaxation time  were normal. In the absence of signs of acute cardiac inflammation in the T2 weighted images and the LGE images, the pericardial effusion was considered as a possible residual of an expired pericarditis/myocarditis.Myocarditis is an inflammation of the heart muscle in the absence of ischemia . If it iFor vaccine associated myocarditis the underlying mechanisms are not fully understood either. Molecular mimicry between the spike protein of SARS-CoV-2 and self-antigens, trigger of preexisting dysregulated immune pathways, immune response to mRNA, and activation of immunologic pathways, and dysregulated cytokine expression have recently been proposed .Vaccine associated myocarditis is still overall rare and more common in males and the young population . The AdvThe reasons for male predominance is unknown, but theories relate to sex hormone differences in immune response and myocarditis and underdiagnosis of cardiac disease in women .Severity and clinical presentation of myocarditis or pericarditis vary among patients. Symptoms might include dyspnea, chest pain or palpitations, although especially in younger children other symptoms might be present . The cliAs also seen in our patients the clinical course of SARS-Cov2 vaccination associated myocarditis is typically mild and self-limited . Most caRegarding the guidelines for a mild and uncomplicated myocarditis/pericarditis a myocardial biopsy or viral serology was not performed in our patients. According to the guidelines the management depends on supportive therapy with targeted cardiac and anti-inflammatory medications and specific interventions if necessary , 11. ExeWe found mild abnormal MRI results independent of the type of SARS-CoV-2 vaccine. We hypothesize, that abnormal findings might be present independent of vaccine and potentially might also be present when patients are flu-vaccinated. Future research work should also focus on this aspect. A more pragmatic approach might be to look first for cardiac abnormalities in cases of cardiac symptoms after vaccination, such as elevated lab values as troponin and NTproBNP or abnormalities at echocardiography as previously described from our group post COVID-19 .In conclusion clinicians should be aware of vaccine-induced myocarditis as a possible adverse event after SARS-CoV-2-vaccination.There is a need of continuing monitoring outcomes of myocarditis cases after COVID-19 vaccination as recently published cases suggest an uncomplicated short-term course whereas the long-term implications are not yet known.Taking into account the available evidence including the risks of myocarditis and pericarditis, it can be determined that the benefits of using COVID-19 vaccines still clearly outweigh the risks. There is a need for a continued educational campaign for the public regarding the risk of COVID-19 and the benefits and risks of a SARS-CoV-2 vaccination.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Charite Unversitätsmedizin Berlin. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.The first draft of the manuscript was written by CJ and all authors commented on previous versions of the manuscript. All authors contributed to the study conception and design, read, and approved the final manuscript.SK received funding from the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research).SK as a researcher is supported by a grant from Philips Healthcare. CS is an employee of Philips Healthcare. The following authors report financial activities outside the submitted work: BP reports having received consultancy and lecture honoraria from Bayer Daiichi Sankyo, MSD, Novartis, Sanofi-Aventis, Stealth Peptides and Vifor Pharma; and editor honoraria from the Journal of the American College of Cardiology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Nasal septum deviation is the leading cause of upper airway obstruction. Chronic upper airway obstruction may cause myocardial injury due to chronic hypoxia. Effects of septoplasty on left venticular diastolic and sistolic functions are not well known. The myocardial performance index is an easy-to-apply and reliable parameter that reflects systolic and diastolic cardiac functions.The present study aimed to investigate the effect of nasal septoplasty on the myocardial performance index in patients with nasal septal deviation.This prospective study consisted of 50 consecutive patients who underwent septoplasty due to symptomatic prominent C- or S-shaped nasal septal deviation. Transthoracic echocardiogarphy was performed in all patients before and 3 months after septoplasty. Calculated myocardial performance indices were compared.p <  0.001), longer isovolumic relaxation time , longer isovolumic contraction time , longer deceleration time , higher ratio of transmitral early to late peak velocities (E/A)  and shorter ejection time  were observed before septoplasty when compared to values obtained 3 months after septoplasty. Left ventricular systolic ejection fraction was similar before and after septoplasty .Significantly higher left ventricular myocardial performance index (0.52 ± 0.06 vs. 0.41 ± 0.04, Septoplasty surgery not only reduces nasal blockage symptoms in nasal septal deviation patients but also may improve left ventricular performance. Thus, treatment of nasal septal deviation without delay is suggested to prevent possible future cardiovascular events. There are various pathologies leading to nasal obstruction such as concha bullosa, inferior nasal concha hypertrophy and nasal polyposis; however, nasal septal deviation (NSD) still remains the main ethiologic cause.Chronic hypoxia and hypercapnia can cause myocardial injury in patients with NSD. Myocardial injury can cause heart failure due to diastolic dysfunction without systolic dysfunction. Heart failure is due not only to left ventricular systolic dysfunction, but also to left ventricular diastolic dysfunction. There are few Doppler echocardiographic variables that combine left ventricular systolic and diastolic measurements. Two-dimensional echocardiography and Doppler echocardiography provide important information about systolic and diastolic functions of the left ventricle. The myocardial performance index (MPI) is easily reproducible and reliable echocardiographic parameter reflecting both diastolic and systolic myocardial functions.This prospective study was conducted in accordance with the Declaration of Helsinki and aproved by the local Ethics Commitee. Patients with symptomatic and definite NSD are included in the study population. Persistent nasal obstruction related to septal deviation despite the optimal medical treatment for at least 4 weeks was determined as the indication for septoplasty. Optimal medical treatment includes topical nasal steroids, topical or oral decongestants, or an oral antihistamine/decongestant combination. Nasal endoscopy, paranasal sinus computed tomography, fiberoptic nasal and nasopharengeal exam were performed to exclude additional nasal abnormalities causing upper airway obstruction. Patients with sinusitis, allergic rhinitis, cocha bullosa and obstructive inferior nasal concha hypertrophy, more than 50% velopharygeal and hypopharyngeal obstruction and Grade 3 − 4 tonsil hypertrophy according to Brodsky scala were excluded. Patients with hypertension, heart failure, coronary artery disease, chronic pulmonary diseases, valvuler heart diseases, cardiac arrhythmias and conduction abnormalities and pacemakers were also excluded.The study included 67 consecutive patients older than 18 years referred to the otolaryngology clinic who underwent septoplasty operation. 17 patients were excluded from the study according to exclusion criteria. Finally, the study consisted of 50 patients. Complete ear, nose and throat examination was performed on all participants. Echocardiography and Nasal Obstruction Septoplasty Effectiveness (NOSE) scale were performed on all patients before and 3 months after the septoplasty.The NOSE scale consists of 5 subsets of a questionnaire: i) nasal congestion, ii) partial or complete nasal obstruction, iii) difficulty in breathing through the nose, iv) trouble sleeping, and v) difficulty getting adequate air through the nose on exertion, which requires a rating from 0 to 4, ranging from no problem to a severe problem that corresponds to minimum value of 0 and maximal value of 20. Acquired scores from the NOSE scale are recommended to be multiplied by 5, because the quality of life scales are usually given between 0 and 100 percent. The Dreher classification was used to evaluate the degree of nasal septal deviation .A hemitransfixion or Killian incision was performed in all patients under general anesthesia. Mucoperichondrial and mucoperiosteal flaps were elevated and reflected, and then the cartilage and bony structures were removed, reshaped, and replaced in proper position on the both sides of the nasal septum. Intranasal septal splints with airway were applied following transseptal suturing. Finally, we removed the splints 1 week after the surgery. Septoplasty operations were done by experienced surgeons.Transthoracic echocardiographic examinations were performed to all patients before and 3 months after the septoplasty using a machine  with a 2.0–3.5 MHz transducer. Doppler and Two-dimensional echocardiography was done in the standard views according to the guidelines of the American Society of Echocardiography.t-test or Mann-Whitney U Test was performed on each group to compare the numerical variables. Distribution of variables are assessed by Kolmogorov-Smirnov test. The categorical variables were compared with Chi-square test; p-value of < 0.05 was considered statistically significant.The SPSS, v. 22.0, statistical progam  was used for the statistical analyses. All values are given as mean ± standard deviation. Independent p < 0.001) Significantly higher left ventricular MPI , longer IVRT , longer IVCT , longer deceleration time , higher E/A ratio  and shorter ET  values were observed before septoplasty compared to the values 3 months after septoplasty. Left ventricular systolic ejection fractions and heart rates were similar before and after septoplasty . There were no significant changes in BMI, diastolic and systolic blood pressure after surgery compared to basal values .Clinical characteristics and echocardiogarphic findings of the patients are presented in This study showed that MPI values decreased significantly 3 months after the septoplasty in patients with NSD. According to our findings left ventricular performance was subclinically impaired in patients with NSD and this impairment may be reversible after ungoing septoplasty. To our knowledge, this is the first study that evaluated MPI, including both systolic contraction and diastolic relaxation periods of the left ventricle, before and after septoplasty surgery. Nasal septal deviation is the most common cause of partial or complete chronic upper airway obstruction.Effective septoplasty surgery provides improvement in scales of health-related quality of life not only because it corrects nasal airflow but also this rearrangement has positive systemic effects, especially on the cardiovascular system. Celiker et al. showed that septoplasty reduces sympathetic tonus which triggers cardiac arrhythmias by assessing heart rate variability in patients with NSD.Echocardiography has been recently used to assess cardiac functions in patients with upper airway obstruction.As a result, septoplasty surgery not only reduce symptoms in NSD patients but also may improve left ventricular performance. Treatment of NSD without delay is suggested to prevent possible future cardiovascular events.The authors declare no conflicts of interest.


Left ventricular mass index (LVMI), global longitudinal strain (GLS), early diastolic strain rate (SRE), and E/SRE were similar. At a median follow-up of 239 days, 3-P MACE  and 4-P MACE  were observed to be higher in the DKD group. Diastolic dysfunction was more common in patients with DKD, compared to those with NDKD, although both groups had similar LVMI and GLS. Those with DKD also had poorer cardiovascular outcomes. This highlights the importance of the assessment of diastolic function in CKD, particularly in those with diabetic CKD.This study aimed to compare the differences in echocardiographic and strain parameters in patients with diabetic kidney disease (DKD) and non-diabetic kidney disease (NDKD) in a cohort with pre-dialysis chronic kidney disease (CKD) and normal ejection fraction (EF). In this single-center prospective study, patients with CKD stages 3–5 and EF > 55% were included. We compared cardiac structure and function using conventional and speckle-tracking strain echocardiography among DKD and NDKD groups. Cardiovascular outcomes were assessed at the end of the study. Of the included 117 patients, 56 (47.9%) had DKD, and 61 (52.1%) had NDKD. Patients with DKD had higher ratios of early mitral inflow velocity and mitral annular early diastolic velocity (E/e’) (11.9 ± 4.4 vs. 9.8 ± 3.5;  Patients with chronic kidney disease (CKD) are at an increased risk of cardiovascular disease (CVD) compared to the general population. CVD is the most common cause of mortality in patients with CKD, accounting for 40–50% of deaths in those with advanced kidney disease , 2. In aEchocardiography is a simple, non-invasive, and affordable means of cardiovascular risk stratification in CKD. Studies have found that echocardiographic findings such as left ventricular hypertrophy (LVH), reduced ejection fraction (EF), and diastolic dysfunction predict future risk of adverse cardiovascular events and all-cause mortality –6. ThereOf those with CKD, patients with diabetic kidney disease (DKD) form a distinct sub-group. These patients account for approximately 40% of the CKD population and are at a higher risk of cardiovascular events, compared to their counterparts with non-diabetic CKD . Little This was a prospective study conducted in the departments of Nephrology and Cardiology during the period March 2019 to Dec 2021 at Kasturba Medical College, Manipal, a tertiary care hospital in South India. The study was approved by the institutional ethics committee and was conducted by the declaration of Helsinki. The study was registered in the Clinical Trials Registry of India (CTRI/2019/03/018119).Patients aged ≥ 40 years with CKD stages 3–5 and normal left ventricular ejection fraction (EF ≥ 55%) in sinus rhythm were included. CKD was diagnosed and staged as per the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines . Those wEligible patients who were willing to participate were enrolled after obtaining written informed consent. A brief clinical history was taken, and baseline data were noted. Physical examination findings and baseline lab parameters were also recorded.Based on the etiology of CKD, patients were grouped as either having DKD or non-diabetic kidney disease (NDKD) as follows:DKD group: CKD patients with diabetes and (a) biopsy evidence of DKD or (b) presence of diabetic retinopathy and no clinical or serological evidence suggesting alternate causes of CKD.NDKD group: (a) CKD patients without diabetes or (b) those with diabetes but biopsy evidence of other causes of CKD .2 in women and 115 g/m2 in men.Detailed echocardiographic evaluation was done using standard views including parasternal long axis and short axis view at three levels of the left ventricle and apical 4-, 3- and 2-chamber views. All echocardiographic studies were performed on the GE VIVID S60 2D echocardiographic system  with 1.3–4.5 MHz 3Sc-RS adult probe. Echocardiographic images were stored for offline analysis. Left ventricular (LV) internal diameter during end diastole (LVEDD), LV internal diameter during end-systole (LVESD), wall thickness of posterior wall of LV (PWT), and interventricular septum (IVST) were recorded. Left ventricle ejection fraction measurements were taken by using M-Mode and Modified Simpson’s method. LV end diastolic volume (LVEDV) and LV end systolic volume (LVESV) were measured by tracing the border between myocardium and LV cavity as recommended in the 2015 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) guidelines . LV massIn the apical four chamber view, doppler echocardiography was used to assess peak early diastolic transmitral velocity (E), peak late diastolic transmitral velocity (A), E/A ratio, and mitral E-wave deceleration time (DT). Tissue doppler velocity analysis was done by placing a 2 mm doppler sample in septal and lateral mitral annulus to measure septal and lateral peak early diastolic velocity (e’). E/e’ was calculated as E divided by the mean of septal e’ and lateral e’ Fig.  12]. Ri. Ri12]. S) and global early diastolic SR (SRE) and late diastolic strain rate (SRA) were calculated from the average of all 18 segments. The E/SRE ratio was calculated as the E velocity (m/s) divided by the global SRE value.Strain and strain rate analysis was done offline using GE EchoPac software v201 . All measurements were performed as recommended by the 2010 EACVI/ASE/Industry Task Force consensus document . Two-dimAt the end of the study, data on patient outcomes such as major adverse cardiovascular events (MACE), all-cause mortality and hospitalization with heart failure, were collected from hospital electronic medical records.3-point MACE (3-P MACE): Composite of cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke.4-point MACE (4-P MACE): Composite of cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke and hospitalization for heart failure. Given the lack of accepted definition for heart failure in CKD population, we defined “hospitalization for heart failure” as symptoms of heart failure along with elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (> 1200 pg/dL) requiring hospitalization and intravenous diuretic therapy and/or ultrafiltration for the purpose of this study [is study .Statistical analysis was performed using SPSS version 22.0. Continuous data were tested for normality using the Kolmogorov–Smirnov test and those normally distributed were presented as mean and standard deviation (SD), while those not following normal distribution were expressed as median and interquartile range (IQR). Categorical data were presented as frequency (n) and percentages (%). Comparison of proportions was performed using the chi-squared test and normally distributed continuous data were compared using the two-sample t-test. Mann–Whitney U test was used to compare non-normal continuous data. All results were considered significant at a p-value of < 0.05.2 .A total of 117 patients with CKD stages 3–5 were enrolled during the study period after obtaining written consent. The mean age of the study population was 57.3 ± 10.5 years, and 96 patients (82.1%) were male. The median serum creatinine was 3.5  mg/dL, with a median eGFR of 17.1 mL/min/1.73mp = 0.017), however there was no difference in the baseline systolic and diastolic blood pressures. Higher number of patients in the DKD group were on statins  and anti-platelet drugs , compared to the NDKD group. There were no other significant differences between the two groups.Fifty-six (47.9%) patients had biopsy-proven or presumed DKD, while 61 (52.1%) had CKD of other etiologies. The baseline characteristics of the study groups are shown in Table p = 0.031) and lateral wall   measured by tissue doppler imaging in the DKD and NDKD groups. The E/e’ ratio was significantly higher in DKD  and so was the mitral E wave deceleration time (in milliseconds) , compared to those with NDKD. Overall, abnormal E/e’ (> 12) was seen in 40 (34.2%) patients. Higher proportion of patients with DKD had abnormal E/e’ compared to those with NDKD .The main findings on traditional echocardiography are shown in Table p = 0.479). E/e’ ratio was higher in patients with low GLS compared to those with normal values .There was no significant difference in the average GLS of both groups Table . Low GLSS), LV early diastolic strain rate (SRE) and LV late diastolic strain rate (SRA) were similar across both groups. There was no statistically significant difference in the E/SRE ratios of both groups, although it was numerically higher in the DKD group .The LV peak systolic strain rate (SRp = 0.047) and 4-P MACE , compared to those with NDKD  days, those with DKD had higher 3-P MACE . E/e’ ratio is an estimate of LV end diastolic pressure and is widely considered to be a non-invasive marker of LV diastolic dysfunction [p = 0.031) and lateral e’  were significantly lower in the DKD group, in addition to higher mitral E wave deceleration times . While the lower septal and lateral e’ values indicate impairment in LV relaxation and early diastolic recoil, longer DT indicates LV stiffness-these are the key underlying mechanisms for diastolic dysfunction [. too found higher E/e’ ratios in patients with DKD compared to those with NDKD [We studied echocardiographic parameters of patients with CKD stages 3–5 and normal ejection fraction and found that the ratio of peak early diastolic transmitral velocity to early diastolic mitral annular velocity (E/e’) was abnormal in nearly a third of patients. Further, E/e’ was higher in patients with DKD, compared to those with NDKD  may be better than E/e’ ratio for detection of LV diastolic dysfunction in certain patient populations [E has also been described to be a superior to E/e’ for prediction of MACE in the hemodialysis population [E of the DKD and NDKD groups, although E/e’ was significantly different. Of note, E/ SRE was numerically higher in the DKD group compared to NDKD  and so the lack of statistical difference could be explained by the relatively small sample size. Moreover, the role of E/SRE in pre-dialysis CKD has not been studied previously and is still uncertain.The role of LV deformation imaging (using speckle tracking echocardiography) for early detection of diastolic dysfunction remains unclear at present. Like e’, SRllenging . It has ulations . E/SRE hpulation , 28. In p = 0.002). Although conventional wisdom is that GLS is a marker of subclinical LV systolic dysfunction, recent studies have suggested that it may provide additional information. A study by DeVore et al., showed that GLS may be a marker of myocardial fibrosis and hence diastolic dysfunction by showing an association between abnormal GLS and higher levels of biomarkers of collagen synthesis and NT-proBNP in blood [A low GLS (> − 16%) suggestive of LV systolic dysfunction was seen in approximately 30% of our study population even though the study included only those with a normal LVEF. This confirms the findings of previous studies that strain imaging-derived GLS precedes changes in EF observed by conventional echocardiography –31. GLS in blood . The finS) between DKD and NDKD. As with diastolic strain rates, the lack of standardization in measurement techniques and cut-offs pose a challenge in the analysis of these newer parameters.There were no differences in peak systolic strain rates (SRp = 0.047) and 4-P MACE  were observed in the DKD group, indicating poorer outcomes even in the short-term. Clearly, these two groups are clinically different in terms of cardiovascular outcomes even in the relatively short follow up period of our study. But the only difference with respect to echocardiography was in diastolic function. Both groups had similar systolic function even when sensitive parameter like GLS was used. Therefore, it is plausible that diastolic dysfunction could be one of the factors associated with future cardiovascular events. However, the number of events in our study is small and it is difficult to draw conclusions on the association of diastolic dysfunction (and other echocardiographic parameters) and clinical outcomes.At the end of a median follow-up of 239 days, higher rates of 3-P MACE  because indices of diastolic function can be affected once left ventricular EF is reduced and may not necessarily indicate diastolic dysfunction per se. Moreover, patients with reduced EF represent those with a more advanced stage of cardiac dysfunction. Here, we attempted to identify early echocardiographic changes prior to the onset of frank LV systolic dysfunction by including only those with normal EF. The limitations of this study are the short duration of follow-up and the small sample size. Approximately one-fourth of patients in the NDKD group had diabetes mellitus. Although none of them had any other diabetes-related target-organ damage such as diabetic retinopathy, neuropathy or atherosclerotic cardiovascular disease at the time of inclusion in the study, the influence of diabetes on the myocardium in this group cannot be ruled out. Those with recent-onset diabetes may not have undergone myocardial remodeling and therefore, the duration of the disease could also have affected the findings. Moreover, a higher proportion of patients in the DKD group had hypertension, compared to the non-DKD group and this may have impacted echocardiographic findings and patient outcomes, even though mean systolic and diastolic blood pressures were similar in both groups at the time of entry into the study. Data on novel echocardiographic parameters such as LA strain (which is increasingly being recognized as a useful tool to assess diastolic dysfunction) and layer-specific strain is also lacking , 36. FinLower e’, longer DT and higher E/e’ was observed in DKD patients compared to those with NDKD suggesting diastolic dysfunction was more common in DKD at a stage when EF was normal. However, LV GLS, which was abnormal in 30% of the overall cohort, was comparable among DKD and NDKD groups. Cardiovascular outcomes were also worse in the DKD group. Further studies are needed to determine if cardiomyopathy in DKD represents a distinct phenotype that carries a prognostic implication different from that of cardiomyopathy in other etiologies of CKD. The impact of these echocardiographic differences on therapeutic approaches also needs to be explored.


Acute kidney injury (AKI) is a significant problem for patients admitted to the intensive care unit (ICU), both due to the high incidence and associated mortality with rates of AKI requiring renal replacement therapy (RRT) of over 5%, and mortality rates with AKI of over 60%  Acute kidney injury is a pervasive issue for patients admitted to the intensive care unit (ICU). Not only is it common, but it is also associated with high mortality rates of up to 60%, so early recognition and optimization of renal resuscitation is paramount Hemodynamic AKI involves hypoperfusion and is attributable to hypovolemia or low oncotic states seen in heart or liver failure. Cardiac ultrasound can be highly beneficial to help further delineate between these potential etiologies. The ejection fraction depends on ventriculo-arterial coupling, thus is determined by both intrinsic cardiac function and the afterload state Renal Resistive IndexThe renal resistive index (RRI) evaluates the resistance to flow and as such can be used to assess macrovascular perfusion to the kidney. The RRI is obtained at the level of the segmental arteries and is calculated as follows RRI = [(peak systolic velocity – end diastolic velocity)/peak systolic velocity] Normal values are roughly 0.6 with levels >0.70 used as a cut-off for an abnormal value in native kidneys and 0.8 in transplanted kidneys . Higher levels portend to worse renal outcomes and are predictive for AKI in general as well as for severity of AKI in various patient populations The RRI may be increased in CKD or AKI when due to obstruction, acute rejection, hepatorenal syndrome, or acute tubular necrosis (ATN) The RRI has several limitations. Firstly, it can be affected by heart rate as tachycardia can falsely elevate the end diastolic pressure and thus falsely decrease the RRI HydronephrosisUltrasound is the main imaging modality to evaluate for hydronephrosis, which causes 1-3% of AKI in the ICU and is seen on ultrasound in up to 95% of patients with obstructionWhile it is important to correct hypovolemia and supplement preload during early management, particularly for distributive and hypovolemic shock, guiding ongoing fluid administration after the initial resuscitation can be nebulous and nuanced. It has been proposed by Malbrain et al. that there are several stages of fluid management, or the 4 D’s. These include drug, dosing, and duration which revolve around the type and amount of fluid resuscitation as well as de-escalation as it relates to fluid removal Static markers such as CVP were used in the past, however, have not been shown to reliably identify patients that benefit from the administration of fluids The inferior vena cava (IVC) should be viewed in long axis from the subcostal position with measurements taken 2 cm distal to the junction with the right atrium, or just distal to the inlet of the hepatic vein. Due to differences in IVC collapsibility by sampling location and displacement associated with respirophasic cycles multiple measurements at different levels should be taken, including the short axis  Measurement of IVC size and its collapsibility can act as a surrogate measure for CVP and RAP where a size >2.1 cm with <50% collapsibility indicates a CVP of 15. Conversely, an IVC <2.1 cm with >50% collapsibility is consistent with a normal RAP of 3 mmHg IVC size and collapsibility in spontaneously breathing patients can be affected by elevated intra-abdominal pressures and heavy spontaneous breathing efforts and it is only loosely related to CVP. Careful consideration should be taken when using ultrasound of the IVC in isolation to determine volume status. Rather, it should be used in conjunction with the overall clinical context and constellation of ultrasound findings.It is critical to avoid volume overload which causes tissue edema and prolonged ventilator weaning, and is an independent predictor of mortality in ICU patients, particularly those with sepsis, ARDS, intra-abdominal hypertension, and acute kidney injury. As such, de-resuscitation is a critical phase of a patient’s ICU management In addition to assessing the left ventricle (LV), right ventricular size and function should be evaluated, particularly with regards to assessing volume status. Enlargement of the right ventricle (RV) can be either a sign of volume or pressure overload. The parasternal short axis view can be utilized to evaluate which of these processes predominates as septal bowing seen in systole corresponds to pressure overload on the RV, suggesting an etiology such as pulmonary embolism, whereas septal bowing in diastole corresponds to volume overload that should prompt diuresis Diastolic function can also be used to assess volume status where e’ maximal velocity reflects the rate of LV relaxation and E/e’ correlates to LV filling pressures. There are studies in the ICU showing an abbreviated assessment can be valuable and diagnostic for increased left ventricular end-diastolic pressure (LVEDP) Using pulse-wave Doppler with the gate just above the mitral valve leaflet tips, obtain a spectral waveform. An E < A wave indicates grade 1 diastolic dysfunction (DD) with normal left atrial pressure and thus normal LVEDP . If E > A, perform an e’ measurement placing TDI over the septal and/or lateral mitral annulus . An E/e’ >15 is consistent with an elevated LVEDP that should prompt diuresis Depending on one’s comfort level with more advanced echocardiography techniques, a lung ultrasound is simple to perform and can also be beneficial in assessing volume status in conjunction with other modalities. The presence of A-lines indicates normal lung aeration with dry interlobular septa and low or normal LAP It is critical to identify the presence of volume overload and venous congestion not only in patients with heart failure or cardiogenic shock, but in all forms of pathology. As volume reaches the upper limits of systemic venous capacitance, venous pressure will rise causing congestive changes that can be visualized on ultrasound of the IVC, portal vein, hepatic veins, and the interlobar renal veins Hepatic VeinGiven the multivariate etiologies for its morphology and respirophasic behavior, other venous waveforms should be assessed in conjunction with the IVC to identify venous hypertension and congestion. The hepatic vein will be thin-walled and branch off of the IVC. It can be evaluated from the right coronal plane in long axis view with the pulsed-wave Doppler gate placed perpendicular to the flow to obtain a waveform. Alternatively, the hepatic vein can be obtained anteriorly with the IVC in short axis. In the absence of pathology, there should be an anterograde S and D wave . There is an initial retrograde a wave generated by increased RAP from atrial contraction at end diastole, which is followed by an anterograde S wave caused by decreasing RAP during early mid-systole. If the tricuspid valve is open, however, retrograde deflection can occur causing reversal of the S wave, as seen with tricuspid regurgitation or significant venous congestion. The final D wave is an anterograde deflection caused by decreasing RAP from rapid early diastolic right ventricular filling. With increasing venous congestion, there is a spectrum of waveform changes that occur. The S wave is typically larger, however, with increased RAP and mild congestion, the D wave becomes deeper than the S wave, and with severe congestion, there will be reversal of flow with a retrograde S wave . In contrast to the hepatic veins, the portal vein and its branches will have thicker, echogenic walls and will have flow directed towards the transducer. The portal vein should be assessed for pulsatility. Normally the portal vein should have only mild respirophasic variation and should be fairly uniform. With increasing congestion and right atrial pressure elevation, however, the cyclical pressure changes in the right atrium from cardiac contractility get transmitted to the portal circulation creating a pulsatile flow pattern. Once severe congestion is present, the flow form may become biphasic with a sinusoidal retrograde and anterograde flow pattern . The pulsatility index can be measured as follows where normal PI is less than 30% and significant venous congestion is present with a PI >50%: PI (%) = 100 x [(maximum velocity – minimum velocity)/maximum velocity]There have been several studies looking at portal vein pulsatility in patients with congestive heart failure and following cardiac surgery. In one study, of the patients who had portal flow pulsatility, over 60% developed an AKI in the week following surgery The interlobar renal veins can also be assessed for the presence of venous congestion. Studies looking at ultrasound findings of venous congestion in patients with congestive heart failure have shown that portal vein pulsatility was also associated with alterations of intrarenal venous flow After obtaining a view of the kidney, color Doppler should be placed over the corticomedullary junction to pick up flow through the interlobar vessels with the pulsed-wave Doppler gate placed at the corticomedullary junction ideally obtaining both arterial and venous waveforms. The resistive index can be calculated from the arterial waveform and the venous waveform morphology can also be assessed. Venous flow should be monophasic and continuous, however, with increasing congestion will become pulsatile throughout the cardiac cycle, and with severe congestion venous flow will only be present in diastole .Bedside ultrasound can be used to help delineate etiologies for acute kidney injury and to assist in management. Furthermore, ultrasound should be used daily in the ICU to help prevent renal injury by optimizing volume management throughout a patient’s admission. Ultrasound should also be used not only in the initial resuscitation, but to guide de-resuscitation as well. More studies are needed regarding the use of bedside ultrasound to better optimize renal perfusion as well as to systematically guide volume removal by continuous renal replacement therapy.The authors have no conflicts of interest to declare.


TM system. Methods: From June 2020 to March 2022, 27 consecutive patients were screened, and 13 underwent transcatheter TriClipTM repair. In-hospital, 30-day and six-month clinical and echocardiographic outcomes were collected. Results: Nine patients had severe, three massive and one baseline torrential TR. Sustained TR reduction of ≥1 grade was achieved in all patients, of which 90% reached a moderate TR or less. On transthoracic echocardiographic examination, there were significant reductions in vena contracta width (p < 0.001), effective regurgitant orifice area (p < 0.001) and regurgitant volume (p < 0.001) between baseline and hospital discharge. We also observed a significant reduction in tricuspid annulus diameter (p < 0.001), right ventricular basal diameter (p = 0.001) and right atrial area (p = 0.026). Conclusion: Treatment with the edge-to-edge TriClip device is safe and effective. The resulting echocardiographic improvements indicate tricuspid valve leaflet approximation does not just significantly reduce the grade of TR but also affects adjacent structures and improves right ventricular afterload adaptation.Background: The natural history of tricuspid valve regurgitation (TR) is characterized by poor prognosis and high in-hospital mortality when treated with isolated surgery. We report the preliminary echocardiographic and procedural results of a prospective cohort of symptomatic patients with high to prohibitive surgical risk and at least severe TR who underwent transcatheter edge-to-edge repair through the TriClip TM system .Moderate or severe tricuspid regurgitation (TR) is a valvular pathology associated with considerable prevalence 0.55%) and increased morbidity and mortality in the general population . The aet5% and inThis prospective, single-arm study, conducted at the University Campus Bio-Medico of Rome, Italy, screened 27 consecutive symptomatic patients referred with the diagnosis of at least severe TR from June 2020 to March 2022. The anatomical feasibility was established according to a detailed transoesophageal echocardiogram (TEE) and a dedicated computerised tomography (CT) for the right cardiac chamber . PatientAll patients underwent pre-procedural planning with transthoracic echocardiogram (TTE) and TEE followed by a dedicated CT scan. The transgastric short-axis view obtained with TEE allowed us to analyse the origin of TR jet and plan an adequate grasping strategy. Additional helpful information was obtained from the 4-chamber, alternative 4-chamber and deep/mid oesophageal right ventricle inflow/outflow views in multiplane collected using Siemens Acuson SC2000 . The grasping strategy was planned on screening images analysed by a committee of echocardiographers and interventional cardiologists by choosing which leaflets to grasp, in which order and at which distance from the commissures. All TTE data were collected using a GE Vivid E95  echocardiography machine. The attending physician manages the volemic status. Standard parameters were recorded according to the American Society for Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI) guidelines ,15. TR aTM device  via right common femoral vein access. Afterwards, a 24 F steerable guiding catheter was placed in the right atrium (RA). Under fluoroscopic and TEE guidance, the TriClip delivery system was introduced in the right atrium and oriented perpendicular to the TV. Subsequently, the clip was opened and advanced in the RV. Once the correct orientation and position were obtained, the clip was pulled back to grasp the target leaflets. Following TEE control, the clip was released. One additional clip was placed in case of insufficient reduction of TR. Venous access was closed using a Perclose ProGlideTM  suture device.Transcatheter edge-to-edge repair was performed with the TriClipThe primary efficacy endpoint was a TR reduction of at least one grade as assessed by transthoracic echocardiography (TTE) at discharge . The primary safety endpoint was a composite of major adverse events (MAE) at one month, including cardiovascular mortality, myocardial infarction, new onset renal failure, stroke, endocarditis and non-elective cardiovascular surgery for TV repair system-related adverse events. Secondary endpoints were: acute implant success  and in-hospital, 30-day and six-month clinical and echocardiographic outcomes. Clinical and functional status was assessed by the New York Heart Association (NYHA) class, and health-related quality of life was assessed with the EuroQol-5-dimension (EQ-5D) questionnaire by assigning a value from 1 to 5 for five domains: mobility, self-care, habitual activities, pain/discomfort and anxiety/depression.Echocardiographic parameters evaluated during the scheduled follow-up time were: the TR grade, the device durability, the right chamber function and dimension, the inferior vena cava dimension and TAPSE/PAPS coupling.All major adverse events and additional safety endpoints  were collected during the follow-up time at 30 days and six months.t-test was used to compare paired nominal data. Paired two-samples Wilcoxon U test was used for not normally distributed data. Distribution was tested according to Shapiro–Wilk test. Differences were considered significant at p < 0.05. All statistical analyses were performed using the SPSS Statistics V23 software package .Longitudinal data for continuous variables were analysed using a generalised linear model with unstructured correlation to account for repeated measures. Data are presented as mean ± standard error for normally distributed or median and interquartile ranges for asymmetrically distributed continuous variables. Proportions are presented for categorical variables, and a Thirteen subjects  with significant comorbidities and high surgical risk were included. The mean age was 81 ± 4 years, with an average EuroSCORE II of 8 ± 4% . TR inclThe mean device time was 49 ± 25 min, and the mean procedural time was 88 ± 31 min. The primary efficacy endpoint  and the acute implant success were achieved in all cases, implanting one device in eight patients (62%) and two in five patients (38%). The device was placed antero-septal in 85% and postero-septal in 46% of cases. Immediately after the procedure, we observed a significant improvement in TR grade: six (46%) subjects had moderate, six (46%) mild and one patient (8%) with previous torrential TR treated with two clips had severe post-procedural TR because of partial leaflet detachment 48 h later. All patients were extubated in the catheterisation laboratory. There were no procedural or in-hospital MAEs.p < 0.001), EROA  and regurgitant volume  occurred between baseline and before hospital discharge. We also observed a change in adjacent anatomical structures with a significant reduction in tricuspid annulus diameter , right ventricular basal diameter , right atrial area  and inferior vena cava diameter . While three patients demonstrated a reduced TAPSE/PASP ratio (<0.31 mm/mmHg) before the intervention, the overall ratio significantly improved after device placement   . Importa= 0.011) .The primary safety endpoint was achieved in all cases. Specifically, no cases of cardiovascular death, myocardial infarction, renal failure, stroke, endocarditis, and non-elective cardiovascular surgery occurred at one month. p < 0.001) and showing marked benefit in quality of life . The overall mortality was 0%, with no subjects experiencing MAEs during a mean follow-up of six months. Single leaflet clip detachment occurred in one patient in whom two clips were implanted 48 h post-procedure and resulted in a reduction from torrential to severe TR grade. There were no cases of re-hospitalisation, major bleeding, pulmonary thromboembolism, new-onset of liver failure or device embolisation  TEER is effective and durable in reducing TR; (2) positive structural right chamber reverse remodelling occurs soon after the procedure; and (3) sustained improvements in clinical status, quality of life and no evidence of re-hospitalisation up to six months were seen in a high-risk patient cohort with no MAE. TR correction timing is critical and particularly challenging. It requires a multimodality imaging approach to confidently determine the aetiology and the severity of the TV lesion, the extent of remodelling and the functional status of ventricles. The difficulty in determining the right moment to perform the valvular repair arises from the fact that the severity of TR is highly dependent on the stress situation and may vary depending on the time of examination in the same patient. As more left valve diseases are treated with transcatheter therapies and evaluating the negative impact of TR on survival, the importance of developing transcatheter solutions for this subset of patients has recently been highlighted ,19. AlthThe epidemiological data from our cohort suggests that TR is predominantly functional due to enlargement of the tricuspid annulus and leaflet tethering, to a lesser extent, by the interference of the movement of the valve leaflets from the ventricular electrodes. However, the proportion of CIED-induced TR is expected to increase due to the ageing population and increased number of implantations. The pathophysiological relationship between the presence of the electrodes and the occurrence of significant TR or exacerbation of a pre-existing disease is a relatively emergent clinical challenge . Regardless of aetiology, among our results, the observed TR reduction, device durability and lack of major clinical complications are likely the essential findings in agreement with previous data on the effects of TR reduction on clinical outcomes ,23,24,25The primary efficacy endpoint was achieved in 100% of patients. Moreover, no further subjects experienced a reduction in TR grade between the 30-day and 6-month follow-ups. In one patient who had a baseline torrential TR, a reduction to severe grade was observed, without a negative impact on the clinical outcome. In the TRILUMINATE trial, the persistence of severe or more TR after TEER was associated with increased mortality and hospitalisations for heart failure at 1 year. Despite the limited follow-up time, clinical improvement occurred in most patients, as evidenced by a NYHA functional class ≤ II at 6 months in all patients. The present results are consistent with those observed in the TRILUMINATE trial at short- and long-term follow-up ,23.In our study, the reverse remodelling appeared to occur early after the procedure. In the TRILUMINATE trial, a reduction in RA and RV volumes was observed at 30 days and persisted at one year, with a progressive improvement in tricuspid annular plane systolic excursion (TAPSE) within the first year. In our study, a straight-line reduction in right ventricular dimension was observed in the acute phase after TEER, attributable to an acute change in RV loading condition. These results are not followed by an increase in right ventricular function immediately after the procedure, which is consistent with previous studies . InteresAmong our patients with a baseline TAPSE/PASP ratio < 0.31, we reported a high prevalence of heart failure symptoms and comorbidities, with more severe TR and advanced RV remodelling. The intervention aimed at reducing RV pressure and volume overload could benefit RV systolic function and improve RV−PA coupling and patient prognosis . This waOur preliminary study in patients with more than severe TR showed that TEER is a feasible, safe and effective procedure with improved short-term echocardiographic parameters and outcomes. Marked changes were not just related to the reduction of TR but also to adjacent anatomical structures, including the tricuspid annulus, right atrium, right ventricle, and inferior vena cava. Effective grasping of the leaflet was shown to improve right ventricular afterload adaptation. In addition, it should be emphasized that one-year follow-ups are underway, which may provide encouraging data on late changes in right ventricular function.The main limitation of this study is the single-site data collection and the small sample size. Due to the small sample size, we cannot draw meaningful statistical conclusions and consider it a preliminary and hypothesis-generating study. Patients and their anatomy were evaluated at enrolment by a committee focused on morphologic suitability for implantation of the device in the TV. In addition, other factors such as imaging views, the coaptation gap, the presence of leads across the TV and their interaction with the valve were also considered. Therefore, the results of this early feasibility study may not be generalizable to the overall population of patients with significant TR. In addition, the sample size may not be sufficient to identify predictors of improved NYHA functional class or echocardiographic results. An important limitation of our study is that it did not provide a long-term follow-up, but the results were very encouraging, even in the short term. Our future research goal is to refine and expand our dataset and continue patient follow-ups for at least one year to overcome these limitations.In this single-centre experience, we have shown that treatment with the edge-to-edge TriClip device is safe and effective in patients with significant TR and is associated with marked clinical benefits. The resulting echocardiographic improvements indicate tricuspid valve leaflet approximation does not just significantly reduce the grade of TR, but also affects adjacent structures and improves right ventricular afterload adaptation.


Nonetheless, optimum scan duration and time interval for image analysis are currently unknown. Further, it is unclear whether rest/stress PET-MPI with 18F-flurpiridaz is feasible in mice.Myocardial perfusion imaging by positron emission tomography (PET-MPI) is the current gold standard for quantification of myocardial blood flow. 18F-flurpiridaz (0.6-3.0 MBq) in 27 mice aged 7–8 months. Regadenoson (0.1 µg/g) was used for induction of vasodilator stress. Kinetic modeling was performed using a metabolite-corrected arterial input function. Image-derived myocardial 18F-flurpiridaz uptake was assessed for different time intervals by placing a volume of interest in the left ventricular myocardium.Rest/stress PET-MPI was performed with K1 ranged from 6.7 to 20.0 mL·cm−3·min−1, while myocardial volumes of distribution (VT) were between 34.6 and 83.6 mL·cm−3. Of note, myocardial 18F-flurpiridaz uptake (%ID/g) was significantly correlated with K1 at rest and following pharmacological vasodilation for all time intervals assessed. However, while Spearman’s coefficients (rs) ranged between 0.478 and 0.681, R2 values were generally low. In contrast, an excellent correlation of myocardial 18F-flurpiridaz uptake with VT was obtained, particularly when employing the averaged myocardial uptake from 20 to 40 min post tracer injection (R2 ≥ 0.98). Notably, K1 and VT were similarly sensitive to pharmacological vasodilation induction. Further, mean stress-to-rest ratios of K1, VT, and %ID/g 18F-flurpiridaz were virtually identical, suggesting that %ID/g 18F-flurpiridaz can be used to estimate coronary flow reserve (CFR) in mice.Tracer kinetics were best described by a two-tissue compartment model. 18F-flurpiridaz in mice, enabling high-throughput mechanistic CFR studies in rodents.Our findings suggest that a simplified assessment of relative myocardial perfusion and CFR, based on image-derived tracer uptake, is feasible with The online version of this article contains supplementary material available (10.1007/s12350-022-02968-9). As such, PET-MPI has shown a high diagnostic accuracy and independent prognostic value in INOCA patients.4 Further, a recent meta-analysis revealed that a reduced CFR was associated with an increased risk of cardiovascular and all-cause mortality across multiple disease populations, including patients with acute and chronic coronary syndromes, heart failure, aortic stenosis, heart transplant, and systemic sclerosis, demonstrating the versatile use of CFR in cardiovascular medicine.5In the past two decades, the diagnosis of coronary artery disease (CAD) has undergone a remarkable evolution from conventional anatomical assessment of coronary arteries to an integral diagnostic approach combining anatomical and functional cardiovascular imaging modalities. Although coronary computed tomography angiography (CCTA) remains the first-line diagnostic tool for patients with suspected CAD,18F-flurpiridaz has recently been introduced as a novel radiofluorinated probe for PET-MPI.8 Despite the excellent performance characteristic of 18F-flurpiridaz, the physical half-life of 109.8 minutes constitutes a major challenge for efficient rest/stress testing protocols. Indeed, conventional 1-day protocols, as they are routinely performed with rubidium-82, 13N-ammonia or 15O-water, are hampered by the residual myocardial radioactivity from the initial 18F-flurpiridaz injection, which affects the time-activity curves (TACs) obtained after the second 18F-flurpiridaz injection. Indeed, several unanswered questions remain regarding the ideal scan duration with 18F-flurpiridaz, as well as the most accurate time frame post injection for the assessment of myocardial perfusion and CFR. Further, given the widespread use of CAD mouse models, the feasibility of rest/stress PET-MPI with 18F-flurpiridaz in mice would ultimately allow the assessment of molecular determinants affecting myocardial perfusion and CFR in these disease models.18F-flurpiridaz injection and (2) to assess whether a simplified and image-derived model would allow sequential rest and stress PET-MPI, thereby providing accurate information on myocardial perfusion and CFR in mice.The aim of the study was (1) to identify the optimal time frame for PET imaging following Animal care and experimental procedures were performed in accordance with the Swiss Animal Welfare legislation and approved by the Veterinary Office of the Canton Zurich, Switzerland. Female and male FVB/N mice  were obtained from Janvier Labs , kept with free access to food and water and were scanned at the age of 7–8 months.18F-Flurpiridaz radiolabeling and precursor synthesis were reported elsewhere.11 PET/CT was performed in animals that were anaesthetized using 1.3–2.0% isoflurane in oxygen-enriched air (1:1). Depth of anesthesia was monitored via respiratory rate measurement . Body temperature was monitored using a rectal probe and was kept at 37°C with a temperature-adjusted air stream. A dose of 0.6-3.0 MBq 18F-flurpiridaz was administered via tail-vein injection 60 sec after the start of the PET scan. Tracer distribution was recorded in dynamic PET acquisition mode over a time period of 41 min, before a bolus of regadenoson (0.1 µg·g−1) and a second dose of 18F-flurpiridaz (2.2-8.1 MBq) were injected via a pre-installed intravenous catheter. PET imaging was performed with a calibrated Super Argus PET/CT scanner  with an axial field of view of 4.8 cm and a spatial resolution of 1.6-1.7 mm in full width at half-maximum,13 followed by a CT scan for anatomical information. PET data reconstruction was carried out using the manufacturer’s 2D iterative  algorithm, and corrections for dead time, decay, scatter, and attenuation, at a voxel size of 0.3875 x 0.3875 x 0.775 mm3. All radioactivities were decay-corrected to the time of tracer injection.18F-flurpiridaz injection , extrapolation curves were subtracted from the respective image-derived time-activity curves at 41 to 82 min post injection. Correction for the injected dose yielded the final rest and stress time-activity curves  via manual delineation of the myocardium to generate volumes of interest (VOIs) and respective time-activity curves. Decay-corrected time-activity curves were calculated for the myocardium VOI either as kBq/cc or % injected dose per gram tissue (%ID/g). An exponential model was fitted for each rest scan to estimate the radioactivity that remained in the myocardium at 41 to 82 min post injection from the initial An arteriovenous shunt and portable coincidence detector  were used to record the tracer concentration in the blood by continuous sampling and simultaneously with the PET data acquisition in five FVB/N mice (30.1–32.6 g). The coincidence detector was cross-calibrated to the PET for kBq/cc output. The delay between tissue and blood time-activity curves was determined as part of the model fitting procedure, and the final input function was corrected for plasma metabolites and plasma-to-blood ratio . Metabolite-corrected input functions were used for all analyses. The resulting five input functions were averaged, and the average was used as a surrogate input function for all animals scanned without arteriovenous shunt system .18F-flurpiridaz was evaluated with a one- and two-tissue compartment model using the following equations:Kinetic modeling was performed with the PKIN tool of PMOD v.3.8 . The kinetics of One-tissue compartment model:−3·min−1] and −1] represent the uptake and clearance rates from the plasma to the first tissue compartment, whereas −1] and −1] are the rate constants describing the exchange between the first and second tissue compartment. 14 Tissue distribution volume (VT) was calculated from the fit 15Two-tissue compartment model:s). Outliers were assessed based on the Grubb’s test.16 A two-tailed P value of ≤ 0.05 was deemed statistically significant. Statistical analyses were carried out with SPSS .Continuous variables are presented as mean ± standard error of the mean (SEM). Student’s t test and analysis of variance (ANOVA) tests were used for group comparisons of continuous variables. For multiple comparisons, Bonferroni correction was applied. Strength and direction of associations were assessed by Spearman’s rank-order correlation .Time-activity curves (TACs) of R2 consistently confirmed that the two-tissue compartment model was the superior model . K1, which is typically considered a measure of absolute MBF for tracers with high myocardial extraction fraction such as 18F-flurpiridaz,8 ranged from 6.7 to 20.0 mL·cm−3·min−1, while myocardial VT values between 34.6 and 83.6 mL/cm3 were obtained. A representative example of the two-tissue compartment model fit is shown in Figure T values obtained from Logan graphical analysis were in agreement with the two-tissue compartment model fit , we employed kinetic tracer modeling using a metabolite-corrected input function that was recorded by continuous arterial blood sampling. Results of kinetic modeling were compared for one- and two-tissue compartment models. While the kinetic results were satisfactory by visual inspection for the two-tissue compartment model Figure , the one18F-flurpiridaz (%ID/g tissue) can be used as a surrogate measure for relative myocardial perfusion changes. Myocardial 18F-flurpiridaz uptake was significantly correlated with K1 from two-tissue compartment modeling. As shown in Tables s) ranged between 0.478 and 0.573 for the rest scans and were higher after regadenoson injection (0.617-0.681), whereas significant correlations were obtained for all tested time slots. Nonetheless, R2 values were generally low, ranging from 0.21 to 0.43, which indicates that K1 does not sufficiently explain a large proportion of the variability in image-derived myocardial 18F-flurpiridaz uptake.In a next step, we sought to assess whether the image-derived myocardial tissue uptake of 18F-flurpiridaz uptake was compared to the respective volumes of distribution (VT), excellent correlations were obtained between %ID/g tissue and VT at rest , while earlier time frames were associated with lower R2 values . Similarly, the correlation model between %ID/g tissue and VT was superior at later time frames following regadenoson injection, as depicted in Figure In contrast, when myocardial t Figure . Notably20 Given that K1 constitutes a measure of absolute MBF, we used the ratio of K1 following regadenoson injection to K1 at resting condition to calculate the CFR. As expected, K1 was significantly higher following regadenoson injection . Similarly, regadenoson-induced coronary vasodilation led to a significant increase in VT . The resulting mean stress-to-rest ratios for K1 and VT were identical , however, with a higher variability obtained for K1. These results support the concept that both, K1 and VT, are similarly sensitive to pharmacologically induced changes of MBF in mice, while VT seems to constitute a more robust parameter for the estimation of CFR. Notably, it was found that stress-to-rest ratios of image-derived myocardial 18F-flurpiridaz uptake accurately predicted CFR, as depicted in Figure 18F-flurpiridaz from 20 to 40 min post injection provided the most accurate mean ratio, as compared to CFR determined from K1 by the two-tissue compartment model.CFR can be calculated from the ratio of MBF during regadenoson-induced vasodilation to the MBF under resting conditions.18F-flurpiridaz in mice follows a two-tissue compartment model. While K1 and VT were both similarly sensitive to vasodilator-induced increase of MBF, VT exhibited a superior correlation with image-derived myocardial tracer uptake at all measured time intervals. In particular, image-derived tracer uptake at later time intervals revealed ideal coefficients of determination (R2 up to 0.99) when correlated with VT. Further, the average stress-to-rest ratio of myocardial tracer uptake (%ID/g tissue), obtained from 20 to 40 min post injection, was identical to the stress-to-rest ratios of K1 and VT. These results suggest that myocardial 18F-flurpiridaz uptake (%ID/g) in mice, as determined from dynamic PET, correlates with MBF and can be used to estimate relative myocardial perfusion changes as well as CFR when pharmacological vasodilation is employed.In the present study, we show that rest/stress MPI with 18F-flurpiridaz in mice. In agreement with previous reports in other species, including pigs21 and humans,19 we found that a two-tissue compartment model was suitable to predict 18F-flurpiridaz uptake in the mouse myocardium. Nonetheless, significant species differences were observed with regard to tracer washout from the myocardium. While myocardial 18F-flurpiridaz washout was negligible in pigs and humans, our time-activity curves unveiled a demonstrably faster kinetics in mice with evident washout from the mouse myocardium starting at 5–10 min post injection.21 Our results point toward species differences in myocardial tracer retention that need to be taken into consideration for kinetic modeling. As such, while k4 (dissociation rate constant) was manually set to zero in previous studies with other species,22 we did not employ any restrictions for k4 in mice. Of note, a fast decline of the parent tracer fraction was detected in the mouse plasma following tail-vein injection of 18F-flurpiridaz , which might, at least in part, explain the observed species differences in tracer washout from the myocardium. To account for the metabolic degradation, we used metabolite-corrected input functions for all animals tested. By ex vivo metabolite analysis, the myocardium was found to show an intact parent fraction of > 99%, suggesting that the contribution of radiometabolites to the overall myocardial radioactivity was negligible. In contrast to the two-tissue compartment model, the one-tissue compartment model did not result in satisfactory results by visual inspection and assessment of different model fit indicators, suggesting that binding to MC-I has a significant contribution to the kinetics as well as perfusion-linked 18F-flurpiridaz delivery to the mouse myocardium.To the best of our knowledge, this is the first study to assess the feasibility of rest/stress PET-MPI with 23 In contrast, 15O-water and 13N-ammonia exhibit superior spatial resolutions to rubidium-82 and are validated perfusion tracers; however, their short physical half-lives do not allow satellite distribution, thus, rendering an on-site cyclotron indispensable.21 Efforts to develop a radiofluorinated myocardial perfusion tracer with increased physical half-life and spatial resolution have ultimately led to the discovery of 18F-flurpiridaz.8 Unlike other probes for PET-MPI, 18F-flurpiridaz binds to the mitochondrial complex I (MC-I), which is highly abundant in cardiomyocytes.21 The latter allows selective visualization of the myocardium, providing remarkably high signal-to-background ratios and thus high image quality.30 In experimental models, 18F-flurpiridaz exhibited a relatively high myocardial extraction fraction of 0.94, which was consistent at different flow rates, and demonstrated favorable performance characteristics as a myocardial perfusion tracer.34 Notably, we observed that peak arterial radioactivity was lower than peak myocardial activity across all animals tested, which might be explained by the relatively high first-pass myocardial extraction fraction of 18F-flurpiridaz.Due to the availability of rubidium-82 generators, which obviates the need for a cyclotron, rubidium-82 is the most frequently used probe for PET-MPI. Nonetheless, the relatively high positron range results in an inferior spatial resolution, as compared to other PET isotopes.18F-flurpiridaz for PET-MPI, the sustained myocardial radioactivity from the initial scan may affect the time-activity curves upon the second injection—particularly if rest and stress scans are performed on the same day. In our study, pilot experiments were conducted to determine the minimum scan duration required to allow adequate extrapolation of the terminal phase via non-linear regression models. Employing these models, we were able to correct for the residual myocardial radioactivity from the first 18F-flurpiridaz injection. In light of the observed species differences in 18F-flurpiridaz clearance from the myocardium, we conclude that a careful evaluation of the terminal phase for the underlying test species seems crucial for 1-day rest/stress PET-MPI protocols with 18F-flurpiridaz.Despite the reported favorable properties of 35 that can be derived from the PET image by placing a VOI in the left ventricular cavity.36 While image-derived input functions are routinely obtained in clinical PET-MPI, this approach is hampered in mice due to the relatively small left ventricular dimensions. Accordingly, quantification of absolute MBF in mice requires arterial blood sampling, which is associated with significant technical challenges. To circumvent this limitation, we assessed whether myocardial 18F-flurpiridaz uptake can be used to provide information on myocardial perfusion changes as well as fundamental kinetic parameters such as K1 and VT. Indeed, although correlations of K1 with image-derived myocardial 18F-flurpiridaz uptake were significant, R2 values were generally below 0.5, indicating a poor fit for all time frames investigated. In contrast, ideal fits were obtained for the correlation of VT with myocardial 18F-flurpiridaz uptake, particularly at later time intervals such as 20–40 min post injection. Although K1 is closely linked to perfusion, our results suggest that the rapid tracer kinetics renders myocardial 18F-flurpiridaz uptake more highly weighted toward MC-I binding than absolute MBF in mice. Further, early time intervals, which are critical for the accurate estimation of K1, are particularly susceptible to spillover effects from the blood pool as well as variability in manual injection time and potential animal distress that resulted from the injection procedure. Accordingly, the relation between K1 and myocardial 18F-flurpiridaz uptake did not allow the prediction of absolute values for MBF from myocardial 18F-flurpiridaz uptake in our study. Notably, however, %ID/g 18F-flurpiridaz was highly correlated with VT. Indeed, our findings suggested that VT was reliably estimated from myocardial 18F-flurpiridaz uptake in the absence of an arterial input function. Given (1) that VT is sensitive to changes in K1 according to Eq. VT and K1, it appears that changes in myocardial perfusion were accurately reflected by the model microparameter VT. Accordingly, although %ID/g 18F-flurpiridaz was not suitable to estimate values for absolute MBF, our data indicate that %ID/g 18F-flurpiridaz can be used for intra- and interindividual comparisons of relative myocardial perfusion in mice. Further, mean CFR values were comparable when calculated from stress-to-rest ratios of K1, VT, and %ID/g 18F-flurpiridaz from 20 to 40 min post injection, suggesting that stress-to-rest ratios of %ID/g 18F-flurpiridaz can be used as a surrogate of CFR when pharmacological vasodilation is employed. In contrast to pharmacological vasodilation, however, it should be noted that the assessment of CFR from exercise stress testing is not recommended in the absence of an input function, particularly due to the substantial increase of cardiac output under exercise testing, which leads to a proportional dilution of the intravenous radiotracer dose.38Absolute MBF quantification has proven its utility in clinical routine; however, the latter requires an arterial input function39 the positron ranges of conventional PET-MPI probes such as rubidium-82, 15O-water, and 13N-ammonia would not allow a sufficient spatial resolution for the assessment of CFR in the small mouse heart.40 Conversely, the availability of a radiofluorinated probe now provides new perspectives for PET-MPI in mice and the fact that myocardial 18F-flurpidaz uptake correlated well with K1 and VT from quantitative kinetic modeling with an invasive metabolite-corrected input function is particularly encouraging. Second, high isoflurane concentrations can prompt coronary vasodilation and may have affected outcome measures of our study.41 However, previous work has shown that heart rate and mean systolic blood pressure remain stable at isoflurane concentration up to 2.0% in mice.43 To minimize the vasodilatory properties of isoflurane, its concentration was kept at or below 2.0% throughout the entire experiment. Nonetheless, a vasodilatory effect of isoflurane cannot be completely ruled out in the present study. Third, an experimental arterial input function was only available in five animals, and the average of all five input functions was used as a population (surrogate) input function for kinetic modeling in animals without arterial shunt, as previously reported.44 However, a linear regression analysis revealed that K1 and VT obtained from the surrogate input function and the respective input functions from shunt surgery were in good agreement . While obtaining an image-derived input function in mice is particularly challenging and prone to error, the approach of a surrogate input function constitutes a valid alternative for high-throughput studies.There are study limitations that should be pointed out. First, the lack of a reference standard to validate PET-MPI findings in mice constitutes a limitation of this study. Indeed, the assessment of CFR by PET-MPI in mice is a major challenge in contemporary cardiovascular research and studies of CFR by rest/stress MPI using PET in rodents are scarce in general. Although the spatial resolution of our PET scanner was in the range of reported left ventricular thickness  < 1.8 mm for mice,18F-flurpiridaz can be used for rest/stress myocardial perfusion imaging in mice and follows a two-tissue compartment model. Myocardial 18F-flurpiridaz uptake was equally sensitive to vasodilator stress as K1 and VT, suggesting that a simplified assessment of CFR, based on image-derived findings, is feasible when pharmacological vasodilation is employed. Further, although arterial blood sampling is required for absolute quantification of MBF, myocardial 18F-flurpiridaz uptake can be used for relative comparison of myocardial perfusion in mice.In conclusion, our results indicate that 18F-flurpiridaz and follows a two-tissue compartment model. Critical kinetic modeling parameters such as K1 and VT were sensitive to vasodilator-induced increase of myocardial blood flow. Further, the average stress-to-rest ratio of myocardial tracer uptake from 20 to 40 min post injection was identical to the stress-to-rest ratios of K1 and VT, indicating that myocardial 18F-flurpiridaz uptake can be used to estimate relative myocardial perfusion changes and coronary flow reserve (CFR) in mice. The translational relevance of this study lies in the detrimental implications of an abnormal CFR in coronary artery disease (CAD) patients. The present findings encourage a wider use of PET-MPI for the assessment of CFR in mouse models of CAD, and pave the way for mechanistic studies that aim at identifying molecular variables affecting CFR.In the present study, we show that rest/stress myocardial perfusion imaging in mice is feasible with


The effect of fetal oval foramen restriction and premature contraction of the arterial catheter for the right heart function of fetuses and infants was studied by evaluating the right and left ventricular (RV/LV) ratios, the tricuspid annular plane systolic excursion (TAPSE) value, and the Tei index of right heart function parameters.P < 0.05 indicates significant.This study was approved by the Ethics Committee of First Affiliated Hospital of Hebei North University (K20190116). We collected 257 fetuses between March 2020 and December 2021. Among these, 98 fetuses that did not have any heart abnormalities were assigned to group A, 91 fetuses with restriction of the left and right atrial channels were assigned to group B, and 68 fetuses with premature contraction of the arterial catheter were assigned to group C. The ventricular transverse diameter, the right heart TAPSE value and the Tei index of fetuses in late pregnancy and 90 days after birth were measured in the three groups, and the diagnostic value of each index for the right heart function injury was evaluated. P > 0.05, which was not significant; however, P < 0.05 after birth was considered significant. For fetuses and postnatal infants in the BC group, the RV/LV ratio was negatively associated with the TAPSE value. However, it was positively associated with the Tei index; Diagnostic test results. To predict impaired right heart function after birth, TAPSE had low diagnostic value, RV/LV and Tei index had high diagnostic value.The P-value of the TAPSE value and Tei index of infants in BC and AC groups and postnatal infants were less than 0.05, which was significant. In the BC group, the RV/LV ratio of fetuses was compared when Oval foramen restriction and premature contraction of the arterial catheter may affect the right heart function after birth and be related to the degree of the right heart enlargement. Although TAPSE prediction of the fetal and postnatal right heart function is limited, the RV/LV ratio and the Tei index can be used to predict impaired right heart function after birth. Theoval foramen and valves form important blood flow channels in the left and right atria during the fetal period. This provides about 76% of the left heart blood flow, plays an important role in promoting the left heart development, and maintains the left and right heart pressure. However, a restriction in this channel will increase the right heart volume load . The artThe two factors above are the main causes of right heart enlargement in the fetal period. Furthermore, whether the right heart enlargement should be clinically managed the same way as other conditions and the extent to which the right heart enlargement may affect the right heart function after birth is a dilemma that we encounter in clinical settings. Hence, we aimed to obtain effective parameters that can predict impaired right heart function after birth by measuring the right and left ventricular (RV/LV) ratios, tricuspid annular plane systolic excursion tricuspid annular plane systolic excursion (TAPSE) value, and the Tei index. These provide reliable imaging information to make favorable clinical choices for pregnant women and their fetuses.This study was approved by the Ethics Committee of First Affiliated Hospital of Hebei North University (K20190116), and all pregnant women gave written informed consent for participating this study. Because the collection of patient information is incomplete, patients quitted midway and the collected images cannot be analyzed and other reasons, finally, two hundred and fifty-seven complete cases were collected between March 2020 and December 2021; 98 fetuses that did not have any heart abnormalities were included in group A, pregnant women were aged 22–35 years, the mean age was 28.93 ± 4.75 years, the fetal gestational age occurred between 28 and 39 weeks, and the average gestational age was 32.45 ± 2.47 weeks. Ninety-one fetuses with restrictions were included in group B. Pregnant women were aged 21–35 years, the mean age was 30.14 ± 4.05 years, the fetal gestational age occurred between 28 and 39 weeks, and the mean gestational age was 33.02 ± 2.34 weeks. Sixty-eight fetuses with premature arterial catheter constriction were included in group C. Pregnant women were aged 21–35 years, the mean age was 30.13 ± 4.28 years, the fetal gestational age occurred between 28 and 39 weeks, and the average gestational age was 32.97 ± 2.70 weeks. The TAPSE value and Tei index of the ventricular transverse diameter and right heart of the three groups were measured during late pregnancy and at about 90 days after birth. The inclusion criteria were as follows: (1) late pregnancy singleton; (2) an accurate gestational age; (3) pregnant women who have no history of heart, kidney, or metabolic diseases. The exclusion criteria were as follows: (1) Fetal abnormalities were found during and after fetus; (2) persistent arrhythmia and myocardial disease; (3) inability to obtain ideal ultrasound images; (4) unavailability of complete information.A PhilipsEPIQ7C diasonograph  was used with a C5-1 probe of frequency 1 to 5 MHz and an S5-1 probe of frequency 1 to 5 MHz. A GE VolusonE10 diasonograph , C5-1 probe with frequency 1 to 5 MHz, and C9-2 probe with frequency 2 to 9 MHz were used for the following: (1) routine fetal ultrasound examination excluding malformations and verified fetal gestational age; (2) fetal echocardiography excluding structural abnormalities in the fetal heart; (3) measurement of the TAPSE value, showing the standard four-chambered heart. The position of the probe was adjusted to move the tip forward or backward, the M-type ultrasound mode was initiated, the sampling line was placed at the tangent position at the junction of the anterior lobe ring and the right ventricular free wall, the angle of the longitudinal movement was adjusted to < 15°, and the distance from the lowest point of movement to the highest was measured , 1B; (4)t-test was used for the data comparison ratio of each group. The values were set as α = 0.05, P < 0.05; differences were considered statistically significant.SPSS 26.0 software  was used for statistical data analysis; measurement data were indicated by (x ±). Correlation between parameters was analyzed using Pearson analysis. ROC (receiver operating characteristic) curves were used to test the accuracy of the diagnostic tests, and an independent sample P > 0.05, The age of the pregnant women, gestational age at fetal echocardiography, and echocardiography examination days of infants after birth in groups A, B, and Care presented in P < 0.05). The RV/LV ratio before birth was higher in group B than in C (P > 0.05), and the difference was not significant. However, the RV/LV ratio after birth was lower in group B than in C (P < 0.05), and the difference was considered significant.The TAPSE value before and after birth was higher in all the groups: A, B, and C. In contrast, the Tei index was lower in groups A, B, and C. The difference in the parameters of TAPSE and Tei index was significant at before and after birth (P < 0.01); however, a negative correlation was observed. The larger the TAPSE value before birth, the lower the RV/LV ratio. A rough uniform overall distribution density and the same change direction were observed. In contrast, the lower the RV/LV ratio, the more were the regions with higher overall distribution density change in the same direction. The magnitude of Pearson correlation coefficients between the TAPSE value and RV/LV ratio were−0.875 and −0.786, respectively, before and after birth. The two-sided test of the correlation coefficient was significant (P < 0.01), and a negative correlation was observed—conversely, the larger were the Tei index values before birth, the larger the RV/LV values. The overall distribution density was roughly uniform, and the change direction was the same. The greater the Tei index value after birth, the larger was the RV/LV ratio. Regions with a higher overall distribution density were located in the regions with smaller Tei index values, and the change direction was the same. The magnitude of Pearson correlation coefficients between the Tei index and RV/LV ratio were 0.893 and 0.805, respectively, before and after birth. The two-sided test of the correlation coefficient was significant (P < 0.01), and a positive correlation was observed.Regarding fetal and postnatal measurements in group B, the larger the TAPSE value before birth, the lower were the Tei index value. Furthermore, the overall distribution density was roughly uniform, and the change direction was the same. The larger the postnatal TAPSE value, the lower the Tei index value. Regions with a higher overall distribution density were located in the regions with larger TAPSE values, and the change direction was the same. The magnitude of Pearson correlation coefficients with the TAPSE value and Tei index were −0.794 and −0.822, respectively, before and after birth. The two-sided test of the correlation coefficient was significant (P < 0.01), and a negative correlation was observed. The larger the TAPSE values before birth, the lower was the RV/LV ratio; the overall distribution density was roughly uniform, and the change direction was the same. The larger the TAPSE value after birth, the lower was the RV/LV ratio; regions with a higher overall distribution density were located in the regions with larger TAPSE values, and the change direction was the same. The magnitude of Pearson correlation coefficients between the TAPSE value and RV/LV ratio were 0.869 and 0.952, respectively, before and after birth. The two-sided test of the correlation coefficient was significant (P < 0.01), and a negative correlation was observed. The larger the Tei index values before birth, the larger were the RV/LV ratios; the overall distribution density was roughly uniform, and the change direction was the same. The larger the Tei index value after birth, the larger were the RV/LV ratios; regions with a higher overall distribution density were located in the regions with smaller Tei index values, and the change direction was the same. The magnitude of the Pearson correlation coefficient between the Tei index and RV/LV ratios were 0.873 and 0.919, respectively, before and after birth. The two-sided test of the correlation coefficient was significant (P < 0.01) and both were positively correlated.The measurements for fetuses before and after birth in group C, the larger the TAPSE value before birth, the lower the Tei index value. The overall distribution density was roughly uniform, and the change direction was the same. The larger the TAPSE value after birth, the lower was the Tei index value; regions with a higher overall distribution density were located in the regions with larger TAPSE values, and the change direction was the same. The magnitude of Pearson correlation coefficients before and after birth between the TAPSE value and Tei index were 0.866 and 0.945, respectively, before and after birth. The two-sided test of the correlation coefficient was significant . Of the 107 fetuses with oval orifice restriction, DCRV (Double Chamber Right Ventricle) was observed in a case after birth. Echocardiography was not performed in one case during late pregnancy, ideal ultrasound images could not be obtained in three cases, and echocardiography was not performed in 13 cases around 90 days after birth; hence, 91 cases were included in the analysis (91/107). Of 76 fetuses with premature contraction of the arterial catheter, one death was recorded, and ideal ultrasound images could not be obtained in four cases. Echocardiography was not performed in three cases around 90 days after birth; hence, 68 cases were finally included in the analysis (68/76).The right heart has an advantage during the fetal period because of the size of the right heart is slightly greater and the blood flow of the right heart is greater than that of the left heart. There are two important physiological processes that coordinate blood flow from the right to the left shunt channels to ensure the normal development of the fetus in this period; (1) a channel formed by the oval foramen and the oval valve located between the left and right atria; (2) another channel formed by the arterial catheter, located between the pulmonary artery and descending aorta . The resi.e., repeatability, the size of the measurement error, the measurement stability, and the reliability of the right heart function evaluation, we finally chose two indicators, namely the TAPSE value and the Tei index. It is believed that the TAPSE value can be used as an important parameter to evaluate the fetal right heart contraction function, and it has good reproducibility and lower requirements for equipment (To date, there are no defined guidelines for the fetal right heart function measurement. Therefore, we referred to the adult right heart function evaluation standard to deduce the right heart function evaluation for the fetuses. After considering the four aspects of the right heart function measurement comprehensively, quipment . In thisquipment . The Teiquipment . There wThe oval foramen is the entry point of the right atrial blood flow into the left atria during the fetal period; the oval valve and the atrial interval form its outlet. Abnormalities in the inlet and outlet of the oval foramen can limit the blood flow from the right into the left chamber, thus causing the volume overload of the right heart. It is believed that if the right and left atrial channel sare only partially and unintentionally closed; close clinical observation can be considered. The prognosis is generally good after birth; however, cardiac insufficiency is difficult to diagnose during the fetal period . The meaPremature contraction of the arterial catheter with fetal edema causes approximately 40% of fetal deaths, before and after birth. Conversely, if the right heart is significantly enlarged without edema, the right ventricular failure shows a poor prognosis . The meaThe oxygen saturation was reduced in two newborns after birth, while others showed no abnormal clinical symptoms. We also studied the fetuses after birth of this study; the differences in the TAPSE value and the Tei index for groups A and C were significant, suggesting that changes in the right heart function caused by the premature contraction of the arterial catheter persisted at 90 days after birth, and a few can cause clinical symptoms. However, there was no statistical difference in the proportion of the right heart enlargement for groups B and C in the fetal stage. On this premise, the value was larger in group C compared with the TAPSE and Tei index test values of the other two groups; the difference was significant, showing that the premature contraction of the arterial catheter had a more pronounced impact on the right heart function than the oval foramen restriction. In this study, we used the right heart enlargement after birth as the standard to inspect the accuracy of the diagnostic tests on indicators of the right heart function during the fetal period, and the study results showed that the RV/LV ratio and the Tei index of groups B and C had high diagnostic values in predicting the right heart function after birth. Although the TAPSE value is a stable index that reflects the right heart function, itsuse is limited in the prediction and diagnosis of the right heart function after birth.In this study, the effects of fetal right heart system enlargement on right heart function after birth were studied and tracked to about 90 days after birth. Since the effect of physiologic pulmonary hypertension on right heart function has disappeared at 90 days of age, measurements of right heart function are reliable. The shortcoming of this study is that it does not elucidate the long-term effects of fetal right heart system enlargement on the right heart function after birth. In the future, cases will be followed up, expected to be followed up to 2 years or more after birth, in order to draw more meaningful conclusions.In this study, fetuses were followed up to 90 days after birth, and the study results showed that oval foramen restriction and premature contraction of the arterial catheter would affect the right heart function of fetuses and infants. In addition, we provided the cut-off values for the predictors of the right heart function after birth during the fetal period. Although these findings can provide accurate information for clinical use, the follow-up period was not finished as fetuses have not been followed up for a year or more after birth. Hence, we do not claim to assign any pathological significance to oval foramen restriction and premature contraction of the arterial catheter. Therefore, future studies with a longer follow-up period are warranted to validate our results.10.7717/peerj.14702/supp-1Supplemental Information 1Click here for additional data file.