Cardiovascular disease includes many diseases such as heart failure, cardiomyopathy, valvular disease, pericardial disease, peripheral vascular disease, rheumatic heart disease, and vascular disease to name a few. Cardiovascular disease in pregnancy is on the rise especially with women being pregnant at an older age. Brain natriuretic peptide (BNP) could be a factor in determining the severity. BNP is elevated in heart failure. This study will attempt to determine the relationship between BNP and pregnancy outcomes in women with heart failure. A keyword combination search was performed using varying databases. Inclusion and exclusion criteria were implemented and relevant articles were obtained to formulate ideas to support the topic. BNP, the amino acid peptide, is secreted by both atrial and ventricular monocytes. BNP and N-terminal (NT)-pro hormone BNP (NT-proBNP) are elevated in heart failure and seen in pregnant women alike. Within six to 12 weeks it returns to normal levels. Normal levels were shown to have good pregnancy outcomes in that the baby is healthy with normal birth weight and the mother is free of cardiovascular complications, whereas at elevated levels the pregnancy outcome was not favorable. NT-proBNP, when elevated in the pregnant patient, is a predictor of poor pregnancy outcomes, especially in patients with precursors. Testing for this peptide in pregnant women during the early stages of pregnancy could help determine the best course of action for a better outcome. Many patients have cardiovascular illnesses as confirmed by the CDC (Center for Disease Control). It is the leading cause of mortality in pregnant women. Cardiovascular illness is growing more common in pregnant women, and it is now a primary cause of maternal morbidity. Outside of pregnancy, biomarkers such as brain natriuretic peptide (BNP) and its amino-terminal co-metabolite N-terminal pro-B-type natriuretic peptide (NT-proBNP) have been utilized to diagnose, prognosticate, and risk stratify heart failure ,2.In response to myocyte stretching, the 32-amino-acid peptide NT-proBNP is generated and released mostly from the ventricular myocardium. However, myocardial ischemia and infarction, as well as increased left ventricular (LV) wall stretch, cause the release of NT-proBNP. NT-proBNP levels have been associated with LV dilatation, remodeling, and dysfunction in people who have had an acute myocardial infarction. NT-proBNP is linked to body mass index (BMI), sexual hormone-binding globulin, and ethnicity ,3. It enCardiovascular function and hemodynamics vary dramatically throughout the pregnancy. An increase in cardiac output (CO) is the most major change related to pregnancy. During pregnancy, CO increases due to an increase in heart rate, blood volume, and a reduction in systemic vascular resistance. Reversible cardiac remodeling includes chamber enlargement (left ventricular diastolic dimension (LVDd) and left atrial dimension (LAD), valve annular dilation, and increased LV mass). In the earlier stages of pregnancy, these changes begin and peak in the second and third trimesters  [PPCM is a common cause of pregnancy-related heart failure that affects women near the end of their pregnancy or soon after giving birth up to five months postpartum ,5. NT-prPreeclampsia is a cardiac condition that occurs during pregnancy and is caused by stress on the heart's ventricles. It is characterized by an increase in BNP levels -8. The lIn this study, we plan to determine the relationship between how NT-proBNP can determine the diagnosis and prognosis of cardiovascular disease in pregnant patients. Our goal will be to show that NT-proBNP can assist in determining the cardiovascular health of pregnant women.MethodsWe obeyed the Preferred Reported Items for Systematic reviews and Meta-analysis (PRISMA) guidelines for conducting our systematic review . We systInclusion criteriaFor our research, we included all the articles in English, free full text, and full text. Articles were from the last five years (2017-2022). The population was female ranging from age 13 and above. All the study subjects were human.Exclusion criteriaGrey literature, books, documents, languages other than English, people located outside the United States, and duplicates were excluded from the study.ResultsA total of 11,193 studies were obtained from databases. Records were analyzed on the basis of title, abstract, and application of inclusion and exclusion criteria. Despite exclusion for a year, one article from 2002 was a part of the results. A total of 652 studies were obtained. After the removal of duplicates, 642 studies were left. Further, all the articles were screened on the basis of title and abstract and 72 remained. The studies were then assessed for quality, and 50 studies were included. Clinical trials were screened through Cochrane Risk Bias Assessment Tool, Observational studies by New Castle Ottawa, Systematic and Meta-analysis by PRISMA, and Literature review by Scale for the Assessment of Narrative Review Articles (SANRA) Checklist. Figure DiscussionCardiovascular disorders have been increasing in pregnant women. Heart failure in pregnancy is a very serious condition because not only is the life of the mother at risk, but also the life of the unborn child as well. BNP has been used to determine patients with heart failure the severity of the disease.What is BNP?The 32-amino-acid peptide hormone BNP belongs to a group of structurally related peptide hormones. They have a 17-amino-acid core loop that is connected by a disulfide bond between two cysteine residues, and carboxy- and amino-terminal tails differ from each other. Both atrial and ventricular myocytes secrete BNP, with the left ventricle being the primary source ,11. The Where there are higher levels of NT-proBNP and BNP, they have been associated with an increased risk of death from any cause, such as cardiovascular death, sudden death, pump failure death, as well as hospitalization for heart failure . Table 2Pregnancy and cardiovascular conditions associated with pregnancyAs the demographics have been changing over the years, there has also been an increase in the number of patients presenting with cardiovascular disease. In more recent years many women have delayed having children from their 20s and 30s to now during their 40s. These older-aged women present with cardiac conditions such as chronic hypertension and coronary disease . In addiDuring the first trimester, peripheral vascular resistance begins to diminish due to uteroplacental shunting and a decrease in vascular sensitivity to the presser effects of angiotensin II and norepinephrine. The heart rate of the mother increases by 10 to 15 beats per minute. An increase in CO is caused by an increase in preload, a decrease in afterload, and an increase in heart rate . The patPPCM has the potential to lead to long-term systolic dysfunction, particularly in black women. Pregnancy-related hypertension disorders are the primary hypertensive disorder of pregnancy (HDP) risk factor for PPCM. Additionally, PPCM often occurs earlier in women with positive HDP results than in those with negative HDP results. HDPs that raise the risk of PPCM include preeclampsia and prenatal hypertension, which are substantially more common in black women. Preeclampsia and PPCM are pathophysiologically related illnesses that are most likely triggered by the placenta's increased production of vasculotoxic and antiangiogenic hormones. Early diagnosis has been shown to have a better outcome . Table 3Relationship of NT-proBNP in pregnant patientsBNP levels rise in patients with heart failure because ventricular stretching produced by increased filling pressure increases BNP secretion. BNP levels are typically two-fold higher during a normal pregnancy than in a non-pregnant state, and they do not alter much during pregnancy or after delivery (four to six weeks) . The norNT-proBNP has a half-life of 60 to 90 minutes whereas BNP has a half-life of 20 minutes . In the LimitationsThis study was done in hopes of showing the necessity of NT-proBNP and its relationship to heart failure in pregnant patients. This study was limited due to not having access to physical patients to be able to perform the laboratory test to confirm. Ethnicities were not accounted for in the study. The study was limited to articles from the past five years thereby restricting data with changes relating to BNP from previous studies. Our study allows for future trials of testing to determine the severity of heart failure and to risk stratify the course of pregnancy and its outcome.The focus of the study was to show the possibility of NT-proBNP and its value in relation to pregnant patients with cardiovascular conditions. BNP has been shown to be around normal levels in pregnant patients, however, in those with underlying cardiac conditions it is elevated. Since NT-proBNP is a byproduct of BNP with a longer half-life, it can be determined that its presence would indicate that there is a correlation to heart failure in pregnant patients. Further testing would be needed to test this theory.


MRI is the best imaging tool for the evaluation of uterine tumors, but conventional MRI diagnosis results rely on radiologists and contrast agents (if needed). As a new objective, reproducible and contrast-agent free quantification technique, T2 mapping has been applied to a number of diseases, but studies on the evaluation of uterine lesions and the influence of magnetic field strength are few. Therefore, the aim of this study was to systematically investigate and compare the performance of T2 mapping as a nonenhanced imaging tool in discriminating common uterine lesions between 1.5 T and 3.0 T MRI systems.A total of 50 healthy subjects and 126 patients with suspected uterine lesions were enrolled in our study, and routine uterine MRI sequences with additional T2 mapping sequences were performed. T2 maps were calculated by monoexponential fitting using a custom code in MATLAB. T2 values of normal uterine structures in the healthy group and lesions  in the patient group were collected. The differences in T2 values between 1.5 T MRI and 3.0 T MRI in any normal structure or lesion were compared. The comparison of T2 values between benign and malignant lesions was also performed under each magnetic field strength, and the diagnostic efficacies of the T2 value obtained through receiver operating characteristic (ROC) analysis were compared between 1.5 T and 3.0 T.p < 0.05). There were significant differences in T2 values between each lesion subgroup under both 1.5 T and 3.0 T MRI. Moreover, the T2 values of benign lesions (71.1 ± 22.0 ms at 1.5 T and 63.4 ± 19.1 ms at 3.0 T) were also significantly lower than those of malignant lesions (101.1 ± 4.5 ms at 1.5 T and 93.5 ± 5.1 ms at 3.0 T) under both field strengths. In the aspect of differentiating benign from malignant lesions, the area under the curve of the T2 value under 3.0 T (0.94) was significantly higher than that under 1.5 T MRI (0.90) (p = 0.02).The mean T2 value of any normal uterine structure or uterine lesion under 3.0 T MRI was significantly lower than that under 1.5 T MRI (T2 mapping can be a potential tool for quantifying common uterine lesions, and it has better performance in distinguishing benign from malignant lesions under 3.0 T MRI. According to cancer statistics, the trend in the incidence and modality of uterine tumors in developing countries is still upward , 2. AmonMagnetic resonance imaging (MRI) has become increasingly important in the diagnosis and evaluation of uterine lesions due to its non-radiation exposure and excellent image contrast of soft tissue. Lesion manifestations, such as shape, location, and signal intensity, on different contrast-weighted (such as T1- or T2-weighted) MRI images are the basis for radiologists to diagnose. The final diagnostic decision is radiologist dependent and subjective to a certain extent . With thTherefore, our study aimed to systematically explore the feasibility of T2 mapping in quantifying common uterine lesions and to compare the performance of T2 mapping in discriminating common uterine lesions between 1.5 T and 3.0 T MRI systems.K is constant, N(H) represents proton density, TR and echo time (TE) are known parameters. Therefore, T2 value can be calculated by mono-exponential fitting according to the above formula, and at least two echoes are needed theoretically. To improve the precision, more echoes are needed to be involved in the calculation. Based on MESE method, the T2 mapping sequence involved 9 echoes on 1.5 T MRI scanner and 8 echoes on 3.0 T MRI scanner in our study, and the additional acquisition time was 4′22″ and 5′15″ for 1.5 T and 3.0 T MR scanner respectively.There are various approaches for T2 mapping, such as multi-echo spin-echo (MESE) method , driven This study was approved by the Institutional Ethics Committee of our hospital, and written informed consent was obtained from all subjects before the examination. A total of 54 healthy subjects and 139 patients with uterine lesions were enrolled in this study from September 2020 to December 2021. Pathological results of each uterine lesion were confirmed after surgical operations.The inclusion criteria for healthy subjects were as follows: 1) childbearing-age healthy women; (2) no obvious lesions of the uterus and ovary through ultrasound examination; and (3) no contraindication for MRI examination. The exclusion criteria were as follows: (1) positive signs of uterus or ovary through MRI examination; (2) severe image artifacts due to intestinal peristalsis, breathing or body movement; and (3) the thickness of the junctional zone was too small (less than 3 mm) to measure. Among all healthy subjects, two subjects were excluded due to the appearance of myoma, while another two subjects were excluded due to severe image artifact and too thin junctional zone (thickness < 3 mm) respectively. Finally, 50 healthy subjects  containing 250 ROIs were included in the study  patients with suspected uterine lesions recommended by clinical gynecologist , and (2) the lesion was found for the first time and did not receive any clinical treatment. The exclusion criteria were as follows: (1) severe image artifacts due to intestinal peristalsis, breathing or body movement; (2) the maximum diameter of the tumor was smaller than 5 mm; (3) myoma with necrosis; and (4) patients with uncertain pathology after operation. Among all patients, 4 patients with severe image artifacts, 2 patients with uncertain pathology, 1 patient with necrotic myoma, and 6 patients with tumors smaller than 5 mm were excluded. Finally, 126 patients  containing 133 lesion ROIs were included in the study  first and then moved to the 3.0 T MRI scanner  to finish the corresponding T2 mapping data acquisition. For patients with uterine lesions, they finished the T2 mapping data acquisition on the above 1.5 T MRI first and then completed the routine contrast-enhanced uterus MRI examinations with an additional T2 mapping sequence on the above 3.0 T MRI scanner. The T2 mapping sequence was implemented before the contrast injection, and all examinations were finished on the same day for each participant. The 13-channel and 16-channel torso phased array coils with their corresponding integrated spine matrix coils were equipped as receivers on the 1.5 T and 3.0 T scanners, respectively.To improve comfort for subjects during scanning, the foot-first supine position was used. The sequences and detailed acquisition parameters on the 1.5 T scanner were as follows: (1) axial T1-weighted imaging (T1WI); (2) T2-weighted imaging (T2WI); (3) fat-saturated T2WI; (4) diffusion-weighted imaging (DWI) with b-values of 0, 50, 800 s/mm2; (5) sagittal fat-saturated T2WI; (6) dynamic contrast enhancement using axial three-dimensional volumetric interpolated breath-hold examination (3D VIBE) sequences at 30 s, 60 s, and 150 s after gadolinium injection; (7) sagittal and coronal 3D VIBE sequences were also acquired at 90 s and 120 s to reveal the lesions. The routine sequences on the 3.0 T scanner were similar to those on the 1.5 T scanner. The detailed acquisition parameters for additional T2 mapping sequences based on the MESE method on these two scanners are listed in Table T2 maps were first calculated from T2 mapping images by monoexponential fitting using a custom code in MATLAB . The T2 data of each participant were then transferred to Advantage Workstation 4.6 . Measurement was carried out on the workstation independently by two experienced radiologists , and the result was the mean value of two measurements.2), junctional zone (size: ~ 100 mm2), external muscle layer (size: 200 mm2), gluteus maximus (size: 500 mm2), and subcutaneous fat (size: 500 mm2), and their T2 values can be obtained from T2 map. Take a 39-year-old healthy subject for example, Fig. n = 21; myoma: n = 32; endometrial polyps: n = 28) and malignant lesions .Taking the axial T2WI images as a reference, the regions of interest (ROIs) were manually delineated on the maximum TE image of the T2 mapping sequence, which has best tissue contrast among all images with different TEs. For healthy subjects, ROIs were placed on the endometrium . Data are expressed as the mean ± standard deviation. The intraclass correlation coefficient (ICC) was used to evaluate the interobserver consistency of the measured parameters. ICC values of less than 0.4, 0.41–0.75, and greater than 0.75 indicated poor, fair, and good agreement, respectively. The Kolmogorov‒Smirnov test was adopted to assess the normality of the data. The differences in T2 values in normal uterine structures and common benign and malignant tumors between different magnetic field strengths were compared by using the Wilcoxon match-pairs signed rank test. The differences in T2 values between common benign and malignant uterine lesions under the same magnetic field strength were also compared by using the Mann‒Whitney U test. The diagnostic efficacy was evaluated by ROC analysis, and AUC, sensitivity and specificity were obtained. The differences in AUCs were compared using the DeLong test.After exclusion, a total of 50 healthy subjects and 126 patients were included in our study. The characteristics of the patients are listed in Table p < 0.05) , followed by endometrium (110.9 ± 6.0 ms), external-myometrium layer (79.3 ± 5.4 ms), gluteus maximus (51.0 ± 4.4 ms), and junctional zone (50.0 ± 4.8 ms) under 1.5 T MRI. Similar results were found under 3.0 T MRI; the mean T2 value in subcutaneous fat was the highest (102.3 ± 3.2 ms), followed by endometrium (96.6 ± 3.5 ms), external-myometrium layer (75.7 ± 2.9 ms), gluteus maximus (44.3 ± 2.5 ms), and junctional zone (47.1 ± 2.5 ms). The T2 values in these tissues under 1.5 T MRI were significantly higher than those under 3.0 T MRI  , followed by cervical cancer , endometrial polyps , adenomyosis lesions , and myoma . The T2 values in these lesions under 1.5 T MRI were significantly higher than those under 3.0 T MRI  (Table p = 0.02).Uterine lesions of the patient group were divided into two subgroups, including the common benign group  and common malignant group . The mean T2 value of the benign group was significantly lower than that of the malignant group (1) Table  under 1.MRI diagnosis is not limited to imaging manifestations, and how to quantitatively evaluate the characteristics of lesions has become a hot research issue –25. The In our study, we found that the T2 values of normal tissues and uterine lesions at 3.0 T were lower than those at 1.5 T  was lower than that of endometrial carcinoma and cervical cancer. Adenomyosis is caused by endometrial glands and stroma invading the myometrium, which was accompanied by old hemorrhage in general. Therefore, the T2 value of adenomyosis integrates the T2 value of the endometrial gland, stroma, myometrium and old hemorrhage. Due to the existence of stroma and hemorrhage, the T2 value of adenomyosis was lower than that of the normal external-myometrium layer .In our study, we also compared the T2 values between benign and malignant tumors preliminarily. The T2 values of benign tumors were significantly lower than those of malignant tumors, which can be explained by their different composition structures. Moreover, the ROC curve comparison of the T2 value in differentiating benign and malignant tumors between 1.5 T and 3.0 T MRI showed that the diagnostic performance of the T2 value under 3.0 T (AUC = 0.94) was significantly higher than that under 1.5 T MRI (AUC = 0.90).This study had several limitations. First, the T2 value of the healthy group was only acquired from women of childbearing age. Therefore, the result of this part could only be the reference to this age group. Second, motion-related artifacts caused by respiration on T2 mapping images influenced the measurements T2 value, especially in 3.0 T MRI in a small number of patients, which were excluded from our study. It was better to consider using a motion-insensitive sequence or motion correction technique to improve the T2 mapping accuracy. Third, we all adopted recommended default acquisition parameters for T2 mapping sequences to ensure the image quality, thus the parameters under two field strengths were not identical, which might cause T2 fitting variance. Future study with exactly the same acquisition parameters under different field strengths should be made to further verify the results. Last, this study only considered cervical cancer and endometrial carcinoma as malignant tumors but did not involve other malignant tumors, such as uterine sarcoma, malignant hydatidiform mole or choriocarcinoma, due to the limited number of cases. And malignant tumors were not further classified according to pathological classification to verify the performance of T2 mapping. Although this preliminary study had the above limitations, the results build a foundation for further quantitative studies regarding uterine tumors.The T2 mapping technique provides an effective tool for quantifying normal uterine tissues, benign and malignant lesions. It can be applied to distinguish between benign and malignant lesions, especially under 3.0 T MRI, offering a new nonenhanced imaging tool for the further quantitative study of uterine tumors.


Cardiac magnetic resonance (CMR) with parametric mapping can improve the characterization of myocardial tissue. We studied the diagnostic value of native T1 mapping to detect cardiac amyloidosis in patients with left ventricular (LV) hypertrophy.One hundred twenty-five patients with increased LV wall thickness (≥ 12 mm end-diastole) who received clinical CMR in a 3 T scanner between 2017 and 2020 were included. 31 subjects without structural heart disease served as controls. Native T1 was measured as global mean value from 3 LV short axis slices. The study was registered at German clinical trial registry (DRKS00022048).p < 0.0001) compared to healthy controls (1225 ± 21 ms), HCM (1266 ± 44 ms) and HHD (1257 ± 41 ms). HCM and HHD patients did not differ in their native T1 times but were increased compared to control (p < 0.01). ROC analysis of native T1 demonstrated an area under the curve for the detection of CA vs. HCM and HHD of 0.9938 (p < 0.0001), which was higher than that of extracellular volume (0.9876) or quantitative late gadolinium enhancement . The optimal cut-off value of native T1 to diagnose CA was 1341 ms .Mean age of the patients was 66 ± 14 years, 83% were males. CA was present in 24 patients, 21 patients had hypertrophic cardiomyopathy (HCM), 80 patients suffered from hypertensive heart disease (HHD). Native T1 times were higher in patients with CA (1409 ± 59 ms, Non-contrast CMR imaging with native T1 mapping provides high diagnostic accuracy to diagnose cardiac amyloidosis in patients with left ventricular hypertrophy.The online version contains supplementary material available at 10.1007/s00392-022-02005-2. Cardiac amyloidosis (CA) in an underdiagnosed infiltrative disorder characterized by the aggregation of misfolded amyloid fibrils in the myocardium with significant impact on morbidity and mortality. The two most common forms of CA are transthyretin (ATTR) and light-chain (AL) amyloidosis. ATTR amyloidosis is a disease of the elderly, its prevalence increases with age. AL amyloidosis is a complication of plasma cell dyscrasia –3. SinceCA is characterized by increased left ventricular (LV) wall thickness. However, increased LV wall thickness is common in the elderly population. Frequent causes are arterial hypertension with hypertensive heart disease (HHD) and aortic stenosis. While aortic stenosis is usually diagnosed by echocardiography, HHD needs to be dissected from less common causes of increased LV wall thickness, such as hypertrophic cardiomyopathy (HCM) and cardiac amyloidosis (CA) .Cardiac magnetic resonance (CMR) tomography characterizes cardiac size, function and morphology. The application of Gadolinium-based contrast is regularly used to detect myocardial scar and interstitial remodeling. The pattern of Late Gadolinium Enhancement (LGE) is characteristic for specific cardiomyopathies and reflects prognosis , 8. MappThe aim of this study was (1) to evaluate the role of native T1 mapping for the differential diagnosis of increased LV wall thickness and (2) to identify specific cut-off values for native T1 time in 3 T CMR to diagnose CA.n = 4), LV dilatation > 60 mm end-diastolic diameter , no final diagnosis (n = 15), without T1 mapping (n = 37) or artifacts  were excluded. In the final analysis, 24 patients with CA , 21 patients with HCM and 80 patients with HHD were included. HCM was defined as increased LV wall thickness on echocardiography or CMR without sufficient explanation by abnormal loading conditions, according to the ESC guideline [n = 19) or bone scintigraphy and blood test for plasma cell dyscrasia [Patients with increased LV wall thickness (≥ 12 mm end-diastole) without myocardial ischemia who were studied on CMR for clinical indication between 08/2017 and 05/2020 were included in the study. Data derived from the institutional CMR database of the University Hospital Leipzig. The study flow chart is shown in Fig. yscrasia . The phywww.drks.de), study ID DRKS00022048.The institutional review board (ethics committee of Leipzig University) approved the study (no. 176/20-ek). Informed consent was not required for this retrospective study. The study was registered at the German clinical trial registry (3). Native and post-contrast T1 mapping in basal, mid and apical short axis slices of the LV was measured using the modified look-locker inversion recovery sequence . Late gadolinium Enhancement (LGE) was assessed at least 10 min after intravenous application of 0.15 mmol/kg body weight Gadobutrol  in a short axis stack using phase-sensitive inversion recovery sequence (PSIR) .CMR was performed using a Philipps Achieva 3.0 Tesla  clinical scanner. The sequence protocol was prefaced of survey images in coronal, sagittal and transversal orientation. Retrospectively gated steady state free precession cine images (SSFP) were acquired in long and short axis orientation of the LV (repetition time (TR), 45 ms; echo time (TE), 1.4 ms; flip angle (FA), 45°; voxel size, 1.7 × 1.7 x 6 mmData were analyzed offline using the Intellispace software  according to the current recommendations . End-diaT1 mapping was measured as a global T1 value from 3 short axis slices  each containing 6 segments before contrast administration. Since the study tested whether non-contrast CMR with native T1 mapping would be appropriate to diagnose CA, mapping was analyzed without the corrections for the presence of LGE. For ECV calculation, regions of interest from native and post-contrast T1 mapping were used after review and correction for motion artifacts as needed.Z score represents a method of standardization of mapping values which related to the mean normal value of the specific scanner and its standard deviation (SD). The formula for calculating z score is z = (a–b)/x, where a is the diagnostic T1 cut-off value for CA, b is the mean T1 from the healthy controls, and x the SD of the control population [pulation .p values were calculated using ANOVA (for continuous variables) with the Tukey test to correct for multiple comparisons or the Chi-square test for categorical variables. Diagnostic accuracy is assessed by receiver operating characteristic curve among patients with increased LV wall thickness.Data analysis is performed using Microsoft Excel and GraphPad Prism. Quantitative data are expressed as mean ± standard deviation or median with 95% confidence intervals, as appropriate. Categorical variables are expressed as numbers and percentages. One hundred twenty-five consecutive patients were included in the study. 31 subjects without evidence of structural heart disease served as control group. Mean age of patients was 66 ± 14 years, 83% were male. Patients with CA were older, had higher NYHA functional class, higher cardiac biomarkers, more impaired kidney function and suffered frequently from atrial fibrillation compared to the other groups. As expected, patients with CA exhibited frequently extra-cardiac comorbidities such as carpal tunnel syndrome, spinal stenosis and polyneuropathy. Of 21 HCM patients, 12 had typical intramural LGE on inferior or anterior RV insertion points or in the inter-ventricular septum which supported the diagnosis [p < 0.0001), indicating advanced concentric LV remodeling (Table p < 0.0001). All patients with CA and 81% of patients with HCM showed LGE. Quantitative LGE was highest in patients with CA (55 ± 32%) compared to HCM (10 ± 9%) and HHD (3 ± 6%) (p < 0.0001). Native T1 times were higher in patients with CA (1409 ± 59 ms) compared to all other groups . Detailed CMR data are shown in Table Both patients with CA and HCM had increased LV wall thickness and LV mass index compared to controls and HHD , quantitative LGE (0.9406 p < 0.0001) and LV mass index . The best cut-off value of native T1 mapping to diagnose CA was 1341 ms with a z score of 4.6. For this cut-off value, sensitivity was 100% and specificity 97.0%. The positive and negative predicted values were 88.9% and 100%, respectively  of 0.9938  Native T1 mapping in patients with increased LV wall thickness who underwent CMR identifies CA with a very high diagnostic accuracy. (B) We identified a cutoff of 1341 ms native T1 time in the 3 T scanner for the diagnosis of CA with a sensitivity of 98% and a sensitivity of 100%. (C) Non-contrast CMR represents a useful tool for a simple imaging approach to patients with increased LV wall thickness who are at risk for CA.99Tc-DPD in combination with blood test for monoclonal protein or endomyocardial biopsy [The diagnosis of CA is currently established by bone scintigraphy using l biopsy , 4. Scinl biopsy , 23, 24.l biopsy . TherefoMany physical factors influence T1 values, such as magnetic field strength . Thus, cZ score mapping has been developed to compare mapping values between different CMR vendors and magnetic field strengths. A recent study demonstrated a similar diagnostic accuracy of z-score mapping compared to native T1 to diagnose CA [z score of 4.6 (corresponding to 1341 ms) for the diagnosis of CA. The higher z-score value in our study compared to others might be attributed to the comparison of patients with other cardiac pathologies, i.e. HCM and HHD, instead of healthy volunteers [gnose CA . Our ROClunteers  or a hetlunteers . Thus, tThis is a monocentric, retrospective study with its inherent limitations. The overall number of 125 patients in the study is a limitation and prohibits further subgroup analyses. The clinical data, derived from the university hospital data warehouse, may be incomplete due to the retrospective nature of the study. Details of potential genetic testing of HCM patients were not available for this study. Hematocrit values for ECV calculation were available in a limited number of patients only because diagnostic workup was performed in the outpatient setting in many patients. Most patients with CA in our study are in an advanced disease stage, indicated by pronounced LV remodeling and LGE. We included consecutive patients with a hypertrophic phenotype who underwent clinical CMR, but a referral bias of outpatients might be present. Therefore, the data require confirmation in patients at early stages of CA.Patients with cardiac amyloidosis showed elevated native T1 times of the LV myocardium compared to those with hypertrophic cardiomyopathy, hypertensive heart disease and healthy control. Native T1 mapping exhibits a high diagnostic accuracy for the diagnosis of CA among patients with increased LV wall thickness. Thus, the study identifies native T1 mapping as a useful method for the diagnosis of CA in patients with LV hypertrophy. The new T1 cut-off data on 3 T CMR provide the basis for prospective clinical trial to evaluate non-contrast CMR with native T1 mapping in patients who are at high risk for cardiac amyloidosis.Supplementary file1 (DOCX 65 KB)Below is the link to the electronic supplementary material.


In the binary logistic regression analysis, the development of MACE 18 months after CABG was associated with the nonconduction of PCI before surgery, the presence of peripheral atherosclerosis, an increase in IVST and Et/e’t and a decrease in LVEF. Conclusions. RV diastolic dysfunction in the preoperative period was associated with the development of MACE within 18 months after CABG, and the ratio Et/e’t was one of the independent predictors of MACE in a multiple regression analysis. This makes it expedient to include an assessment of not only systolic but also diastolic RV function in the preoperative examination. The inclusion of an assessment of RV diastolic function in the pre-CABG evaluation of patients deserves further study.Background. This study aimed to investigate the association of preoperative right heart filling indicators with outcomes after coronary artery bypass grafting (CABG) at an 18 month follow up. Methods. Patients who underwent CABG at a single center were included in this study. In addition to the baseline preoperative indicators and perioperative data, initial parameters of the right ventricle (RV) systolic and diastolic function were assessed. Results. Among the 189 patients, a total of 19 (10.0%) MACE  were recorded during an 18 month follow up. In patients with the development of MACE during the initial examination, the following changes in RV function were revealed compared with the group without MACE: a decrease in the e’t index (8.2 versus 9.6 cm/s,  During myocardial revascularization, the state of the heart chambers, reflecting the degree of damage to the heart muscle, can determine both the tactics of treatment and the prognosis. First of all, in such cases, the state of the left ventricle is considered; for example, a decrease in the ejection fraction indicates a deterioration in the pumping function of the heart and, accordingly, is included in the preoperative risk assessment scales . Other iHowever, the assessment of the right heart in the perioperative period certainly deserves attention. So, it was shown that in the postoperative period in patients after CABG, there is a significant decrease in the function of the right ventricle. This decrease is explained both by the influence of a number of perioperative factors  and by perioperative complications  . As a ruMost often, the investigation of the right heart was performed before cardiac surgery in patients with a low left ventricular ejection fraction ,12. It hA single-center prospective cohort study was conducted at the cardiovascular surgery clinic of the Research Institute for Complex Problems of Cardiovascular Diseases. The initial cohort of 200 patients undergoing coronary bypass surgery was selected for the period from February 2017 to November 2018. The criteria for the inclusion and exclusion of patients in this study were presented in detail in previously published articles ,10. SubsBaseline preoperative indicators were obtained from the electronic database of the CABG registry. We took into account the following indicators: demographic , anamnestic , clinical  and medicine therapy. Additionally, all patients underwent a standard laboratory examination before surgery , ultrasound assessment of extracranial arteries and invasive coronary angiography. Among the perioperative parameters, we took into account the number of shunts, the use of a cardiopulmonary bypass, the duration of CPB, the time of aortic clamping and combined interventions .All patients underwent standard transthoracic echocardiography using a Philips Clear Vue 550 ultrasound scanner (USA) according to modern recommendations ; the stuAdditionally, the diastolic function of the ventricles of the heart was assessed. In the Doppler mode, the parameters of the LV and RV in diastole were studied: the peak velocity of early (E) and late transmitral filling (A) and their ratio (E/A), isovolumetric relaxation time (IVRT), early (Et) and late (At) transtricuspid filling of the RV and their ratio (Et/At). The speed of the early and late diastolic movement of the fibrous ring of the mitral and tricuspid valves and their ratio  and the speed of the systolic movement of the mitral (s’) and tricuspid (s’t) valve rings were assessed. The Tei index for both ventricles was determined.At values of the Et/At ratio within 0.8–2.1, the diastolic function of the right ventricle was considered normal. When the Et/At ratio values were <0.8 or >2.1, and/or the Et/et’ ratio was >6, diastolic RV dysfunction was diagnosed . At the The midterm results of the CABG were assessed after 18 months during patient examination in the clinic or during telephone contact with the patient or his relatives. As adverse outcomes (MACE), the following indicators were analyzed: death, nonfatal myocardial infarction and stroke. Additionally, elective surgeries on the arteries (percutaneous coronary intervention and operations on noncoronary arteries) and any other hospitalizations for cardiovascular diseases were evaluated. For subsequent analysis, patients were divided into 2 groups: those with a favorable prognosis in prospective observation and those with the presence of events .p < 0.05) for all the analyzed variables). To compare the two groups, we used the Mann–Whitney test and the χ2 test. With a small number of observations, Fisher’s exact test was used with Yates’ correction. To identify the factors associated with the presence of unfavorable outcomes  18 months after CABG, we used a binary logistic regression (forward likelihood ratio). For the evaluation of both demographic parameters (gender and age) and baseline clinical and laboratory parameters, we included preoperative echocardiographic results and perioperative variables in the model. The performance of the variables for diagnosing the development of unfavorable outcomes  was evaluated through a receiver operating characteristic curve analysis. The level of critical significance (p) during analysis was equal to 0.05.A statistical analysis was carried out using the standard statistical software packages “STATISTICA 8.0”  and SPSS 17.0 . Qualitative variables were presented as absolute values and percentages, and quantitative variables were presented as medians and quartiles (25th and 75th percentiles) since the distribution differed from normal (the Shapiro–Wilk test (W-statistic) showed a significant departure from normality (n = 170) and with an unfavorable outcome .When evaluating the prospective follow up 18 months after CABG, it was not possible to obtain information on 11 patients. Accordingly, 189 patients were included in the analysis . MACE wan = 146) and an unfavorable outcome (n = 43).Additionally, we evaluated the frequency of elective interventions on the arteries and emergency hospitalization during the observation period: PCI was performed in two cases, operations on the noncoronary arteries were performed in six cases, unstable angina without myocardial infarction was detected in ten patients and rhythm disturbances were detected in six cases. Based on the data obtained, groups were formed with a favorable outcome (p = 0.038) and with symptoms of chronic heart failure in at least the III functional class (p = 0.014). Additionally, some of the differences had borderline statistical significance: in the group with MACE, there were slightly more men (p = 0.052), more often in the anamnesis of myocardial infarction (p = 0.053), and the duration of CPB was somewhat longer (p = 0.053) (= 0.053) .p = 0.027); ESD—4.1 cm and 3.6 cm, p = 0.005; EDV—180.0 mL and 147.0 mL, p = 0.028; and ESV—70.0 mL and 51.0 mL, p = 0.008. These differences can be explained by the greater predominance of men in the MACE group and the higher incidence of old myocardial infarction; they were also accompanied by a decrease in EF  and an increase in ESVi  in this group. At the same time, there were no differences between the groups in parameters of the LV diastolic function.The initial dimensions and volumes of the left ventricle in the MACE group were higher than in the group without MACE : the mede’t index was lower  and the Et/e’t ratio was higher . As a result, although the overall incidence of RV diastolic dysfunction did not differ in the groups, pseudonormal filling was significantly more often detected in the MACE group (p = 0.03). These data indicate more pronounced initial disorders of the RV filling in the group with the presence of MACE.The initial indicators of the systolic function of the right ventricle in the groups did not differ . Additiop = 0.019), they took aspirin less often (p = 0.011) and had higher values of the LV wall thickness. Accordingly, signs of LV diastolic dysfunction were more pronounced in this group than in patients with favorable outcomes . Initial indicators of the right heart in the groups with a favorable and unfavorable outcome did not differ.When comparing groups with an unfavorable outcome  and with a favorable outcome , the difp = 0.001. The model explained 29.9% (Nagelkerke R2) of the MACE developmental variance and correctly classified 89.7% of cases. An unfavorable outcome 18 months after CABG was significantly (χ2(2) = 28.18, p = 0.005) associated with the presence of III FC according to NYHA, the presence of arrhythmia, an increase in IVST and not taking aspirin (2) of the MACE developmental variance and correctly classified 80.3% of cases.When conducting a binary logistic regression analysis, the development of MACE 18 months after CABG was associated with the nonconduction of PCI before surgery, the presence of peripheral atherosclerosis, an increase in IVST and Et/e’t and a decrease in LVEF . The log aspirin . The modThe association of the initial parameters with the development of MACE is presented in The present study assessed the possible prognostic value of right ventricular diastolic dysfunction during a follow up of patients after CABG. We were able to show that in addition to the clinical parameters  and echocardiographic parameters of the left ventricle (IVST and LVEF), the parameters of the RV filling (Et/e’t ratio) had an independent effect on the development of MACE within 18 months after CABG.p = 0.045) [p = 0.034) [It has previously been shown that RV systolic dysfunction before cardiac surgery is associated with poor prognosis. Thus, in a multicenter prospective study involving more than 900 patients, it was shown that the preoperative assessment of systolic function and RV dimensions can significantly improve the prediction of in-hospital mortality during heart surgery compared to the isolated evaluation Euroscore II scale  . In valv= 0.045) . Moreove= 0.045) . With is= 0.045) . Additio= 0.034) . The abo= 0.034) . Therefop = 0.015) [There have been few such studies to date. Thus, in a cohort of patients with low LVEF (<35%) undergoing CABG, a significant increase in preoperative Et/e’t ≥10 and the absence of suitable target bypass arteries were significantly associated with 30-day postoperative mortality . In a re= 0.015) ,22.Currently, the standard perioperative risk assessment for cardiac surgery does not include preoperative measures of right ventricular function. This is explained primarily by the fact that the routine assessment of RV function is not included in the scope of the preoperative examination. The studies of recent years that we cited above and the reviews ,24 emphaWhen evaluating the results of this study, a number of its limitations should be taken into account. First, this study was conducted in a single center, so the applicability of its results to other patient cohorts has not been proven. Secondly, we took into account only preoperative echocardiographic parameters, but did not take into account their changes immediately after surgery, although it is a decrease in RV function that is more often detected in the postoperative period. To overcome this limitation, we took into account perioperative indicators that could affect the deterioration of RV function in our binary logistic regression model; they did not affect the incidence of MACE. Thirdly, we did not use some modern methods for evaluating RV function (speckle tracking and 3D echocardiography). As clinical practice shows, they are still rarely used ; in addiOur study showed that the development of MACE  within 18 months after CABG was associated with such independent factors as the presence of peripheral atherosclerosis, a history of non-PCI, an increase in the thickness of the interventricular septum, a decrease in LVEF and an increase in the ratio Et/e’t. The latter indicator characterizes the RV diastolic dysfunction in the preoperative period. This makes it expedient to include an assessment of not only the systolic but also diastolic RV function in the preoperative examination.


Anthracycline chemotherapy carries a risk of myocardial dysfunction and heart failure even at relatively low doses, and the clinical prediction of cancer treatment-related cardiac dysfunction (CTRCD) is inexact. Careful imaging or biomarker surveillance during chemotherapy can identify CTRCD before the development of heart failure. Currently, this surveillance is performed using ejection fraction (EF). While this is a reliable and reproducible test with three-dimensional techniques, the most widely used imaging technique is two-dimensional echocardiography, for which EF measurements have broad confidence intervals.The use of global myocardial strain (GLS) provides a more reliable and reproducible means of assessing global cardiac function and shows meaningful changes before a significant change of EF. Observational studies have shown that although absolute measurements of GLS, both at baseline and during therapy, are predictive of CTRCD risk, the most reliable approach is to assess the change of GLS with therapy — a meaningful relative change of 10–15% being significant. A clinical trial comparing GLS to EF surveillance did not show a significant change of EF in the overall study group, but did show that patients managed with a the GLS-guided approach were less likely to develop a meaningful change of cardiac function to an abnormal level. In at-risk patients, there is good evidence for the protective value of neurohormonal antagonists and statins: the use of GLS enables these benefits to be directed to those most likely to benefit, while minimizing their use in the majority of people, who do not need them.Although GLS requires an element of training and efforts to ensure uniformity, it has proven to be a feasible, robust, and reproducible technique, ready for wide adoption. The increasing survival from cancer is leading to a huge cohort of cancer survivors . Among tThe condition that we are seeking to avoid is the development of HF in cancer survivors. While this may occur acutely, it is more commonly detected years after chemotherapy. Of course, awaiting the clinical presentation of HF is not a prudent approach to this diagnosis, because it takes so long to develop and because the patients at that stage have disease that is too far advanced make a therapeutic impact. Consequently, the definition of CTRCD is based upon a meaningful drop of ejection fraction  to below the normal range, albeit with some differences in exact definitions .The cause of LV dysfunction in cancer patients is inherently multifactorial, with significant contributions from not only chemotherapy, but also risk factors that are shared between cancer and cardiac disease . NonetheCTRCD may arise from exposure to cytotoxic agents or biological agents. While the classification into types I and II cardiotoxicity, respectively, has been criticized as being too simplistic, it has some value. CTRCD from biological agents is usually reversible, and uncommon — most studies suggest frequencies of 2% with lapatinib, imatinib, trametinib, and bevacizumab, although up to 11% is reported with sunitinib, and up to 27% with trastuzumab , possibl2 [A Bayesian approach is necessary whenever imaging is used in risk assessment, and patients over the age of 65, those with previous anthracycline use and radiotherapy, those with coronary or other heart disease, and hypertension are particularly at risk of developing anthracycline-related cardiotoxicity . Paradox2 . The use2 , 10.The fundamental need for HF surveillance in this group is a solution that will work in large numbers of people (which has implications for cost and availability), at a high level of accuracy (taking note of the risks of misdiagnosis), at a high level of test-retest consistency, and irrespective of differing baseline risk. Three successive stages precede the development of HF — an initial phase where the causative pathway is identified, abnormal myocardial deformation, and asymptomatic LV dysfunction Table . The usereduction of EF to below the normal range, and there are challenges to both defining normal and defining reduction. The ability to interpret change can be confounded by alterations of loading conditions, implying that it may change despite the presence of stable myocardial function if BP changes in the course of serial follow-up. High and low heart rate, mitral regurgitation, and left bundle branch block all provide technical challenges.Ejection fraction (EF) is part of the current definition of CTRCD, and is uniformly referenced in the guidelines , 11. HowTwo-dimensional echocardiography is the most widely used technique for surveillance, and calculations of LV volumes using this technique are dependent on geometry, with changes from one visit to the next being influenced by different imaging planes. These relatively common differences in imaging planes lead to wide confidence intervals for the detection of sequential changes — absolute EF differences of up to 10% cannot be attributed to a change of myocardial status and may simply reflect measurement variation . The defEF may be calculated without geometric assumptions when a full 3-D data set is obtained, most commonly using 3D echocardiography or cardiac magnetic resonance. In contrast to the 10% confidence intervals of 2D echo, a meaningful change of 3D-EF is 5–6% . HoweverEF is widely assessed at baseline in patients undergoing anthracycline chemotherapy, with a recent data-linkage of chemotherapy for breast cancer with administrative data showing its use in > 85% at baseline. In contrast, only about 50% of patients have an echocardiogram performed during follow-up, and fewer than 50% have monitoring is recommended in guidelines , 17.Myocardial strain measures the magnitude of deformation of a defined length of myocardium during each cardiac cycle, referenced to the original length. Because the myocardium shortens, this is classically described as a negative number, but when strain is averaged in all myocardial segments , it is always negative, and therefore can reasonably be expressed without a negative sign  . This ceThe initial calculation of strain was performed using color tissue Doppler, which provided high temporal resolution, but had the disadvantage of being susceptible to noise, dependent on alignment with the Doppler beam, and being quite challenging to measure. However, the development of speckle strain, now two decades ago, has made the assessment of strain more feasible, reliable, and reproducible. Initial problems relating to inconsistencies of measured GLS by different machines, attributable to different methods of post-processing between manufacturers, have largely been addressed following a concordance process. The variability of strain between systems is now analogous to the variability of other common measurements such as LV dimensions •. A numbGLS has a well-defined learning curve, and is easy to learn, requiring a minimum of 50 patients to achieve expert competency (intraclass correlation coefficient > 0.9) in groups with varying levels of baseline skill over a period of 3 months . Other sIn addition to the true error of the measurement, sources of variation may arise from patient characteristics , equipment (image acquisition and post-processing), and technical limitations on the part of the observer (particularly related to experience). The use of strain as a reliable physiologic marker is dependent on attention to detail. Imprecision in tracing the region of interest, inadequate tracking, failure to exclude the pericardium, and annulus are all potential source of variability and will lead to underestimation of GLS . As GLS The process of establishing strain in an echocardiography laboratory should start with a concordance process between the personnel doing the measurements. Although different laboratories may show minor but important differences in strain measurements , once coA number of observational studies concerning the use of myocardial deformation have been reported over the last decade. The reliability of these for detecting CTRCD was reviewed in a recent meta-analysis ••. ImpaiBecause of the tighter confidence intervals of GLS compared to EF, earlier changes of myocardial function may be detected with GLS. Very often, this means that GLS is a window to subsequent change of EF, effectively providing an opportunity for earlier, and thereby hopefully more effective intervention.p = 0.02). This was primarily because 44 of 154 in the strain-guided group developed an abnormal response and were initiated on cardioprotective therapy, compared to 20 in the EF-guided group. The EF change in the 44 cardioprotection-treated, GLS guided patients was only 2.9%, compared to 9.1% in the EF-guided group, consistent with later (and therefore less effective) initiation of therapy.Nonetheless, it needs to be acknowledged that it is hard to prove prognostic benefit of one cardioprotective strategy, compared to others. In the SUCCOUR trial, 331 patients were randomized between GLS guided and EF guided cardiac surveillance •. Both gDiastolic dysfunction is a common manifestation of myocardial injury from various causes and can reasonably be expected to be a potential marker of CTRCD. Indeed, in a 2-year follow-up of 362 breast cancer patients, Upshaw et al. showed persistent worsening of diastolic function  . AbnormaAbnormal brain natriuretic peptide or high-sensitivity troponin have been reported with CTRCD and would certainly be more feasible than imaging for surveillance. Unfortunately, the levels of these biomarkers are also quite variable, implying that sampling has to be done at exactly the right time in order to identify myocardial injury. Moreover, not only cardiotoxicity but also other circulatory stress may lead to release of these biomarkers. Thus, while proposed as a potential cornerstone of surveillance , their rThe most reliable assessment of LV volumes and ejection fraction is obtainable with CMR, and this has been shown to be effective in predicting outcomes . The varThere are two potential responses to an abnormal test — initiation of cardioprotection, or modifying or interrupting cardiotoxic therapy. The latter is very much a last option because it may have a detrimental effect on treatment of the cancer, and is rarely required unless the patient has developed overt heart failure or other steps have failed.Four groups of medications have been used for cardioprotection. Dextrazoxane has been known to have a cardioprotective effect during anthracycline chemotherapy for nearly 50 years, but its uptake has always been impeded by concerns that it may limit the efficacy of anthracyclines, and thereby inhibit successful cancer remission. While its activity was traditionally attributed to protection from oxidative stress (through iron chelation), it seems more likely that its efficacy pertains to differential expression and/or regulation of topoisomerase II isoforms in cardiac and cancer cells, leading to the selective modulation of anthracycline action . BecauseIn a systematic review of 25 studies with neurohormonal blockade using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers, Elghazawy  showed sThe third group of agents that have been shown to be effective are statins, which are thought to limit the oxidative stress through which anthracyclines mediate cardiotoxicity. A recent meta-analysis of six studies  showed aThe final class of cardio-protective treatments are modern heart failure drugs such as Entresto and SGLT2 inhibitors, but this evidence base is small and not yet ready for routine use.The use of GLS surveillance is based on a fundamental decision to pursue selective rather than universal cardioprotection. A number of medications — angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-adrenoceptor blockers and statins — have proven benefit in the prevention of cardiotoxicity. The use of cardioprotection in all patients at risk would be simpler than an imaging-based approach, and it avoids concerns about timing, test accuracy, and interpretation. However, the fundamental problem is that such an approach is dependent on acceptance that 80% of patients would receive this treatment unnecessarily, as cardiotoxicity develops in < 20%. In the placebo groups of randomized controlled trials, the average change of EF — while variable — is most commonly < 5% . DecisioIf a selective (image-guided) strategy is used, there is some time urgency in the response to an abnormal imaging surveillance test. In a study of over 200 patients with anthracycline related CTRCD, Cardinale reported 64% to respond to ACE inhibitors and beta-blockade administered within 2 months, < 30% to respond to treatment administered between 2–4 months, and < 10% to respond to treatment provided thereafter . This reAnthracycline chemotherapy continues to carry a risk of myocardial dysfunction and heart failure. While neurohormonal antagonists and statins reduce the risk of cancer treatment-related cardiac dysfunction (CTRCD), the frequency of this problem is too low to justify the uniform use of these cardioprotective therapies. Consequently, most centers use a risk-guided strategy of cardioprotection — most commonly using 2D-EF. The problem is that 2D-EF measurements have broad confidence intervals, so substantial changes are required to designate the presence of LV dysfunction. GLS provides a more reliable and reproducible means of assessing global cardiac function, and observational studies and a randomized trial have shown the most reliable approach is to use a 10–15% relative change of GLS with therapy. GLS is a feasible, robust, and reproducible technique that requires limited training and is ready for wide adoption.


Newer approaches in transcatheter tricuspid valve replacement (TTVR) have recently showed optimistic data of efficacy and safety in patients at high risk for surgery. However, the absence of residual regurgitation (and subsequently higher likelihood for developing afterload mismatch) with TTVR compared with transcatheter tricuspid valve intervention may become a critical concern if RV dysfunction is misdiagnosed. Indeed, such sudden increase in afterload on the right ventricle (RV) may not be tolerable, resulting in higher risk of acute right heart failure in the early postoperative period. In this context, strain imaging may find a further application to provide a more comprehensive stratification of the severity of RV dysfunction and thus help to better define the eligibility criteria and timing for TTVR. Meanwhile, it is of paramount importance to underline the contribution given by the Trivalve study on the understanding of the role of RV function in TTVI, that so far was largely undefined, being evaluated only in small noncontrolled cohorts. Significant tricuspid regurgitation (TR) is currently the fourth most frequent isolated valvular disease and is often found in association with other valvular defects.Eurointervention.P = .031), with a clear benefit in terms of reduced mortality in case of successful intervention (P = .007). With respect to the relationship between RV function and TTVI, the subgroup with mid‐range reduction in RV function showed a better survival compared to groups with preserved and reduced RV function (P = .004). Upon multivariate analysis, only procedural success  and EuroSCORE II  remained independent predictors of an adverse outcome in TTVI population. Some limitations are reported from the authors: the lack of randomization was partially corrected by matching with the use of a propensity score, making the population more homogeneous than previous similar studies. Nevertheless, such an approach does not fully protect from unidentified confounders. The cohort also included patients with significant mitral regurgitation treated with transcatheter mitral valve intervention at the same time of the tricuspid repair while the same patients in the control group were excluded. The control group therefore missed an entire population of patients at higher risk of RV dysfunction and post‐repair TR recurrence. Similarly, also patients with congenital TR were not included in the cohort. As a further limitation, rate of rehospitalization for heart failure or improvement in functional class was not evaluated. Such data would have been useful both to better understand the reasons underlying the improvement of prognosis of the group with mid‐range RV dysfunction and to better delineate the effect of TTVI in patients other than mid‐range RV dysfunction. Figure Recently, the results of the largest study investigating the 1 year outcome of TTVI in relation to different degrees of RV function were published in These results may contrast with what reported by Miura et alFinally, newer approaches in transcatheter tricuspid valve replacement (TTVR) have recently showed optimistic data of efficacy and safety in patients at high risk for surgery.None.1


To analyze the preoperative predictive value of retinometer visual acuity (VA) in eyes following Descemet membrane endothelial keratoplasty (DMEK).Patients undergoing DMEK between August 2011 and July 2020 were included. Preoperative interference visual acuity was assessed using Heine Lambda 100 Retinometer. Depending on the presence or absence of concomitant ocular disease, the Retinometer was evaluated for its ability to preoperatively predict best-corrected visual acuity (BCVA) six months after surgery using correlation, simple and multiple linear regression, contingency analyses, and receiver operating characteristic (ROC) analysis. Preoperative corneal backscatter was correlated with Retinometer prediction accuracy.r = 0.647, P < 0.001). Regardless of the presence or absence of concomitant ocular disease and the surgery procedure (DMEK & triple DMEK), Retinometer VA was the most significant predictor of postoperative BCVA (P < 0.001). ROC analysis revealed reliable diagnostic performance of the Retinometer . A Retinometer VA ≥ 0.5 accurately predicted a postoperative BCVA ≥ 0.5 in 91% of cases. No association was found between corneal backscatter and prediction accuracy (P = 0.566).A total of 198 eyes were included in the analysis. There was a significant correlation between Retinometer VA and postoperative BCVA (Retinometer VA can be used for preoperative prediction of postoperative BCVA in DMEK and triple DMEK patients, independent of increased backscatter values and the presence or absence of concomitant ocular disease. By using this simple but effective tool, indication for DMEK can be facilitated and postoperative outcomes can be realistically predicted preoperatively.The online version contains supplementary material available at 10.1007/s00417-022-05605-w. Since its introduction in 2006 , DescemeWhen surgeons decide to perform DMEK, they and their patients are highly interested in the expected postoperative visual outcome, especially in the presence of concomitant ocular disease. Preoperative measurement of BCVA determines visual acuity status, which is influenced by concomitant ocular disease such as media opacities.For this purpose, preoperative measurement of interference visual acuity (VA) can be used. The optical principle of interference VA is the projection of two coherent light beams into the eye, creating a striped pattern on the retina. This allows assessment of retinal resolving power in isolation , 9, largPrevious studies have investigated the prognostic relevance of interference VA in cataract patients without –15 and wThe extent of corneal decompensation as detected by corneal density measurements may interact with interference VA, as increased corneal backscatter values have been found in patients with Fuchs endothelial dystrophy (FED) at all stages of disease .The purpose of this study was to evaluate the accuracy of interference VA in patients undergoing DMEK and to identify cutoff values that preoperatively predict DMEK outcome. Furthermore, the effect of corneal decompensation and presence of concomitant ocular disease on the accuracy of interference VA measurement were investigated.Retrospective interventional case series.n = 69).Data from patients receiving DMEK at the Department of Ophthalmology, University of Leipzig Medical Center, Germany, between August 2011 and July 2020 was reviewed. Retrospective data was collected until December 2018, with Retinometer VA documented in 212 cases. Since January 2019, the study was continued prospectively by systematically measuring interference VA in all DMEK patients  according to the technique published by Melles  and modiInterference VA measurements were performed using Heine® Retinometer , a hand-held device based on the principle of light interference. The device shows a spot of light projecting a circular interference pattern of alternating black and red stripes onto the patient’s retina , 19. BotPreoperative central corneal thickness (CCT) and corneal backscatter in grey scale units (GSU) of the central annular zone at 0–2 mm from anterior corneal layer  were meaExclusion criteria were intraoperative and postoperative complications that, in the surgeon’s judgment, affected postoperative VA. Furthermore, subjects with inadequate cooperation or comprehension problems during Retinometer measurement leading to unreliable interpretation of data were excluded.Concomitant ocular disease was classified into five categories: 1) anterior segment pathology relevant to VA, (2) central fundus and vitreous body pathology relevant to VA, (3) glaucoma and other optic nerve defects, (4) amblyopia and non-organic visual loss, and (5) ocular conditions not relevant to VA. Patients with nonorganic vision loss were defined as deterioration of vision despite normal ophthalmologic examination including electrophysiologic testing. Patients were classified accordingly, with patients without concomitant ocular disease assigned to category 5. Multiple assignments within the first four categories per patient were possible. Allocations of each ocular pathology to the five categories are presented in Online Resource Table  anteriorIn order to analyze Retinometer prediction accuracy, eyes were categorized as in previous Retinometer studies : underesAs described by Rassow et al. , a postoData was analyzed using SPSS® . The scatterplot was created with R . If data from a patient’s right and left eyes were eligible, one eye was randomly selected according to the recommendation of Armstrong et al. , in ordeRetinometer prediction accuracy was defined as BCVA minus Retinometer VA. The proportion of variance explained (PVE) in postoperative BCVA rank by Retinometer VA rank and concomitant ocular disease categories was computed following Shim et al. .r ± 0.70), moderate (r ± 0.50), or weak (r ± 0.30), depending on which value r was closest to. Simple and multiple linear regressions were performed to assess the predictive value of the independent variables Retinometer VA and individual concomitant ocular disease. Diagnostic performance was evaluated by using receiver operating characteristic (ROC) analysis to calculate the area under the curve (AUC). The higher the AUC, the more accurate the test. Sensitivity, specificity, positive (PPV), and negative predictive value (NPV) were calculated. Sensitivity indicates the percentage of patients with BCVA ≥ 0.5 for whom the Retinometer indicated VA ≥ 0.5. Specificity indicates the percentage of patients with BCVA < 0.5 for whom the Retinometer indicated VA < 0.5. The PPV represents the patient percentage with a Retinometer VA ≥ 0.5 that had a BCVA ≥ 0.5. The NPV states the percentage of patients with a Retinometer VA < 0.5 who had a BCVA < 0.5.We performed descriptive analysis and Fisher’s exact test for analysis of categorical variables. Correlations were performed using Pearson coefficient r. Analogous to the interpretation in Schaub et al.  correlatP < 0.05.The level of significance was defined as n = 206, r = -0.554, P < 0.001) between corneal thickness and Retinometer VA rank. Outliers within the normal distribution of corneal thickness were identified in corneas more than twice as thick than the average of 550 µm. To avoid statistical bias, only eyes with corneal thickness values ≤ 1100 µm (n = 198) were included for further analysis.A total of 281 eyes were examined. Afterwards, one eye was randomly selected in subjects for whom data were available from both eyes. There was a moderate negative correlation . Retinometer VA rank correlated significantly with BCVA rank both in DMEK alone and triple DMEK . Comparison of postoperative BCVA rank and preoperative Retinometer VA rank is displayed in Fig. There was a moderate positive correlation between Retinometer VA rank and BCVA rank  and (4) amblyopia and non-organic visual loss . Within the category (2) central fundus and vitreous body pathology relevant to VA  and (3) glaucoma & other optic nerve defects , there was a moderate correlation.Within each category of existing concomitant ocular disease, there was a strong correlation between Retinometer VA rank and BCVA rank: (1) anterior segment pathology relevant to VA .There was no significant correlation between prediction accuracy and corneal backscatter  or absence of concomitant ocular disease .Simple linear regression models showed that Retinometer VA rank was a significant predictor of BCVA rank, independent of the presence  showed all variables as significant predictors of postoperative BCVA rank. Among all variables, the proportion of variance in the rank of BCVA was most significantly explained by the rank of Retinometer VA .A multiple linear regression analysis incorporating Retinometer VA rank and the four categories of existing concomitant ocular disease as potential interacting predictors of postoperative BCVA rank (P < 0.001) and is displayed in Fig. The ROC curve assessing diagnostic performance for discriminating between postoperative BCVA ≥ 0.5 and < 0.5, respectively, had an AUC of 0.829 , with a sensitivity of 77.7% and a specificity of 70.7%. If the Retinometer predicted VA ≥ 0.5, BCVA was ≥ 0.5 in 91% of cases (PPV). However, in 45.3% of patients with a Retinometer VA < 0.5, the postoperative BCVA was < 0.5 (NPV). In only 8.96% of cases, postoperative BCVA was < 0.5 despite a Retinometer prediction of VA ≥ 0.5.The significant association between Retinometer VA ≥ 0.5 and BCVA ≥ 0.5 was confirmed using Fisher’s exact test (P = 0.017), VA relevant changes of the central fundus and vitreous body (P < 0.001), and glaucoma and other optic nerve defects (P < 0.001), but not within the category amblyopia and non-organic VA loss (P = 1.00).There was a significant association between Retinometer VA ≥ 0.5 and postoperative BCVA ≥ 0.5 within the comorbidity categories anterior segment pathology relevant to VA . If Retinometer VA is good, the indication for DMEK can be given without hesitation and with prospect of positive outcome. In only 45.3% of patients with Retinometer VA < 0.5, postoperative BCVA was < 0.5 (NPV). This indicates that if Retinometer VA is poor, the patient may still benefit from surgery. Accordingly, surgery should not be rejected purely based on poor Retinometer VA. This observation supports the assumption that the Retinometer may tend to moderately underestimate postoperative VA, meaning that in clinical practice, postoperative BCVA is mostly as good as or even better than the predicted Retinometer VA.Because predicted VA was higher than the actual postoperative BCVA in only 8.96% of the cases, there is little concern about a potentially disappointing overestimation of postoperative VA through the Retinometer.A limitation of this study is that Retinometer measurements were performed in the retrospective cases only if the indication for DMEK was controversial. Prospective data of all subsequent DMEK patients collected was able to mitigate this selection bias. There might be several reasons why the correlation coefficient of 0.647 has only moderate strength. Both measurement methods are subjective and rely on the correct collaboration with the patient. There was no averaging of the values by repeated measurements. Furthermore, Retinometer is not capable of measuring precisely the same metric values as in BCVA measurement, but only certain levels. Categorization was used to reduce this bias.In addition, the numbers of cases within each comorbidity category, especially in amblyopia and non-organic visual loss, and the number of corneal backscatter values were relatively low. Due to this fact, a prospective study with higher case numbers would be desirable. Another limitation is the potentially low generalizability of the study results due to the study cohort predominantly consisting of patients with Fuchs endothelial dystrophy.In conclusion, this study demonstrates the prognostic relevance of preoperative Retinometer VA for postoperative BCVA six months after DMEK. The Retinometer can be used even in the presence of concomitant ocular disease. Therefore, the Retinometer is a valuable tool for facilitating the indication for DMEK, for avoiding unnecessary surgery, and for setting realistic preoperative outcome goals.Supplementary file1 (DOCX 18 KB)Below is the link to the electronic supplementary material.


The prevalence of left ventricular (LV) thrombus formation following percutaneous mitral valve edge-to-edge repair (TMVR) with the MitraClip system is unclear. Decreased total stroke volume and perfusion of the LV apex after mitral valve repair may facilitate thrombus formation especially in the context of reduced LV function. LV thrombus may cause disabling stroke or other thromboembolic events in this elderly and multimorbid patient cohort. Analyses of the prevalence of and risk factors for left ventricular thrombus formation in patients treated with the MitraClip system due to severe mitral valve regurgitation. All discharge and follow-up transthoracic echocardiographic examinations up to 6 months of 453 consecutive patients treated with the MitraClip system were screened for the presence of LV thrombus. Prevalence of LV thrombus formation was 1.1% (5/453). Importantly, LV thrombi were exclusively found in patients with severely depressed left ventricular systolic function (LV-EF < 30%), comprising a prevalence of 4.4% in this subgroup (5/113). Importantly, two of these patients were under active DOAC therapy with Rivaroxaban and Apixaban, respectively. Apart from LV-EF, we did not identify other factors that might have facilitated LV thrombus formation. LV thrombus formation following percutaneous mitral valve repair occurred exclusively in patients with severely depressed LV-EF. As two patients developed LV thrombus despite of DOAC therapy, anticoagulation with a Vitamin K antagonist should be considered in patients with an indication for oral anticoagulation following TMVR. The presence of left ventricular thrombus is associated with a high risk of MACE and mortality4. Optimal therapy of left ventricular thrombus is still under debate. Whereas the use of Vitamin K antagonists is first-line therapy in most centers, small studies and case reports have demonstrated that direct oral anticoagulation (DOAC) therapy might be an alternative6. Percutaneous mitral valve therapy has become a valuable treatment option in patients with HFrEF and severe, mainly functional, mitral regurgitation (MR)7. Consequently, current guidelines advocate edge-to-edge repair of the mitral valve (TMVR) in selected patients8. This therapeutic approach leads to alteration of LV inflow through the newly created double or triple orifice and may interfere with the laminar perfusion of the LV apex, which is already impaired in the context of reduced left ventricular systolic function9. Based on these considerations, the formation of an apical LV thrombus may be facilitated after edge-to-edge therapy.LV thrombus formation in patients with heart failure with reduced left ventricular (LV) ejection fraction (HFrEF), especially in the context of a dilated left ventricle, is a known complication with a prevalence up to 19% in this patient subgroup10. In this study, LV thrombus formation was found in approximately 20% of patients with severely depressed LV ejection fraction (in this study not guideline-conform defined as LV-EF < 20%). Thus, prevalence of LV thrombus formation in the context of mitral valve edge-to-edge therapy is unclear. Aim of this study was to evaluate the prevalence of LV thrombus formation following mitral valve edge-to-edge therapy at a high-volume center in Germany, to identify risk factors and to assess the effectiveness of the post-procedure anticoagulation regimens.So far, only one case series with three patients has provided some insight regarding the development of LV thrombus formation in patients treated with the MitraClip system (MC)We conducted a single center observational retrospective all-comers study of all consecutive patients treated with the MitraClip system between 11/2010 and 10/2017. All patients were discussed in a multi-disciplinary heart team prior to the procedure.11. In our center, every patient was invited for outpatient visits including echocardiography after one, six- and twelve-months post-procedure.Patients were screened for the presence of LV thrombus in post-procedure transthoracic echocardiography (TTE) or early post interventional TTE examinations (up to six months post-procedure). If a LV thrombus was found, pre-procedure TTE were screened to exclude patients with preexisting LV thrombus. If a structure potentially representing a thrombus was found but the diagnosis was uncertain, or if left ventricular images were suboptimal, contrast echocardiography was performed to differentiate between thrombus and trabeculation according to current guidelinesBaseline characteristics, procedural measurements, as well as echocardiographic data prior and after MitraClip procedure were collected. These included LV dimensions, LV ejection fraction, mitral valve opening area, grade of mitral regurgitation, mitral valve gradient and sphericity index. Echocardiograms were obtained in the left lateral decubitus position under continuous ECG recording with a Philips IE 33 or a GE Vivid E95.Routine dual antiplatelet therapy (DAPT) with aspirin and clopidogrel was administered following MitraClip procedure for one month and aspirin monotherapy for an additional 5 months. In patients with an indication for oral anticoagulation, their initial anticoagulation therapy without any supplementary medication was continued.This is a retrospective analysis of a cohort that was approved by the local ethic committee  and was conducted according to ICH-GCP standards and the declaration of Helsinki. The need for a written informed consent was waived by our local ethic committee  due to the retrospective character of the study. The datasets used and analyzed during the current study are available from the first author upon request.p < 0.05. Figures were created with BioRender.com.All data are expressed as mean values ± SD . Statistical analyses were performed using Fisher´s exact test. Statistical significance was defined as 453 patients were included in the analyses Table . Median We identified LV thrombus formation in five patients, corresponding to a prevalence of 1.1% (5/453). All patients with LV thrombus diagnosis had severely depressed LV-EF, no LV thrombi were identified in the subgroup of patients with LV-EF ≥ 30%The prevalence of diagnosed LV thrombus in the cohort with LV-EF < 30% was 4.4% (5 of 113 patients) and obviously statistically significantly higher than in patients with EF ≥ 30% (p < 0.0001). Consequently, we carried out further analyses with the two subgroups divided by a LV-EF of 30%. Baseline characteristics of the subgroups is given in Table 2, Table As we found LV thrombi only in patients with LV-EF < 30%, this subgroup was subjected to further analyses Fig. . The groIn the subgroup of patients with LV-EF < 30% that did not develop LV thrombus (n = 108), a total of 70 patients (64.8%) received oral anticoagulation therapy. Among these, the majority  was treated with a Vitamin K antagonist, whereas 20 patients were on a DOAC. One patient with an indication for oral anticoagulation did not take any anticoagulation therapy at all due to a history of bleeding. Importantly, two out of the five patients with thrombus diagnosis were under oral anticoagulation therapy with a DOAC, either Apixaban ) or Rivaroxaban (history of deep venous thrombosis). Two patients had a history of cancer but were in remission without evidence of active disease, so that there was no indication for continuation of oral anticoagulation therapy 12. The numbers we found (LV thrombus in 4.4% of patients with severely depressed LV-EF) are higher, therefore suggesting that mitral valve edge-to-edge repair increases the already increased risk of LV thrombus formation in this cohort.Left ventricular thrombus formation following the MitraClip procedure is a rare complication and was clearly associated with severely reduced left ventricular systolic function in our study. In the subgroup with LV-EF < 30%, five patients were identified  as being newly diagnosed with LV thrombus 1–5 months after the procedure. While the prevalence of left ventricular thrombus formation in patients with reduced left ventricular function is controversial in older reports with a small sample size13. Even in patients without transcatheter mitral valve repair (TMVR) and LV thrombus, the ideal therapeutic strategy is unknown as contradicting studies have been published recently16. In our cohort, two bleeding events were observed under Vitamin K therapy. However, both of them occurred during the bridging of Vitamin K antagonists with heparin. This observation once more demonstrates that bridging dramatically increases the risk of bleeding, especially in patients with risk factors. Therefore, bridging therapy should only be applied in selected cases17. We believe that due to the evolvement of LV thrombi despite ongoing DOAC treatment and the high inherent thromboembolic risk of this diagnosis, the switch to a Vitamin K antagonist should be strongly considered after TMVR. Importantly, the INR needs to be closely monitored, and heparin bridging  should be applied very cautiously, if at all.We observed two cases of thrombus formation under direct oral anticoagulation (DOAC) therapy with Rivaroxaban or Apixaban, respectively. Whereas the exact reasons for thrombus development under DOAC therapy are unknown, effectivity of DOACs may be reduced in these patients with multimorbidity, as factors such as impaired renal function and altered body mass index may interfere with optimal effectivity of the drug. These cases led us to change the standard operating procedure at our center in a way that in patients with an indication for oral anticoagulation and with LV-EF < 30%, Vitamin K antagonists are routinely used following MitraClip, even when DOAC therapy was administered before. This change of strategy has drawbacks as several DOAC approval studies in atrial fibrillation showed significant advantages in terms of bleeding rates in comparison to Warfarin7—most of the left ventricles would have been too large (LVEDD > 70 mm) or ejection fraction would have been too low (LVEF < 20%). However, this observation is in line with published real-world data that suggest that patients with similar echocardiographic characteristics are frequently treated with TMVR18, most probably, as up to date there are no echocardiographic parameters that clearly predict outcome19. An earlier publication of another large scale MitraClip Center in Munich, Germany, supports our findings. Orban et al.10 investigated a MitraClip Cohort in an earlier phase with a total of 150 patients treated between 06/2009 and 07/2012. They found a total of three patients with thrombus formation following MitraClip—all of these patients had dilated left ventricles and heart failure with reduced ejection fraction (LV-EF < 20%). Still, a number of differences between our study and the one by Orban et al. remain. These include the extent of LV function deterioration (≤ 20% vs. < 30%), the timing of thrombus diagnosis, baseline anticoagulation regime, and, clinical status of patients. All LV thrombi in Orban et al. were diagnosed in the very early post procedural phase (discharge echocardiography) whereas in our cohort it took up to five months until LV thrombus was found. Given this finding, the previous study may have missed LV thrombus due to the short follow-up. Furthermore, two out of three patients were on anticoagulation with Vitamin K antagonists (Phenprocoumon) before MitraClip but had insufficient INR values and PTT < 60 s in the post procedural phase. Indication for anticoagulation in patient one was a calcified structure in the LV wall before procedure. As calcified structures within the LV are mostly organized thrombi, this raises the question if the periprocedural anticoagulation regime with discontinuation of the Vitamin K antagonist may have led to the formation of appositional thrombus formation. The second patient was on oral anticoagulation due to atrial fibrillation and was in critical clinical condition because of cardiogenic shock prior and during the MitraClip procedure. All three patients died 1 week—3 months post procedure (2 pts due to heart failure 1 pt with pneumonia), indicating the very severe end stage heart failure. Thus, two out of three patients that developed LV thrombus in the previous study are not representative for the majority of patients treated with the MitraClip in Germany and Europe21 and interpretation and generalization of the study results is difficult. Thus, our data for the first time shed light on this important clinical szenario.In our cohort, only one patient (patient 2) would have met eligibility criteria for the COAPT trial9 or spreading and deceleration of inflow in the setting of multiple devices in association with an already disease-modified LV geometry and LV function may critically impact on LV thrombus formation. But not only LV thrombus formation may appear following TMVR. There are published cases showing LA thrombus formation following TMVR23. These findings may also be linked to the change of flow by creating a double or triple transmitral inflow as the pendulum volume that is caused by relevant mitral regurgitations is dramatically reduced after successful TMVR. These hemodynamic considerations appear plausible, However, we have to clearly state the hypothetical nature of this notion.The five patients that developed an LV thrombus following MitraClip procedure did not differ significantly from patients without LV thrombus with respect to baseline characteristics or to echocardiographic parameters prior or following treatment. Thus, we were not able to identify factors that are associate with increased risk of thrombus formation after TMVR. Therefore, cardiologists that perform follow-up echocardiography after TMVR need to be especially alert and need to specifically rule out apical LV thrombus in patients with severely depressed LV systolic function. Hemodynamically and mechanistically, the alteration of LV inflow after MitraClip implantation via “split inflow”Our study has several limitations due to its retrospective design, due to the generally low frequency of complications and the nature of detection of LV-thrombi by echocardiography that can be challenging. However, our study demonstrates 3 important aspects that are important for all cardiologists that follow up patients treated with the MitraClip. These include (1) the observation that LV thrombi may develop after MitraClip even under DOAC therapy (2) patients with severely depressed LV-EF are at risk (3) heparin bridging of Vitamin K antagonists in this cohort of patients is associated with a high risk of bleeding.LV thrombus formation following mitral valve edge-to-edge repair implantation is a rare complication that occurs exclusively in patients with severely depressed LV-EF even under DOAC therapy. LV thrombus may have severe impact on patient outcomes and quality of life. Treatment with Vitamin K antagonists should be considered in this subgroup if an indication for oral anticoagulation exists.In patients with heart failure with severely reduced LV systolic function treated with TMVR, increased awareness for LV thrombus formation in routinely performed transthoracic echocardiography studies is warranted. In patients with an indication for anticoagulation following TMVR, anticoagulation therapy with Vitamin K antagonists should be considered.