Moreover, bothersome nocturia could predict both LAE and left ventricular hypertrophy (LVH)  in the elderly. Older age, hypertension, and LAE were risk factors for bothersome nocturia. Moreover, bothersome nocturia was predictive of LAE and LVH in the elderly. Patients with bothersome nocturia without other significant lower urinary tract symptoms should be referred to cardiologists.Nocturia can be caused by urological disorders and systemic diseases, including heart diseases. We aimed to investigate the relationship between nocturia and structural abnormalities on echocardiography. Adult patients who underwent echocardiography for cardiac symptoms or heart murmur or had a history of structural heart disease were included. The voiding times during sleep hours were collected prospectively. Univariate and multivariate analyses were performed to evaluate the predictive value of bothersome nocturia (nocturia ≥ 2) on echocardiographic abnormalities. Of 299 patients, 182 (60.9%) reported bothersome nocturia. In patients aged ≥ 65 years, hypertension and left atrial enlargement (LAE) were associated with higher occurrences of bothersome nocturia. On multivariate analysis, bothersome nocturia was a predictive factor of LAE (odds ratio [OR] 2.453, 95% confidence interval [CI] 1.363–4.416,  Nocturia prevalence ranges from 11 to 35.2% in young men and 20.4% to 43.9% in young women. Moreover, the prevalence is between 68.9 and 93% in the elderly population2. Nocturia is associated with poor quality of life and increased morbidity3. Furthermore, nocturia is strongly associated with depression4 and leads to a higher risk of incident falls in the elderly5. In addition to urological disorders, nocturia is also caused by systemic diseases6. Previous studies have reported that heart failure and uncontrolled hypertension were responsible for clinically significant nocturia8. Other cardiac diseases may also contribute to nocturia. One study revealed that electrocardiographic evidence of left ventricular hypertrophy (LVH) and left atrial enlargement (LAE) were significantly associated with nocturia9. However, to the best of our knowledge, no studies have so far thoroughly evaluated the association between structural cardiac abnormalities and nocturia. We, thus, investigated the relationship between nocturia and structural abnormalities on cardiac sonography.Nocturia is the most common and troublesome lower urinary tract symptom (LUTS)The study was approved by the Institutional Review Board of Taipei City Hospital  and performed in accordance with the guidelines of the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from all patients.2 was defined as obesity in the Asian population10.We prospectively included adult patients from the cardiology outpatient department who underwent cardiac sonography between June 1, 2021, and July 31, 2021. Cardiac sonography was undertaken for clinical symptoms like chest pain or tightness, physical examination with heart murmur, or follow-up of structural heart disease. Patients with urinary tract infection, neurogenic bladder, or a prior history of lower urinary tract or pelvic surgery were excluded. Before the echocardiographic examination, nocturia was assessed using Question 7 of the International Prostate Symptom Score (IPSS) questionnaire “How many times did you typically get up at night to urinate?”. The patients’ basic data included age, body mass index (BMI), and presence of comorbidities, such as diabetes mellitus, hypertension, heart failure and cardiomyopathy. Elderly patients were defined as those aged ≥ 65 years. BMI ≥ 25 kg/m11. Previous literature showed that the majority of people report being troubled when the number of nocturia episodes is ≥ 2 and that over two voids per night is associated with impaired health-related quality of life12. Therefore, we classified the participants into two groups based on the number of nocturia episodes: bothersome nocturia (nocturia ≥ 2) vs non-bothersome nocturia (nocturia ≤ 1).The 2018 International Continence Society (ICS) defines nocturia as waking for passing urine during the main sleep hours13. Echocardiological parameters, including the size of the left atrium (LA), left ventricle (LV), aorta, aortic valve (AV), mitral valve (MV), tricuspid valve (TV), and pulmonary valve (PV), were measured. The aortic valve sinus diameter, interventricular septal thickness at end-diastole (IVSd), left ventricular posterior wall thickness at end-diastole (LVPWd), left ventricular internal diameter in diastole (LVIDd), and left ventricular internal diameter in systole (LVIDs) were recorded. Left ventricular systolic and diastolic function and valve regurgitation were also measured using Doppler echocardiography.Cardiac sonography was performed by a single technician and interpreted by a cardiologist. A cardiologist has validated this cardiac sonography report. All three cardiac staff were blinded to the patients’ nocturia conditions. The performance and measurements of echocardiographic parameters were based on the 2015 recommendations of chamber quantification of the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI)13. LV diastolic dysfunction (LVDD) was measured by mitral valve E velocity divided by A-wave velocity (E/A ratio) and mitral valve E velocity divided by mitral annular e′velocity (average E/e’ ratio), and the normal range was E/A ≥ 0.8 and E/e’ ratio < 10, grade I was E/A ≤ 0.8 and E/e’ ratio < 10, grade II was E/A > 0.8 to < 2 and E/e’ ratio 10–14, and grade III was E/A > 2 and E/e’ ratio > 1414. Left atrial enlargement (LAE) was defined as a left atrial dimension of > 40 mm15. Aortic root dilation was defined as an aortic valve sinus diameter > 38 mm in men and > 36 mm in women16. Left ventricular mass (LVM) was calculated using the following formula: LVM = 0.8 × [1.04 × {(LVIDd + LVPWd + IVSd)3- (LVIDd)3}] + 0.6 g17. The left ventricular mass index (LVMI) was calculated by normalizing the LVM by the body surface area based on Devereux’s formula18. Left ventricular hypertrophy (LVH) was defined as an increased left ventricular mass index (LVMI) (≥ 125 g/m2 in men and ≥ 110 g/m2 in women)19. Concentric LV remodeling was defined as LVMI ≤ 115 g/m2 in men or ≤ 95 g/m2 in women and LV relative wall thickness (RWT) > 0.4220. Moderate-to-severe AV regurgitation (AR) was considered to have intermediate-to-large color flow in AR jet width, increment vena contracta width (> 3 mm), and a decrease in pressure half-time (< 500 ms). Moderate-to-severe TV regurgitation (TR), MV regurgitation (MR), and PV regurgitation (PR) were defined as intermediate-to-large color flows in the TR, MR, and PR jet widths and dense continuous wave signals of the TR, MR, and PR jets, respectively21.Left ventricular ejaction fraction (LVEF) was calculated using the Simpson’s biplane method. In males, the normal LVEF range was 52–72%, mildly abnormal was 41–51%, moderately abnormal was 30–40%, and severely abnormal was less than 30%. In females, the normal range was 54–74%, mildly abnormal was 41–53%, moderately abnormal was 30–40%, and severely abnormal was less than 30%p < 0.05.Statistical analyses were performed using IBM SPSS Statistics for Macintosh, ver. 24 . Pearson’s chi-square test was used to analyze factors associated with bothersome nocturia. Univariate and multivariate analyses were performed with logistic regression to evaluate the predictive value of bothersome nocturia on echocardiographic abnormalities after adjusting for sex, age, obesity, hypertension, diabetes mellitus, diuretic use and heart disease. Statistical significance was set at A total of 299 patients aged between 20 and 95 years were included in the study, of whom 134 (44.8%) were men and 165 (55.2%) were women. Elderly patients accounted for 70.6%, while patients with obesity accounted for 50.8%. Hypertension was found in 226 (75.6%) patients, and 4 (1.3%) patients had a history of heart diseases, including three with heart failure and one with cardiomyopathy. Bothersome nocturia was reported in 182 patients (60.9%). Regarding echocardiographic abnormalities, 27 (9%) had abnormal LVEF, 10 (3.3%) had grade II-III LV diastolic dysfunction, 109 (36.5%) had LAE, and 85 (28.4%) patients had LVH (Table p < 0.001). Patients with hypertension  and LAE  also had higher occurrences of bothersome nocturia. Additionally, there was a tendency for patients with LVH to have higher occurrences of bothersome nocturia with a borderline significance  , and those with LVH tended to have higher occurrences of bothersome nocturia with a borderline significance . Furthermore, the prevalence of bothersome nocturia was lower in obese patients compared with that in non-obese patients  . Moreover, in the subgroup of patients older than 65 years, bothersome nocturia was predictive of LAE  and LVH   levels in patients with LAE23. A previous study showed that increased ANP due to subclinical heart failure can cause nocturnal urinary symptoms24. ANP increases the glomerular filtration rate (GFR), renal plasma flow, and sodium excretion, which causes diuresis and natriuresis25. Another possible mechanism is that LAE leads to cardiac structural changes and causes sodium and water retention in the extracellular space26. When sleeping in a supine position, the redistribution of fluid from edematous legs may cause nocturnal polyuria27.Nocturia is closely associated with cardiac complications. Nocturia may be a risk factor for coronary heart disease in young men and increases the possibility of death in older men27. Congestive heart failure may decrease renal plasma flow, increase the filtration fraction during ambulation, and cause sodium retention. Nighttime sleep in the supine position improves renal hemodynamics and sodium excretion, leading to nocturia28.Bothersome nocturia was also predictive of LVH in patients older than 65 years. Left ventricular hypertrophy increases the risk of both systolic and diastolic heart failure30. The incidence and severity of nocturia increase with age in both men and women31. Urological problems and systemic diseases affect nocturia in older patients equally, including bladder storage problems, polyuria, nocturnal polyuria, and sleep-related issues32. Nocturia in the elderly leads to impaired quality of life, for both the patients and their cohabitants, and increases the incidence of falls, resulting in higher morbidity30. Interventions such as behavioral, pharmacological, or surgical management should be considered to improve nocturia severity in the elderly33.We found that bothersome nocturia was more prevalent among older adults. This is consistent with the results of previous studies34. Another study that analyzed 14135 patients from the National Health and Nutrition Examination Survey in the United States showed that obesity is significantly associated with nocturia35. Our results, which differ from previous studies, may be due to the differences in race, age, and study population. We focused on elderly patients with cardiac symptoms and potential structural heart disease, which may have a stronger negative effect than obesity on nocturia and modify the effect of obesity on nocturia. Moreover, the definitions of obesity based on BMI also differ between Asians and Caucasians36. These disparities could have contributed to the different results.Our study reported that the prevalence of bothersome nocturia was lower in obese patients compared with that in non-obese patients in the elderly patient group, implying a protective role of obesity in the development of bothersome nocturia. In contrast, previous studies demonstrated a positive association between obesity and nocturia. A study that included approximately 3,600 patients in Finland concluded that obesity is strongly associated with increased nocturia37. Hypertension affects renal glomerular filtration and tubular transport. In addition, hypertension can increase renal plasma flow and decrease sodium reabsorption, leading to nocturia39. A previous study indicated a significant relationship between diabetes mellitus and nocturia40. Hyperglycemia and osmotic diuresis occur in patients with diabetes mellitus, predisposing them to nocturia41. Proper control of serum glucose levels in diabetic patients helps improve nocturia41. However, in this study, a history of diabetes mellitus was not significantly associated with bothersome nocturia. One possible explanation is that all patients included in our study received appropriate treatment for blood sugar.Our study showed a significant relationship between hypertension and bothersome nocturia. Uncontrolled hypertension and elevation of blood pressure are reportedly related to nocturiaOur study had several limitations. First, we included patients from the cardiology department rather than the general population. The association between bothersome nocturia and echocardiographic abnormalities, especially in those without obvious cardiac symptoms, may be underestimated. Second, although this was a prospective study, we did not analyze the effects of antihypertensive drugs other than diuretics on nocturia. Third, we did not perform prostate ultrasonography to evaluate the size of the prostate gland in male participants, which may also have an impact on the severity of nocturia. Fourth, we did not follow-up with the patients in a cross-sectional study to evaluate the association between nocturia and echocardiographic abnormalities. Fifth, we evaluated LA size using conventional M-mode LA dimension rather than LA volume. Measurement of LA size using conventional M-mode LA dimension is simple and convenient but not reliably accurate, given that the LA is not a symmetrically shaped three-dimensional structure. It is unknown whether treatment of structural heart diseases, such as LAE or LVH, could also improve the severity of nocturia. Nevertheless, the results of this study have important implications. Our results suggest that urologists should refer patients with bothersome nocturia without other significant LUTS to cardiologists to evaluate the presence of structural heart disease, which may be potentially critical to patients.Older age, hypertension, and echocardiographic evidence of LAE are associated with a higher incidence of bothersome nocturia. Furthermore, bothersome nocturia could predict structural heart diseases, including LAE and LVH, in the elderly. Referral to cardiologists should be considered for patients with bothersome nocturia.


Valvular regurgitation is common in developed countries with an increasing prevalence due to the aging of the population and more accurate diagnostic imaging methods. Echocardiography is the gold standard method for the assessment of the severity of valvular heart regurgitation. Nonetheless, cardiovascular magnetic resonance (CMR) has emerged as an additional tool for assessing mainly the severity of aortic and mitral valve regurgitation in the setting of indeterminate findings by echocardiography. Moreover, CMR is a valuable imaging modality to assess ventricular volume and flow, which are useful in the calculation of regurgitant volume and regurgitant fraction of mitral valve regurgitation, aortic valve regurgitation, tricuspid valve regurgitation, and pulmonary valve regurgitation. Notwithstanding this, reference values and optimal thresholds to determine the severity and prognosis of valvular heart regurgitation have been studied lesser by CMR than by echocardiography. Hence, further larger studies are warranted to validate the potential prognostic relevance of the severity of valvular heart regurgitation determined by CMR. The present review describes, analyzes, and discusses the use of CMR to determine the severity of valvular heart regurgitation in clinical practice. The prevalence of valvular regurgitation is increasing worldwide, especially in high-income countries , 2. In tCurrent guidelines are mostly symptom-based and recommend intervention for severe valvular regurgitation in symptomatic patients or the presence of certain high-risk events , 4. The Echocardiography is the most practical diagnostic method for the assessment of valvular pathology and the current first-line imaging modality for this purpose due to the excellent visualization of valve anatomy it affords, its availability, and its ease of use. This cardiovascular imaging technique allows the user to analyze valve morphology and motion and the valvular annulus, quantify valvular regurgitation using different methods, and assess ventricle size and function . The EACOver the last 20–25 years, cardiovascular magnetic resonance (CMR) has emerged not only as the gold standard method for assessing left and right ventricular volume, mass, and function but also as a robust and accurate tool for evaluating volumetric quantification and accurate flow using a number of methods independent of jet morphology. However, recent guidelines still consider CMR as a “second tool” when echocardiographic parameters are inconsistent due to the absence of large prospective studies defining the clinical impact of valvular regurgitation quantification by CMR and due to its availability, time, and cost. It is therefore essential to define, in light of the most recent available data, the crucial role of this modality, which can provide, in an “all-in-one technique,” a unique approach to study both valve lesions and their consequences on the heart chambers and hemodynamics. In this review, we discuss the emerging potential of CMR for the diagnosis and prognosis of regurgitant lesions. We will detail for each type of valvular regurgitation  its ability to assess regurgitation severity, the consequences for the ventricles, and we will propose a CMR-specific cut-off to help in the decision-making process for valve replacement/repair.Moderate or severe mitral regurgitation (MR) is frequent in the general population and represents an important cause of morbidity and mortality worldwide . In the Cardiac imaging is critical for evaluating the cause of MR (primary or secondary), assessing its severity and the consequences for the LV, and defining the best surgical timing.Assessing the cause of MR requires visualization of the anterior and posterior mitral valve (MV) leaflets, the mitral annulus, the chordae, the anterolateral and posterolateromedial papillary muscle, and left ventricular (LV) wall motion abnormalities. Although echocardiography  is an excellent imaging of the MV which CMR cannot match, CMR can help in identifying MV morphology and MR mechanisms. With a high signal-to-noise ratio and an excellent blood–myocardium contrast-to-noise ratio, cardiac balanced steady-state free precession (bSSFP) imaging is the method of choice for cine (motion) images. Retrospective cardiac gating, corresponding to the continuous acquisition of both ECG and image signals collected over several consecutive heartbeats and used after image reconstruction, should be used to allow optimized temporal and spatial resolution. In the setting of atrial fibrillation, however, prospective gating may result in better image quality. According to recent SCMR recommendations and a consensus on the use of CMR in MR , 13, the-A stack of contiguous thin (slice thickness between 5 and 7 mm) bSSFP cines in the short axis covering the MV.-A stack of contiguous cines through-plane on the MV and perpendicular to the mitral commissure to cover all of the mitral scallop; from A1–P1 to A2–P2 and A3–P3 .-Standard long-axis cine images, including a 2-chamber view , a 3-chamber view [left ventricular outflow tract (LVOT)-1 view], and a 4-chamber view.Leaflet motion abnormalities can be described as classically defined by echocardiography  . HoweverThe LVOT-1 view can be used for determining the MV leaflet length, MV tenting, and tenting height, major determinants of ischemic MR. However, there are no data comparing CMR measurement of the mitral annulus or MV length to surgical findings, and echocardiography remains the gold standard in the perioperative assessment of primary MR.With a slice thickness between 5 and 7 mm, imaging the length and thickness of the mitral chordae is less accurate than echocardiography. In addition, since CMR images are reconstructed over several heartbeats, thin and very mobile structures such as vegetation, cordal rupture, or fibroelastoma are often poorly visualized when their motion is variable in the cardiac cycle. Moreover, due to lower spatial resolution than echocardiography , annular or leaflet calcifications seen with a slightly darker-than-myocardium signal in bSSFP sequences cannot be properly identified by CMR . Thus, eOn cine images, regurgitant jets can be visualized as a signal loss  created by the turbulence of flow in the left atrium. The jet can be difficult to be clearly identified on fixed 2D images, especially if the direction of the jet is not linear. Moreover, the size and length of the jet can be reduced or increased by just changing parameters or sequences. Rapid spoiled gradient-recalled echo sequences with longer repetition and echo times or gradient echo (GRE) or hybrid GRE echo-planar sequences have been proposed for higher sensitivity , 17. TheThere are several CMR methods for evaluating MR severity; all are independent of the characteristics of the mitral regurgitant jet and do not require calculation using a complex equation. These methods are less accurate in arrhythmic patients or poor breath-holders. A free-breathing phase-contrast sequence with an increased number of averages (≥3) can be applied in these cases. The methods available in clinical practice are summarized in The most widely used CMR method to quantitatively assess the severity of MR is an indirect method combining 2D cine imaging and phase-contrast velocity mapping to quantify the regurgitant volume and fraction.Mitral regurgitant volume (MRvol) is expressed as the difference between the left ventricular stroke volume (LVSV) and aortic forward flow (AFF), and the regurgitant fraction (RF) as the MRvol divided by the LVSV, expressed as a percentage.The LVSV can be obtained from multiple LV short-axis cine bSSFP images, and the AFF from phase-contrast velocity flow in a trough-plane acquired at the level of the sinotubular junction or the aortic valve but not at the mid-ascending aorta due to the risk of overestimation . This seThis method is highly reproducible , 20, indIn cases with aortic stenosis, the through-plane flow imaging slice is placed beyond the turbulent jet. In exceptional cases, the pulmonary forward flow (PFF), instead of the AFF due to non-laminar and high aortic velocity in the ascending aorta, can be used.Technical considerations are detailed in The accuracy of the AFF may be compromised by potential errors:-Mismatch of encoding velocity: the velocity encoding value (Venc) should be set within 25% of the true maximal velocity in the aorta to avoid aliasing.-Misalignment of imaging plane: to avoid inaccurate aortic peak velocity, the imaging plane should be orthogonal to the direction of flow.-Phase offset errors, due to local magnetic field inhomogeneities, can be corrected by using a background correction.-During analysis, noise pixels should not be included in the contouring of the aorta.Validation of AFF by CMR has been established by comparison to left ventricular stroke volume with echocardiography with good correlation  22, 23), 2322, 2An alternative and simple approach using only bSSFP sequences in the short axis is the “volumetric method,” expressed as the difference between LVSV and right ventricular stroke volume (RVSV), which represents the quantity of MR in the absence of other types of valvular regurgitation or intracardiac shunts.Using a single method is less prone to measurement error than using two different techniques.Due to the shape of the right ventricle (RV) and extensive trabeculations, RV contouring is more prone to errors in RVSV measurements.Direct quantification of MR flow is theoretically feasible with phase-contrast velocity mapping by directly measuring the regurgitant flow across the MV.However, given the significant dynamic motion of the MV during systole, high velocity, a non-circular orifice, and jet angulation, positioning a fixed slice across the MV  can be challenging and inappropriate, especially for patients with eccentric MR, multiple jets with different directions, and high heart-rate variability. Therefore, we do not recommend this approach for clinical practice.4D flow velocity-encoded CMR imaging is an emerging technique that involves phase-contrast acquisition with flow encoding in all three spatial directions and to the dimension of time (3D + time = 4D). It allows the visualization of flow in multiple orientations to follow the spatial motion of the heart valves and the variable direction of the jets over time. The use of such a retrospective tracking method in a single volume acquisition covering the entire heart may enable direct MR jet volume quantification, overcoming certain limitations of 2D sequences . Recent Late gadolinium enhancement (LGE) imaging, acquired after gadolinium administration, has the unique ability to provide tissue characterization of the myocardium by assessing and quantifying regions of fibrosis and scars across the left atrium , the LV Late gadolinium enhancement sequences [pulse sequences according to published guidelines ] should In ischemic MR, the quantification of MR and myocardial infarct size with CMR can help for risk stratification in patients with advanced ischemic cardiomyopathy . In primIn MR, little is known about diffuse interstitial fibrosis. One recent study suggested that in primary MR, ECV increases with MR severity, regardless of MV prolapse or the presence of replacement fibrosis . Diffuse2) by the PISA method and RF ≥ 50%  is the second most frequently occurring type of regurgitation after MR . As for With a high contrast between the valve leaflets and blood pool, together with a high signal-to-noise ratio, SSFP imaging can be used to visualize aortic valve anatomy in any plane, irrespective of cardiac anatomy . A perpeAssessing the aortic diameter is crucial for determining AR etiology and follow-up. The diameter of the ascending aorta can be measured using non-contrast-enhanced MR angiography (NCE-MRA) with a respiratory navigator or breath-hold contrast-enhanced MRA (CE-MRA). Measurements are performed at end-diastole using the internal diameter of the aorta at the level of the sinus, the sinotubular junction, and the level of the pulmonary trunk on the ascending aorta  or at thAortic regurgitant jets can be visualized on cine images using long-axis LVOT views  as a dark jet due to a signal void from turbulence back flowing into the LVOT during diastole . The locVarious CMR methods used in clinical practice to assess AR severity are summarized in Cardiovascular magnetic resonance has the ability to measure flow velocity and direction over time. Unlike MR , direct flow quantification of AR is feasible. The most commonly used CMR method to quantitatively assess the severity of AR is a direct measurement using through-plane velocity mapping performed just above the aortic valve (2D phase-contrast imaging: 2D-PC) in a plane perpendicular to the direction of blood flow . A dedicThis method is highly reproducible and accurate, especially for laminar regurgitant flow, with an imaging plane perpendicular to the aorta . It requAn incorrect velocity encoding setting (below the peak velocity in the vessel) results in aliasing and an underestimated peak velocity . We recoAccording to recent CMR guidelines , velocitARvol can be measured indirectly as the difference between the AFF and PFF in the absence of other regurgitation or intracardiac shunts.This method requires only 2 single breath-holds and allows for rapid post-processing. If there are concerns about the direct method, this method can serve for internal validation.This method is not valid in situations of pulmonary regurgitation or intracardiac shunts.Similar to MR, the volumetric method can be used to quantify ARvol using only bSSFP sequences in the short axis. ARvol is expressed as the difference between LVSV and RVSV in the absence of other types of valvular regurgitation .This method is simple and does not require specific acquisitions because bSSFP cine sequences are performed during every CMR examination.Technical considerations are described in the MR chapter.4D flow with its ability for measuring eccentric, non-laminar flow in any orientation in space could be in the near future appropriate for AR quantification .T1 mapping, with its potential to assess cellular and extracellular compartments, could be of interest in AR as a prognostic marker for clinical outcomes .Unlike MR, there is a paucity of large and prospective studies comparing these two modalities. In all studies, the direct CMR method was used and thresholds to define severe AR were the same as those used for echocardiography: Rvol ≥ 60 ml and RF ≥ 50% according to recommendations , 36, 61 2D PISA is limited to the alignment of the flow and by the need for computation and geometric assumptions. 3D echocardiography, not restricted by any imaging plane, could overcome these limitations and provide a better correlation with CMR, especially in eccentric .As previously noted, ARvol and/or RF measured by CMR are categorized based on established echocardiographic guidelines , defined-Mild to moderate AR: 30 mL ≤ ARvol < 45 ml,-Moderate to severe AR: 45 mL ≤ ARvol < 60 ml,-Severe AR: ARvol ≥ 60 ml; RF ≥ 50%As for MR, there is a paucity of data on specific CMR thresholds for ARvol and RF, with a lack of large trials with a validation cohort. ARvol > 40 ml and RF ≥ 30% have been proposed to define severe AR with CMR that correlates best with echocardiography , 62 or fIn the absence of a reference method, it is difficult to determine which imaging modality can better predict the need for aortic correction, particularly for asymptomatic patients. However, several studies have reported a better prediction with CMR , 65, 69.2 or LVEF ≤ 50%). CMR is a “second tool,” indicated when various echocardiographic parameters are inconsistent , which is probably underestimated. In a recent study performed in the United States , the age and sex-related prevalence of TR (diagnosed by Doppler echocardiography) was 0.55%, higher among women, and increased with age (4.4% among women aged ≥ 75 years and 3.1% among men) . ModeratCauses of TR can classically be divided into two types:-Primary TR due to a primary lesion of the tricuspid valve caused by congenital or acquired disease.-Secondary  TR, with a structurally normal valve, more commonly associated with left-sided heart disease, pulmonary hypertension, RV dysfunction, dilatation, or without a detectable cause and thus called isolated (or idiopathic) TR, but often associated with atrial fibrillation.Whether isolated TR or not, understanding TR, its consequences, and accurately assessing its severity is crucial, particularly since the emergence of transcatheter interventions, which have moved the tricuspid valve from the shadows into light. Echocardiography is the preferred and recommended initial imaging technique to assess TR based on an integrative approach, including qualitative and quantitative criteria. The use of conventional quantitative parameters (vena contracta and PISA) is based on geometrical assumptions (circular jet and flat orifice) extrapolated from the MV . HoweverDue to the complex interplay between TR and the RV (TR can cause RV dilatation and vice versa), assessing TR requires the accurate assessment of RV structure and function. CMR is the method of reference to assess RV volume, function, and mass, without geometric assumptions .RV structure can be studied using-a stack of contiguous bSSFP short-axis images, the same as those used for LV, with careful placement of the basal slice on the myocardial side of the RV . In case-Long-axis cine images, including three specialized views for the RV: RV out-flow tract (RVOT) and RV vertical long axis (3-chamber) .The RV regional wall-motion abnormalities can be determined visually. Recently, feature tracking, similar to speckle tracking in echocardiography, has emerged to more accurately detect changes in wall motion and earlier ventricular dysfunction, which may be an independent predictor of mortality in severe TR .2) and 1.1 cm2 (> 0.5 cm2/m2), respectively  in the short-axis view. Leaflets can be described as prolapsed, restricted, thickened, or with tenting . Tentingectively . However2)    . It is iThe qualitative assessment of TR can be performed using bSSPF imaging . TR is visualized as a dark jet created by flow turbulence generating spin dephasing back flowing into the right atrium. As for MR and AR, this is a gross assessment and is not reliable on its own. In the presence of a turbulent jet, regurgitant flow appears as a low signal that can mask the visualization of the leaflets.Quantitative assessment of TR by CMR can be performed using two indirect and one direct method.Similar to MR, the regurgitant volume of TR (TRvol) can be measured indirectly as the difference between RVSV and PFF (or AFF in the absence of AR) using 2D cine (for RVSV) and retrospective acquisition with velocity-encoded phase-contrast sequence in a through–plane on the pulmonary valve , 5 mm above the valve  Figure .This is the most widely used CMR method and is valid in the absence of intra-ventricular shunts . The advAs for MR and AR, the volumetric method can be used to quantify the TRvol, expressed as the difference between RVSV and LVSV in the absence of other forms of valvular regurgitation. The advantages and technical considerations are similar to those for left-sided valvular regurgitation and have already been discussed in the MR and AR chapter.These two indirect methods can be performed in addition to echocardiography to increase the confidence in the assessment of TR severity.2D PC imaging also allows the direct measurement of TR regurgitant flow through the tricuspid valve. As for MR, this technique is limited by significant motion and the saddle-shape of the tricuspid annulus and is not commonly used in clinical practice.Data concerning 4D flow in TR are very scarce. One recent study have suggested high concordance of 4D flow with standard 2D PC (indirect method) .Unlike LV, tissue characterization (LGE and T1 mapping) of the RV is more complex due to the thin RV wall (thickness 1–3 mm), which creates partial volume effects. Transmural RV enhancement can be visualized, but non-transmural lesions are very challenging to visualize. LGE patterns may help to understand the underlying mechanism of TR, as it allows to detect ischemic patterns associated with pulmonary hypertension, or fibrosis associated with cardiomyopathies such as arrhythmogenic right ventricular cardiomyopathy. T1 assessment in TR has not yet been reported.Calculation of TRvol by echocardiography is more challenging than for MR and AR, and the current guidelines place CMR-derived TRvol as an alternative  Table 4Table 4. The largest and more recent study to compare echocardiography (integrative approach) and CMR (2D PC indirect method) has used the same thresholds defined in the ASE guidelines : TRvol m2, associated with higher cardiovascular mortality  is common in the general population, with little clinical significance. By contrast, significant PR is uncommon and usually related to either congenital heart disease  or pulmonary hypertension . Echocardiography is the initial imaging modality to assess PR. However, the position of the valve behind the sternum, which makes visualizing the PV and RVOT difficult and thus the derived measurement for PR quantification, does not position echocardiography as the preferred method for PR assessment. Since CMR can provide unrestricted image planes for PV anatomy and RV function, it plays a crucial role in PR assessment, especially for patients with repaired tetralogy of Fallot (rTOF).The assessment of RV structure and function is essential for determining the prognosis and planning surgical/percutaneous intervention for patients with rTOF .Contrary to echocardiography, CMR provides good visualization of RVOT anatomy using a stack of SSFP cine images in the short and long axes (RVOT and 3-chamber). The anatomy of the pulmonary valve, with three semi lunar leaflets , can be visualized in through-plane images on the valve .PR can be seen as a dark jet in cases of flow turbulence in diastole, extending into the RVOT. However, in cases of laminar flow with a wide jet, there is almost no turbulence, making the jet nearly invisible. As for other forms of valvular regurgitation, it is a gross assessment and is not alone reliable.Similar to AR, direct measurement of pulmonary backward flow is feasible using 2D-PC with retrospective acquisition in a through-plane acquisition on the pulmonary valve, 5 mm to 1 cm above the level of the valve  Figure .This is the most widely used method and the current reference standard technique . In patiAs for other forms of valvular regurgitation, the volumetric method can be used to quantify PRvol by comparing RVSV and LVSV on bSSFP short-axis cine images , in the PRvol can be measured indirectly as the difference between PFF and AFF in the absence of tricuspid regurgitation .PRvol can be measured indirectly as the difference between RVSV and AFF in the absence of tricuspid regurgitation.The presence of focal RV and LV enhancement in patients with rTOF is a common finding, mostly located at surgical sites of the RVOT, the patching of the ventricular defect, and in the inferior RV insertion . Such foMost of the studies comparing echocardiography and CMR in PR assessment have been performed on patients with rTOF, with CMR as the gold standard –90.2, indexed RV end systolic volume ≥ 70 ml/m2, indexed LV end diastolic volume ≤ 65 ml/m2 and RVEF ≤ 45%  and regurgitant fraction (RF) independent of jet morphology and direction. However, large studies are needed to validate the severity and prognosis of valvular heart regurgitation using CMR. Notwithstanding this, there is growing evidence showing that CMR could be an accurate complementary method to echocardiography for the measurement of Rvol and RF for grading regurgitation severity, particularly for mitral valve regurgitation (MR) and aortic valve regurgitation (AR). Emerging techniques, such as 4D flow are promising to enhance the accuracy of CMR for the quantification of valvular heart regurgitation. Furthermore, due to its unique ability to assess focal and diffuse LV fibrosis, CMR provides potential information in the clinical evaluation of MR and AR for planning and deciding the timing and indication of a specific therapy or intervention. Accordingly, taking into consideration the potential accurate uses of CMR in the evaluation of valvular regurgitation, this imaging modality could be useful in the assessment of valvular heart regurgitation in the setting of unclear severity of valvular regurgitation  measured by echocardiography.EV provided conception and design of the research and wrote the manucript. EV, LI, FL, and CR provided iconography. BG, SM, YB, and CT provided critical revision of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


As regards right sections, the most relevant reverse remodeling was obtained in patients with functional MR with a baseline poorer RV function and more severe RA and RV dilation. Conclusion: TEER induces reverse remodeling involving both left and right chambers at mid-term follow-up. To deliver a tailored intervention, MR mechanism and history of AF should be considered in view of the impact on remodeling process.Background: The aim of this study was to determine the impact of transcatheter edge-to-edge repair (TEER) on left and right ventricular  and left and right atrial  remodeling according to the mechanism of mitral regurgitation (MR) and history of atrial fibrillation (AF). Methods: Twenty-four patients  underwent TEER at our center. All the patients underwent echocardiography 1.6 ± 0.9 months before the procedure and after 5.7 ± 3.5 months; functional MR accounted for 54% of cases. Results: Compared to baseline, a statistically significant improvement in LV end-diastolic diameter (LVEDD), LV indexed mass (ILVM), LV end-diastolic and end-systolic volumes , indexed LA volume (iLAV), and morpho-functional RV parameters was recorded. LVEDD and LVEDV improved in primary MR cohort, whereas in secondary MR, a significant reduction in LVEDV and LVESV was found without a significant functional improvement. LA reverse remodeling was found in organic MR with a trend toward ameliorated function. Furthermore, a significant reduction of LA volumetry was detected only in patients without history of AF (AF baseline 51.4 mL/m Mitral regurgitation (MR) is the second-most common valvular disease in Europe. Chronic severe MR leads to the remodeling of left and right heart with left ventricular (LV) and atrial (LA) dilatation and dysfunction and the development of a significant pulmonary hypertension in almost half of the patients . The incMitral valve repair or replacement represents the standard of care for patients with significant MR and, when performed in time, promotes LV and RV reverse remodeling improving the prognosis of patients .Unfortunately, a significant percentage of patients with severe MR are not suitable for surgical mitral valve repair or replacement due to prohibitive surgical risk and/or comorbidities. In this setting, transcatheter edge-to-edge repair (TEER) has been shown to be an effective and safe alternative associated with a favorable clinical outcome . AlthougIn this monocentric study, we retrospectively reviewed 35 patients with severe organic or functional MR referred for TEER at Modena University Hospital, between November 2017 and September 2021. Patients with inadequate echocardiographic views for STI were excluded 11 patients), for a final cohort of 24 patients. All TEER were performed with the MitraClipTM system. Appropriateness for TEER was evaluated by a local heart team as indicated by current guidelines , and no  patientsAll patients underwent baseline 2D and STI echocardiographic evaluation, which is the same evaluation used to assess cardiac remodeling was performed 6 months after the procedure. All echocardiographic studies were performed with dedicated equipment and ECG gating. The left lateral decubitus images were acquired at a variable depth of 14–20 cm. Data were acquired on the parasternal long axis, short axis, and apical projections . Indexing was carried out for the body surface area (BSA) according to Mosteller equation. LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction (LVEF), and LA volumes were measured in the 4- and 2-chamber views using the biplane Simpson’s method, as recommended by international guidelines . The lonp value of < 0.05 was considered significant for all analyses. Statistical analyses were performed using IBM SPSS Statistics .Continuous variables were expressed as mean ± standard deviation (SD) for normal distributions; median and interquartile ranges (IQR) were used for non-normal distributions. Categorical data were reported as numbers and percentages. The normality of the parameters tested was evaluated using the Shapiro–Wilk test. Due to the small size of the sample, continuous variables were compared using the Wilcoxon matched pairs signed ranks test. A two-side A total of 24 high-surgical risk patients undergoing TEER for severe MR were included  were males). Baseline echocardiographic evaluation was performed 1.6 ± 0.9 months before the procedure; all patients underwent follow-up echocardiography 5.7 ± 3.5 months after the procedure. The median STS score value was 3.5% [IQR 1.7–4.8%] and the median Euroscore II was 4% [IQR 3.1–6.2%]. Organic and functional etiologies of MR were equally represented in the population at 45.8% vs. 54.2%, respectively. All patients were severely symptomatic (New York heart Association (NYHA) class III 17/24, 70.8%; NYHA class IV 7/24, 29.2%), despite optimized guideline-directed heart failure medical therapy. Baseline demographic and clinical characteristics are detailed in p < 0.001). A positive procedural result in terms of reduction of the degree of MR was reached in all the subjects . LA dilation was found in almost all patients (median iLAV-2D 50.5 mL/m2). Elevated tricuspid valve regurgitation maximal velocity (TR Vmax 2.9 (2.5–3.1) m/s) and increased estimated peak systolic pulmonary artery pressure (EPSPAP 40.0 (35.0–50.0) mmHg) were found in most cases. In the baseline comparison between functional and organic MR subgroups LVESV, LVEF, and TAPSE were found to be significantly more compromised in the functional cohort. Baseline echocardiographic characteristics are detailed in 2 vs. post-procedural 2D-iLVEDV 53.5 mL/m2 and baseline 2D-iLVESV-2D 35.4 mL/m2 vs. post-procedural 2D-iLVESV 27.1 mL/m2, respectively). On the contrary, none of the parameters of LV systolic function showed a significant improvement during the follow-up period  8.0 cm/s vs. post-procedural LV S’ TDI 8.0 cm/s)   but not in LVES diameter (LVESD). Similarly, indexed LVED and LVES volumes significantly improved (baseline 2D-iLVEDV 67.5 mL/m.0 cm/s) . When co.0 cm/s) .2 vs. post-procedural 2D-iLAV 44.1 mL/m2). Atrial function assessed by PALS improved during the follow-up period but without reaching statistical significance , see A statistically significant reduction in LA maximum volume was observed after TEER procedure (baseline 2D-iLAV 50.5 mL/mA significant reduction in RV diameters (RVD)-basal, mid-cavity, and longitudinal-was observed with 2D echocardiography . Moreover, a significant improvement in RV systolic function’s parameters was noted in terms of fractional area change (FAC) , tricuspid annular plane systolic excursion , and RV free wall longitudinal strain .Regarding RV after-load dependent parameters, a significant reduction in TR jet max velocity and derived PAPs was recorded during the follow-up period  . The subIn this pilot study of 24 patients that underwent TEER and were evaluated at baseline and after 5.69 ± 3.50 months with morpho-functional echocardiographic assessment, our main findings were as follows: (i) a significant improvement in all the RV morphological and functional parameters; (ii) a significant reduction in LVED diameters and volumes without significant improvement in LV function; (iii) significant decrease in LA volume and a trend toward an ameliorated LA function; (iv) a difference in the relative impact of TEER on cardiac remodeling when considering primary and secondary MR and subjects with and without history of AF. Our results add to the current body of evidence by giving a freeze-frame of short-term cardiac remodeling after TEER in a cohort of patients with equally distributed primary and secondary MR that was treated by following current guidelines and recommendations .The most relevant result of our study is the evidence of reverse remodeling in the right sections at 6 months after TEER, with a more impactful effect in the functional MR cohort. The importance of this finding of pivotal importance due to the renowned negative prognostic impact of right involvement in valvular heart diseases and heart failure ,15. ThisIn our study, we reported the comparison between primary and secondary MR cohort in terms of right sections remodeling. As expected, we found a more significant impact in RV and RA reverse remodeling, better longitudinal function, and lower PAPs in patients with functional MR and severe RV involvement. Interestingly, patients with primary MR and less compromised RV function also showed an impact from afterload reduction provided by TEER, reflected into reduced cavity dimensions and ameliorated contractile performance. Moreover, systematic application of advanced echocardiography evaluations such as RV deformational imaging could help in identifying subclinical RV dysfunction, which can be reverted by TEER procedure.In our analysis, we reported LV remodeling in terms of LV end-diastolic linear internal diameter and end-diastolic and end-systolic volumes reduction without significant improvement of indices of systolic function. This is apparently contradictory, but some physiological considerations are worth mentioning. First, concomitant reduction in both end-diastolic and end-systolic parameters could lead to minor changes in LVEF. Second, it should be kept in mind that pre-procedural LVEF could be overestimated due to regurgitant volume. Third, in a progressive disease such as MR, the development of LV dysfunction is a continuous process that could be ongoing before the reduction of LVEF. From this perspective, the lack of further worsening in LVEF could be considered as a therapeutic success. On the contrary, LV diameters and volumes are strongly dependent on loading conditions, and therefore the reduction of LV preload after correction of MR induces a reduction of these parameters regardless of the initial mechanism. The geometrical changes in LV after TEER have been reported since the first experiences with TEER. In 2012, Scandura et al. reported a significant change in terms of sphericity index and LVEF after six months in a cohort of patients with mixed MR etiologies . SimilarIn our study, we report significant changes in geometrical reverse remodeling in the total population and in the primary MR subgroup. On the other hand, the small impact on the functional subgroup could be due to the less-dilated mean volumes and less-reduced mean LVEF in our FMR subgroup with respect to the population analyzed in previous studies ,25. PrepAs regards LA assessment, in the overall cohort, we report a significant reduction of LA volume and a trend to an improved reservoir function even without statistical significance. Chronic volumetric overload caused by regurgitating volume in the LA affects both volumetric and functional parameters. Restoration of the adequate competence of the mitral valve inducing LV unloading promotes mitral annulus size reduction and favors LV and LA reverse remodeling. The positive impact of TEER on LA remodeling is less consistent when considering the functional cohort in our population. In other reports on TEER in patients with FMR, a significant reduction of LA volume was achieved only after 12 months of follow-up . FurtherOur study depicts the hemodynamic impact of TEER on patients with mixed MR etiologies. The most relevant change is the improvement of right heart hemodynamics  early after reduction of afterload with MR correction. The improvement of the afterload-dependent parameters occurs even without a significant change in terms of left ventricular function. The impact of the procedure on LV preload led to the improvement of preload-dependent parameters such as volumetric and linear measurements and LA volumes even without improvement in functional parameters.The main limitation of the study was the relatively small number of patients in the study population. Moving from this point, our findings are to be considered as hypothesis-generating, and additional research is necessary.The observational and retrospective nature of the study has intrinsic limitations, linked to the selection bias and the possible presence of confounding factors. For some patients, it was not possible to recover and process the pre- and/or post-procedural echocardiographic parameters due to inadequate acoustic windows.Additionally, as a result of the data collection process, we were only able to report on the usage of pharmacological classes before and after the procedure and were unable to assess dosage changes, which is a drawback, particularly for heart failure drugs.TEER induces reverse remodeling involving both left and right chambers at mid-term follow-up. The most relevant impact is right chamber reverse remodeling that occurs even in the absence of the improvement of LV functional parameters. The MR mechanism and the history of AF significantly impact this process and should be considered for personalized patient management.


Heart failure (HF) is a progressively deteriorating medical condition that significantly reduces both the patients’ life expectancy and quality of life. Even though real progress was made in the past decades in the discovery of novel pharmacological treatments for HF, the prevention of premature deaths has only been marginally alleviated. Despite the availability of a plethora of pharmaceutical approaches, proper management of HF is still challenging. Thus, a myriad of experimental and clinical studies focusing on the discovery of new and provocative underlying mechanisms of HF physiopathology pave the way for the development of novel HF therapeutic approaches. Furthermore, recent technological advances made possible the development of various interventional techniques and device-based approaches for the treatment of HF. Since many of these modern approaches interfere with various well-known pathological mechanisms in HF, they have a real ability to complement and or increase the efficiency of existing medications and thus improve the prognosis and survival rate of HF patients. Their promising and encouraging results reported to date compel the extension of heart failure treatment beyond the classical view. The aim of this review was to summarize modern approaches, new perspectives, and future directions for the treatment of HF. Heart failure (HF) is a progressively deteriorating medical condition that is associated with a high risk of hospitalization and unscheduled hospital visits and significantly reduces the patients’ life expectancy and quality of life . AlthougOver the last 30 years, the medical management of HF has significantly progressed, thus leading to the amelioration of quality of life and outcomes, especially for patients with reduced left ventricular ejection fraction (HFrEF). The discovery of various pathological mechanisms has made this possible and it has led to a better comprehension of heart failure and thus to the development of novel and effective therapies. Despite recent advances in the pathophysiology of HF and the breakthroughs in the pharmacological and non-pharmacological management of chronic HF, the overall patients’ prognosis remains poor. Thus, the research and discovery of new underlying mechanisms of HF physiopathology pave the way for the development of novel HF therapeutic approaches . In thisThe autonomic nervous system, the renin–angiotensin–aldosterone system (RAAS), and the natriuretic peptide (NP) system play a pivotal role in the modulation of the mechanisms involved in the development and progression of HF . It is wOmapatrilat was the first drug developed for the inhibition of both ACE and neprilysin pathways, but the results from the OVERTURE  trial did not show superior benefits when compared to angiotensin-converting enzyme inhibitor (ACEi) alone in lowering heart failure hospitalization rate or mortality risk . Due to At the time of enrollment, all patients in the PARADIGM-HF trial were hemodynamically stable and treated with an ACEi or angiotensin receptor blocker (ARB). The goal of the PIONEER-HF  study was to assess the safety and effectiveness of sacubitril–valsartan in comparison with enalapril in hospitalized patients with worsening HF, more than half of whom were not receiving neither an ACEi nor an ARB at the point of enrollment . SurprisTaken together, all these data indicate that ARNI is a promising approach for the treatment of HF. Thus, in the American College of Cardiology Foundation (ACCF), American Heart Association (AHA), and Heart Failure Society of America (HFSA) guidelines, ARNI therapy became a class 1A recommendation, and it should be the primary renin–angiotensin modulator, whereas ACEi or ARB may be used if ARNI therapy is not possible . MeanwhiWhile sodium-glucose co-transporter-2 inhibitors (SGLT2i) were first developed as oral drugs to lower blood glucose by the inhibition of renal tubular sodium-glucose cotransporters, large randomized controlled studies have recently shown that SGLT2i improve cardiovascular outcomes independent of diabetes, along with reducing the risk of HF hospitalization, cardiovascular death, and all-cause mortality ,16,17,18In the EMPA-REG OUTCOME , the first trial that assessed the impact of SGLT2i on cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM), empagliflozin showed a lower rate of the primary composite outcome of cardiovascular death, and also a reduced incidence of any cause of mortality or HF hospitalization versus placebo . InteresThe remarkable amount of data demonstrating the beneficial effects of SGLT2i has prompted more studies into their potential implications for cardiovascular events and mortality in broader cohorts, which are not confined to diabetes groups. On that account, an increasing number of studies, including two major randomized controlled trials, DAPA-HF (Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with Chronic Heart Failure) and EMPEROR-Reduced , examined the effects of SGLT2i in both diabetic and non-diabetic HF patients ,32. AlmoApproximately half of all HF patients suffer from HFpEF, and it is expected that this group of HF patients will increase due to a prolonged life expectancy and a growing prevalence of comorbidities  that are now recognized as direct contributors to HFpEF . Unlike Empagliflozin is also a successful approach for HFpEF with LVEF ≤65% since it was able to decrease HF hospitalization and significantly improve Health-Related Quality of Life (HRQOL), as shown in the EMPEROR-Preserved  trial ,41,42.In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) clinical trial, sotagliflozin, a dual SGLT1/SGLT2 antagonist, substantially reduced the incidence of fatal cardiovascular events, hospitalizations, and urgent visits for HF among diabetic patients with worsening HF compared to placebo . The incThe nitric-oxide-soluble guanylate cyclase (NO-sGC) pathway is altered in decompensated HF due to a reduced NO bioavailability and a shift in the redox state of sGC, which renders it insensitive to NO. Therefore, restoring NO-sGC-cGMP (cyclic guanosine monophosphate) signaling should have the potential to alleviate the HF burden ,47. VeriOn the contrary, sGC activators, such as cinaciguat, operate exclusively on abnormal sGC, irrespectively of endogenous NO. In patients with HF, cinaciguat significantly decreased the pulmonary capillary wedge pressure (PCWP) at 8 h, but also increased the incidence of arterial hypotension, which determined the early withdrawal of this trial. Due to its distinctive pharmacokinetic and pharmacodynamic characteristics, vericiguat has a minor impact on arterial blood pressure values when compared with other medications of this class, reducing systolic blood pressure by almost 2 mmHg on average ,51,52. ISOCRATES-REDUCED (Phase IIb Safety and Efficacy Study of Four Dose Regimens of Vericiguat in Patients with Heart Failure with Reduced Ejection Fraction Suffering From Worsening Chronic Heart Failure) and VICTORIA (Vericiguat in Participants with Heart Failure with Reduced Ejection Fraction) are the two clinical trials that assessed the safety and effectiveness of vericiguat in HFrEF patients ,52. In tIn the VITALITY-HFpEF (Outcomes in Vericiguat-treated Patients with HFpEF) trial, the vericiguat alongside standard of care in HFpEF patients did not increase the quality of life assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) score . This maPatients with a recent worsening HF episode and a baseline NT-proBNP value riciguat . The newriciguat . In futuVarious drugs that increase cardiovascular outcomes have been identified in patients with HFrEF, but none of them addresses the main drawback of HFrEF, which is impaired systolic function, subsequent decreased cardiac output (CO), and augmented filling pressures . In addiMyosin uses chemical energy to generate force for cardiac myocyte contraction, an activity which is modulated by intracellular calcium levels and regulated by several upstream signaling cascades . CardiacIn the COSMIC-HF  interventional clinical trial, 544 patients with HFrEF treated with omecamtiv mecarbil showed an improved left ventricular systolic function, as assessed by a rise in systolic ejection time and EF. Moreover, an improvement in the myocardial strain was also reported, while left ventricular both systolic and diastolic volumes, NT-proBNP, and heart rate (HR) decreased ,66. The Ghrelin, first discovered in 1999, is a 28-amino acid growth hormone (GH)-releasing peptide, produced mostly by X/A-like cells of the stomach and, to a lesser degree, by the heart and other organs ,70. SeveThese significant and valuable cardiac effects, together with vascular protection, suggest that ghrelin is a promising candidate for the treatment of congestive heart failure and should be further investigated . SynthetEven though real progress has been made in the past decades in the discovery of novel pharmacological treatments for HF, the prevention of premature deaths has only been marginally alleviated. Despite the availability of a plethora of pharmaceutical approaches, proper management of HF is still challenging. Thus, further research, experimental, and clinical studies focusing on the discovery of novel drugs targeting new pathological mechanisms involved in HF are still mandatory.Recent technological advances have made possible the development of various interventional techniques and device-based approaches for the treatment of cardiovascular diseases. In the following paragraphs, we aimed to summarize the advances made in the development of such procedures and device-based therapies for HF (other than cardiac resynchronization therapy), since these approaches complement and increase the efficiency of the classical drug-based treatments. Moreover, since many of these modern approaches interfere with various well-known described pathological mechanisms in HF, they have a real capability to increase the efficiency of existing medications and improve the prognosis and survival rate. Thus, we consider that among the classical and recently discovered drugs for the treatment of HF, non-pharmacological approaches (other than cardiac resynchronization therapy) must also be discussed.2 consumption, resulting in a reduction in cardiac output during relaxation [The autonomic nervous system (ANS) plays a critical role in the regulation and homeostasis of the human body, particularly of the cardiovascular system. Since in HF ANS dysregulation has a detrimental effect on cardiac function, improving this pathological alteration by various approaches may represent a pillar in the management of HF . The symlaxation . Primarilaxation . Complexlaxation . Brieflylaxation . In the laxation .HF is characterized by an imbalance of the ANS, which generates a vicious cycle, meaning that the increased sympathetic activity together with reduced vagal activity promote the progression of ventricular remodeling and worsening of heart failure, and likewise, the development of HF further exacerbates the discrepancy between sympathetic and vagal activity . High leCardiac sympathetic denervation (CSD) is a surgical antiadrenergic intervention that has significant antiarrhythmic effects, as demonstrated by both preclinical and clinical studies, being effective in severe ventricular arrhythmias [hythmias ,91. CSD hythmias . Left-sihythmias , and venhythmias ,95,96.Renal denervation (RDNx) is a catheter-based procedure used to ablate renal nerves as a solution to ameliorate the pathophysiology of HF by lowering the activity of the sympathetic nervous system. In both HF experimental and clinical studies, RDNx is able to induce antihypertensive effects but also improve adverse cardiac remodeling [modeling ,99,100. modeling . In the modeling . FurtherVagus nerve stimulation (VNS). During an inflammatory response, the vagus nerve acts as an afferent and efferent pathway between the brain and peripheral organs, including the heart [he heart . In the he heart . Thus, ihe heart . Schwarthe heart . Howeverhe heart ,107,108.he heart .Tragus nerve stimulation. One of the main drawbacks of vagus stimulation is the invasive nature of this therapy, which is accompanied by surgical risks and low patient tolerance [olerance . Low-levolerance . Currentolerance . Human tolerance . In a piolerance .Cardiac contractility modulation (CCM) is a novel approach that employs non-excitatory electrical impulses to the interventricular septum during the absolute refractory period [y period . Implanty period . Increasy period . After ty period , FIX-HF-y period . At a 2-y period . This way period ,122.Baroreceptor activation therapy (BAT). The carotid body and sinus are innervated by both PNS  and SNS . Electrical stimulation of carotid sinus baroreceptors generates afferent signals to the dorsal medulla, resulting in SNS reduction and enhanced vagal tone, which reduces blood pressure and heart rate [art rate ,124. In art rate . Barorecart rate . In precart rate . The BeAart rate . Moreoveart rate .Endovascular Ablation of the Right Greater Splanchnic Nerve (GSN). Exertional dyspnea, decreased aerobic capacity, and higher mortality are all linked to elevated intracardiac filling pressures at rest and during exercise in HF patients with both reduced and preserved ejection fraction [fraction ,129,130.fraction .Reduced inotropic and chronotropic reserves, as well as impaired relaxation, all contribute to higher filling pressures at rest and during activity. The vascular system is also involved in this process by reducing pulmonary arterial compliance and increasing pulmonary arterial resistance. Excessive blood volume distribution from extrathoracic compartments into the thorax is a major factor in high filling pressures in HF patients ,132. SplSplanchnic nerve activity modulation has thereby been developed as a possible treatment approach in HF patients to reduce volume redistribution and improve symptoms and outcomes. Recent research has explored the impact of temporarily and permanently blocking the GSN over the HF spectrum. Splanchnic nerve modulation has been proven beneficial for both acute decompensated (ADHF) and chronic heart failure (CHF), according to the Splanchnic Nerve Anesthesia in Heart Failure and Abdominal Nerve Blockade in Chronic Heart Failure trials. In 11 ADHF patients with advanced HFrEF who underwent short-term blockade of the greater splanchnic nerve via anesthetic agents, there was a significant decrease in PCWP and an increase in the cardiac index . ComparaREBALANCE-HF (Endovascular Ablation of the Right Greater Splanchnic Nerve in Subjects Having HFpEF) is an ongoing, multicenter, randomized, sham-controlled trial whose objective is to assess the safety of unilateral ablation of the right greater splanchnic nerve and its effectiveness in improving hemodynamics, quality of life, and exercise tolerance in patients with HFpEF . The preSleep-disordered breathing, a widespread condition affecting both the circulatory and respiratory systems, is one element now recognized as contributing to the increased morbidity and mortality in HF. Two primary sleep apnea syndromes have been described: obstructive sleep apnea syndrome (OSA) and central sleep apnea syndrome (CSA) .Stimulation of Phrenic Nerve. This procedure involves inserting an electrode into a brachiocephalic or pericardiophrenic vein to detect the diaphragm’s contractions throughout breathing and activate the diaphragmatic nerve during apnea, with the purpose to preserve fairly constant pO2 and pCO2 levels and avoid SNS and RAAS overactivation [tivation ,142. In tivation . A 5-yeativation . Accorditivation . Large-stivation .Synchronized Diaphragmatic Therapy. Increased intrathoracic pressure exerts persistent stress on the heart muscle and may exacerbate heart failure (HF). The respiratory muscles have a substantial effect on intrathoracic pressure, and, thus, the implantation of a device coupled to an electrode that detects the heartbeat that activates the diaphragm was developed [eveloped . In the eveloped . At the eveloped . AlthougAlthough loop diuretics continue to represent the backbone of decongestive treatment in HF, the occurrence of drug resistance, particularly with prolonged usage, poses a therapeutic issue that requires the development of novel approaches .TARGET-1 and TARGET-2  Using an Automated Fluid Management System) trials evaluated the safety and effectiveness of controlled decongestion using the Reprieve system, which is intended to detect urine output and administer a specific amount of substitute solution to reach the predefined fluid balance. In both trials, patients experienced an increase in urine output, a decrease in body weight, and a drop in central venous pressure (CVP), while the SBP remained constant and without renal dysfunction . The firThe VENUS-HF (VENUS-Heart Failure Early Feasibility Study) regarding the preCARDIA system, a device implanted into the superior vena cava to induce transient blockage, resulting in a reduction in right ventricular preload, revealed a reduction in right atrial pressure and PCWP . The WhiIn the ALLEVIATE-HF-1 (NCT04583527), ALLEVIATE-HF-2 (NCT04838353), and ALLEVIATE-HFrEF (NCT05133089) studies, patients with HFpEF, HFmEF, and HFrEF will be enrolled for treatment through a no-implant interatrial shunt, using clinical, echocardiographic, and invasive hemodynamic data. The transcatheter system is designed to lower left atrial pressure by developing a therapeutic interatrial shunt, without the need for a permanent cardiac implant or open-heart surgery.RELIEVE-HF (Reducing Lung Congestion Symptoms in Advanced Heart Failure- NCT03499236), a randomized clinical trial, is evaluating the impact of the V-Wave Ventura Interatrial Shunt System on heart failure patients, including the ability to lower hospitalizations and improve symptoms, exercise capacity, and quality of life. This small, hourglass-shaped device facilitates blood to flow from the left to the right atrium, lowering the pressure on the left side during physical activity.It is a certainty now that the technological advances from the last years have paved the way for the development of non-pharmacological approaches that may efficiently complement classical HF therapy. Although further experimental studies are required to elucidate the underlying mechanisms through which many of these therapies act, the promising and encouraging results reported to date compel us to extend the HF treatment beyond the classical view.A late-breaking discovery presented at the European Society of Cardiology’s (ESC) Heart Failure 2022 congress was a voice analysis software that can be used by heart failure patients at home that can detect fluid in the lungs in up to 80% of cases, three weeks prior to an unexpected hospitalization or escalation in outpatient medication therapy . As cardFor accurate quantitative and qualitative evaluation of heart failure, AI has been incorporated into different cardiac imaging techniques, such as echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography. Machine learning algorithms have been found to deliver a near-instantaneous echocardiography evaluation. Knackstedt et al. showed that the LVEF and longitudinal strain could be determined in less than 8 s . This quCurrent HF healthcare services are insufficient to satisfy the demands of an ageing population with rising comorbidities and disease complexity, as well as the disparity in medical care distribution between rural and urban areas. As a result of these factors, an urgent need to develop alternative healthcare treatments has arisen. eHealth apps have the ability to relieve a large amount of the strain on healthcare services while also improving patient care. The PASSION-HF  project intends to create a virtual doctor, a digital decision support system that offers options based on current clinical standards. Patient independence is enhanced by providing tailored HF management 24 h a day, 7 days a week. In addition, the program establishes processes and decision points at which medical experts must be involved .Although AI has the potential to solve many of the fundamental challenges faced by the current HF pandemic, it is still a fast-growing field, and therefore some caution is advised. Transparency in data quality, population representativeness, and performance evaluation will be critical. Clinicians, patients, caregivers, and IT professionals should all be included in discussions about legal, technological, and regulatory problems, with ethics and equity being prioritized .Heart failure is becoming an irrefutably significant disease entity as the population ages. Thus, various mechanisms contributing to the development and progression of HF have been discovered and targeted with novel medications and non-pharmacological approaches throughout the last three decades. This has improved the clinical outcome of millions of people worldwide with HF in terms of mortality, quality of life, and survival. Researchers are aiming to identify subgroups in which specific drugs and/or devices may be most successful, innovative methods for enhanced diagnosis and prediction of prognosis in HF patients, and novel tools for treating HF. New therapies will hopefully bring more benefits and extend these results to the treatment of HFpEF also, as well as other causes and phenotypes of HF.


The results were compared with those of individuals with healthy heart (n = 150) and another primary myocardial disease with also thickened myocardium and severe diastolic and systolic LV-dysfunction . In addition to standard echocardiographical measures, the STE-derived data were evaluated and documented utilizing polar-diagrams to obtain overviews of longitudinal myocardial mechanics of the entire LV. Compared with healthy individuals, patients with CAM and LV-NC showed significantly reduced LV-ejection-fraction (EF), global longitudinal systolic peak-strain, strain-rate, and displacement. Pre-systolic stretch-index, post-systolic index, and the EF/global peak-longitudinal-strain-ratio (EF/S) were increased. In contrast to healthy-hearts and the LV-NC group only patients with CAM demonstrated significantly reduced time-to-peak systolic longitudinal strain and time-to-peak strain-rate. Although the level of the segmental values in longitudinal mechanics was significantly different between the groups, comparable intraventricular baso-apical parameter-gradients were found for systolic longitudinal peak-strain and strain-rate, pre-systolic-stretch-index, post-systolic-index, and peak systolic displacement. Compared to ATTR-amyloidosis (ATTR-CAM), patients with AL-amyloidosis (AL-CAM) demonstrated significantly lower end-diastolic and end-systolic LV-volumes, LV-mass-indices, relative apical strain, time-to-peak systolic longitudinal strain, and time-to-peak longitudinal strain-rate. CAM and LV-NC demonstrated altered myocardial mechanics with significantly different STE-derived echocardiographical parameters. ATTR-amyloidosis and AL-amyloidosis had at least significantly different time-to-peak strain, time-to-peak strain-rate and relative apical sparing values.Cardiac amyloidosis (CAM), the most common cardiac storage disease is associated with significant changes in left-ventricular (LV) morphology and function. To gain particular insights into LV systolic longitudinal myocardial mechanics we investigated seven parameters derived by speckle-tracking-echocardiography (STE) in patients with confirmed CAM ( Cardiac amyloidosis is the most frequent cardiac storage disease, which generates myocardial stiffness secondary to intramyocardial deposition of amyloidal fibrils with increasing severity and varying progression rates of diastolic and systolic LV-dysfunction over time according to the extent of myocardial infiltration, CAM-type –7, and oCurrently, especially AL-CAM is mostly verified using myocardial biopsy for histological and immune-histological analyses. Nuclear medicine offers tracers to identify ATTR-CAM –18. In mHowever, echocardiography is the preferred imaging technique at first patient contact that offers parameters which are highly suggestive of myocardial storage disease –24. In tAccordingly, the objective of the present study was to characterize longitudinal myocardial mechanics , 20 in pOur hypothesis was that it may be possible to characterize longitudinal myocardial mechanics in CAM—beyond relative apical strain alone—using different STE-derived parameters in comparison with the data for LV-NC and healthy hearts. Additionally, it should be investigated whether a differentiation between ATTR-CAM and AL-CAM could become feasible.The present retrospective study was conducted between January and December 2020. Besides standard echocardiographical parameters, mappings of the longitudinal myocardial mechanics of the entire LV were created for each of the STE-derived parameters and groups using a 17-segment polar diagram . All parPeak systolic longitudinal strain (%): change of myocardial length in the baso-apical direction compared with the initial value;Peak systolic longitudinal strain rate (%/s): strain over time;Time-to-peak longitudinal strain (ms): time from R-wave (ECG) to peak systolic strain;Time-to-peak longitudinal strain rate (ms): time from R-wave to peak systolic strain rate.Pre-systolic stretch index (%): early systolic stretching relative to the total combined shortening = sum of systolic stretching and shortening. Formula: pre-systolic stretch index = 100 × peak positive strain in early systole/(peak positive strain in early systole–peak negative strain in systole);Post-systolic index (PSI) (%): relative amount of total shortening after aortic valve closure (AVC). Formula: PSI = 100 × (peak systolic strain after AVC–strain at AVC)/peak systolic strain after AVC;Peak systolic longitudinal displacement (mm): systolic myocardial contraction movement in the baso-apical direction;STE analyses included the following parameters:n = 28, AL-kappa n = 2). The echocardiogram used for the study was performed at first patient contact and no patient had medical treatment for amyloidosis before.59 adult Caucasian patients  with histo-pathologically confirmed CAM by endomyocardial biopsy were divided into two subgroups: ATTR-CAM  and AL-CAM  were not accepted to exclude any possible impact of this rhythm disorder on STE-derived analyses.We compared the data in CAM with 30 patients with symptomatic isolated LV-NC   than than8] tAlthough LV-EF is only a global and imprecise measure of the complex systolic myocardial function, LV-EF/S was introduced to be a sensitive parameter to distinguish CAM with an increased value around 5.5 ± 1.5 compared to hypertrophic cardiomyopathy (HCM) (3.7 ± 0.5) and hypertensive heart disease (3.2 ± 0.4) . Our resStrain analyses are crucial for the evaluation of myocardial mechanics like in CAM. In our patients with CAM, global longitudinal systolic strain Table  was compThe CAM cohort showed significantly shortened time intervals until the reduced peak of longitudinal strain and strain-rate was reached Fig. , 2, wherInterestingly, the analyses of time-to-peak systolic longitudinal strain and time-to-peak strain-rate revealed significant differences between ATTR-CAM and AL-CAM. Currently, the cause is unknown but apparently, the underlying pathology that caused shortening of these time intervals in CAM, had an intensified impact in AL-CAM. Therefore, further investigation is required to determine whether one or both parameters may have the potential to differentiate between AL- and ATTR-amyloidosis Fig. b, d.The analyses of pre-systolic stretch-index, post-systolic index, and systolic longitudinal displacement indicated severe LV-dysfunction in CAM and LV-NC Tables , 2. Pre-Finally, an echocardiographical characterization emerged for both myocardial diseases when comparing CAM, healthy hearts and LV-NC taking all investigated STE-derived parameters into account which were summarized in Tab. Segmental analyses of myocardial mechanics provided mappings of the absolute values and intraventricular gradients for each investigated parameter , 21 Fig. In healIn all three groups in the present study, the baso-apical intraventricular gradients of myocardial mechanics were detected with various rates of baso-apical change of values and on significantly different levels. This indicates that segmental myocardial function is present with different strength in the three groups.The observed gradients of longitudinal parameters in circumferential direction were dependent on the investigated myocardial disease. However, no specific circumferential shifting pattern of the parameter’s maxima or minima could be identified for either cardiomyopathy compared with healthy hearts.Higher relative apical strain values may occur in cases with reduced basal and/or midventricular strain for any reason . However, increased relative apical strain  appears to be an accepted indicator for the presence of CAM—with reported values ranging from 0.97 ± 0.3 , 25 to 2In our study, significantly higher relative apical strain values were found in patients with ATTR-CAM versus AL-CAM. The most plausible explanation may be differing distribution patterns of infiltrative material, taking the published findings in cardiac MRI into account. Duncu et al.  and WillAn apical sparing seems to be easily visible using the color-coded polar diagram of a longitudinal systolic peak strain analysis. However, the color coding of the currently available echo-analyzing systems does not take into account the significant physiological intraventricular baso-apical gradients of longitudinal strain in healthy individuals . The curIn healthy hearts, a nearly constant inverse proportionality was observed from basal to apical throughout the entire ventricle between the increasing peak longitudinal systolic strain and the decreasing longitudinal systolic displacement  Fig. 5)5). This When investigating myocardial diseases or even myocardial adaptation/remodeling, strain analyses are the adequate evaluation to gain information about global and segmental impact of the disease. In combination with standard echocardiographical parameters the evaluation of strain-rate, time-to-peak strain and strain-rate and the other STE-derived parameters may follow to differentiate between diverse myocardial diseases or adaptations. When interpreting STE analyses baso-apical gradients of longitudinal parameters of myocardial mechanics should kept in mind as physiological, which is especially important in case of relative apical strain.A kind of constant baso-apical mechanics can be evaluated because strain increases from basal to apical rapidly whereas displacement decreases in a nearly constant inverse proportionality. Cardiomyopathies with reduced systolic function show baso-apical gradients similar to normals but on a reduced level. However, it becomes feasible to differentiate between AL-CAM versus ATTR-CAM.Patients with AL-CAM compared with ATTR-CAM showed significantly lower end-diastolic and end-systolic LV-volumes, LV mass-indices (triple plane technique), time-to-peak systolic longitudinal strain, time-to-peak longitudinal strain-rate, and relative apical longitudinal strain, whereas EF/S was higher.A lower mass-index in AL-CAM is plausible because end-systolic and end-diastolic LV-volumes were lower than in ATTR-CAM but myocardial thickness was similar in both subgroups. Possible causes for differences in the other parameters may be the lower mean age of patients with AL-CAM compared with ATTR-CAM (79.2 ± 6.6 vs 66.0 ± 8.7), the gender distribution in the subgroups , or different stages of the disease in the two groups. However, another plausible explanation is the different protein-structure and distribution of the fibrils and the reaction of surrounding myocardial tissue, which may cause different myocardial mechanics of AL- and ATTR-CAM on a cellular level.Our findings need to be interpreted in light of limitations. Age-related differences of especially longitudinal peak strain have been reported to be predominantly present for the apical LV section in healthy hearts when comparing between age-groups of 30–39 and > 60 years . In our The conditions of the study were not directly comparable to those of routine daily practice, because we evaluated LV myocardial mechanics for all groups under identical technical conditions in a single center. In addition, our findings cannot be generalized to analyses performed with other types or brands of echocardiographic equipment. Furthermore, patient groups with CAM and LV-NC were selected because patients with bundle branch blocks were not accepted due to a potential effect of these rhythm disorders on STE analyses.In patients with myocardial diseases analyses of global and especially segmental myocardial LV mechanics using STE is important. Although CAM and LV-NC showed increased myocardial thickness in combination with severe systolic and diastolic LV-dysfunction, both diseases demonstrated significant differences of global and segmental longitudinal myocardial mechanics of the LV and could be characterized. Differentiation between ATTR-CAM and AL-CAM may become feasible, because several parameters were significantly different between both subtypes of CAM. Whether an echocardiographical characterization for different myocardial diseases or even myocardial adaptive processes using STE-derived parameters is possible, needs investigations of other cardiomyopathies to allow comparisons.


Despite improved survival a substantial number of Fontan patients eventually develop late failure. Fontan-associated liver disease (FALD) is the most frequent end-organ dysfunction. Although impaired hemodynamics and Fontan failure correlate with FALD severity, no association between hepatic functional metabolic impairment and Fontan hemodynamics has been established.Metabolic liver function measured by liver maximum function capacity test (LiMAx®) correlates with Fontan hemodynamics and Fontan failure.From 2020 to 2022, 58 adult Fontan patients  were analyzed in a cross-sectional study. Hemodynamic assessment included echocardiography, cardiopulmonary exercise testing and invasive hemodynamic evaluation. Fontan failure was defined based on commonly applied clinical criteria and our recently composed multimodal Fontan failure score.*kg). In 18 patients a mild to moderate impairment was detected (140–314 μg/h*kg), no patient suffered from severe hepatic deterioration (≤ 139 μg/kg*h). Fontan failure was present in 15 patients. Metabolic liver function was significantly reduced in patients with increased pulmonary artery pressure (p = 0.041. r = −0.269) and ventricular end-diastolic pressure , respectively. In addition, maximum liver function capacity was significantly impaired in patients with late Fontan failure .LiMAx® test revealed normal maximum liver function capacity in 40 patients (>315 μg/hMaximum liver function capacity as determined by LiMAx® was significantly reduced in patients with late Fontan failure. In addition, elevated pulmonary artery pressure and end-diastolic ventricular pressure were associated with hepatic functional metabolic impairment. Despite its tremendous success in treating patients with univentricular anatomy, the Fontan operation remains a palliative procedure, which is characterized by abnormal hemodynamics , 2. In t13C-methacetin into 13CO2, reliably correlates with hepatic parenchymal volume and metabolic function  Fontan hemodynamics by clinical, echocardiographic and invasive assessments and (II) late Fontan failure.From 2019 to 2022 58 adult Fontan patients, who successively presented in our outpatient clinic for follow-up, were included in our cross-sectional observational study. All patients received measurement of maximal liver function capacity using LiMAx® test as well as a detailed hemodynamic and hepatic assessment. Exclusion criteria were intolerance to methacetin or paracetamol and/or patient age below 18 years. The institutional review board and ethics committee approved the study (decision number: EA2/127/18). All individual participants consented to participate in the study prior to inclusion.2peak) was measured in ml/kg*min and normalized in % of age-, gender- and body dimension-adjusted reference values. Cardiac catheterization included measurements of mean pulmonary artery pressure (mPAP) and systemic ventricular end-diastolic pressure (SVEDP). Transpulmonary pressure gradient (TPG) was calculated as the difference between mPAP and pulmonary capillary wedge pressure. Cardiac output (CO) and pulmonary vascular resistance (PVR) were determined by Fick's principle using oximetry . Fontan failure was defined as severe dysfunction of the Fontan circulation caused by impaired ventricular function, moderate to severe atrioventricular valve incompetence, increased pulmonary vascular resistance, recurrent arrhythmia or therapy-refractory protein-losing enteropathy based on commonly applied clinical criteria  and cardiac catheterization. Systolic ventricular function was measured by echocardiography based on the modified Simpson's method . Atrioveoximetry . For comcriteria  and our criteria . Brieflycriteria .www.biopredictive.com).Hepatic assessment was performed based on our previously published institutional protocol  and consThe LiMAx® test was performed following the standardized protocol of Stockmann et al. .13C-labeled methacetin was administered intravenously. The hepatozyte-specific CYP1A2 system metabolizes 13C-labeled methacetin into paracetamol and 13CO2, which is continuously measured in the exhaled air. The LiMAx test result is calculated based on the individually determined maximum delta-over-baseline ratio of 13CO2/12CO2  of O2/12CO2 .p-value < 0.05 was considered statistically significant.Data were collected from medical records of the German Heart Centre Berlin. Data are expressed as median and interquartile range, which were calculated as the 75th minus 25th percentile. Fontan follow-up duration was defined as the interval between Fontan operation and last follow-up. Correlations between maximum liver capacity, echocardiographic, hemodynamic and hepatic parameters as well as the Fontan failure score were assessed using Spearman's correlation and Mann-Whitney U test. Statistical analyses were performed using SPSS statistical software . A Patient characteristics of the entire cohort are provided in 2peak was 44.4 % (IQR 21.3) in the entire cohort. Invasive hemodynamic evaluation revealed mPAP, SVEDP and TPG to be within normal reference ranges (2 (IQR 0.8) and median PVRi 2.3 WU*m2 (IQR 1.1). Late Fontan failure was diagnosed in 15 patients.Results of hemodynamic assessment are presented in e ranges . Calculap = 0.017). Results from hepatic ultrasound revealed that surface nodularity, ascites and segmental atrophy/ hypertrophy were more frequently detected in patients with Fontan failure (p = 0.001), whereas Fibrotest® fibrosis score did not differ between patients with and without Fontan failure.Results of hepatic assessment are listed  failure . Additio*h (IQR 160.8), which corresponds to a normal hepatic function (≥ 315 μg/kg*h). In 18 patients maximum liver function capacity was moderately impaired (140–314 μg/kg*h), while no patient suffered from severe hepatic damage (≤ 139 μg/kg*h). No correlation was detected between systolic ventricular function or the extent of AVVI and maximum liver function capacity . Additionally, no association was found between VO2peak and LiMAx® test results . No correlation was detected between maximal liver function capacity and resting or peak oxygen saturation . In patients with mPAP ≥ 15 mmHg maximal liver function capacity was significantly reduced compared to patients with mPAP <15 mmHg [294.0 μg/kg*h (IQR 126.0) vs. 388.5 μg/kg*h (IQR 177.0), p = 0.019, *h (IQR 136.5) vs. 401.0 μg/kg*h (IQR 173.0), p = 0.029; *h (IQR 140.0) vs. 390.0 μg/kg*h (IQR 162.0), p = 0.007; Median maximum liver function capacity was 355.0 μg/kgThis is the first study to describe the association between Fontan hemodynamics, Fontan failure and maximum liver function capacity assessed by LiMAx®. Briefly, no correlation was detected between echocardiographic parameters or CPET results and metabolic liver function. Additionally, hemodynamic parameters such as CI and PVRi also showed no association with results from the LiMAx® test. However, maximum liver function capacity was significantly decreased in patients with increased mPAP (≥15 mmHg), and those with increased SVEDP (≥12 mmHg) as well as in patients with Fontan failure. In these patients, hepatic functional impairment was graded as moderate whereas no severe hepatic failure was detected.The LiMAx® test was introduced to accurately quantify metabolic liver function based on the hepatocyte-specific cytochrome P4501A2 (CYP1A2) system and was evaluated in several clinical settings –19. We pDue to the non-physiological hemodynamics, failure of the Fontan circulation is inevitable in the long term –22. Sinc*h (IQR 148.8) vs. 369.5 μg/kg*h (IQR 182.5), p = 0.029), however, none of these patients fulfilled the criteria for a combined heart and liver transplantation such as hepatocellular carcinoma or severe liver cirrhosis. In patients who survived cardiac transplantation, improvements in morphological and laboratory FALD parameters were detected. This observation has also been reported by other institutions and might underline the remarkable hepatic potential for regeneration (The LiMAx® test may represent a valuable complementary diagnostic modality in the hepatic assessment of Fontan patients and provides a reproducible quantitative measurement of hepatocyte function. Since a deterioration of maximum liver function capacity seems to occur relatively late during the disease course, when a significant impairment of Fontan hemodynamics and Fontan failure is already evident, its occurrence may prove as a valuable indicator for the requirement of a timely evaluation for cardiac transplantation. In our cohort, maximum liver function capacity was moderately reduced in patients who received cardiac transplantation [247.0 μg/kgneration , 30, 31.However, further well-conducted research efforts are warranted to address these questions, including additional studies, which compare maximum liver function capacity before and after cardiac transplantation as well as explore correlations of hepatic metabolic function with histologic findings of liver biopsies.This study has several limitations. Since this is a cross-sectional single center study with a comparably small patient cohort, future multi-institutional studies are necessary to evaluate metabolic liver function in larger patient cohorts. Additionally, the longitudinal relationship between Fontan hemodynamics and hepatic function was not addressed by this study. Since the parameters SVEDP and PAP are included in the calculation of the Fontan failure score, the association between LiMAx and Fontan failure might be confounded. However, considering that SVEDP and PAP are only 2 of 15 parameters used for score calculations, the confounding effect seems negligible. Additionally, all of the 15 Fontan failure patients fulfill the clinical consensus definition criteria of Fontan failure . Parts oWe herein demonstrate that maximum liver function capacity measured by the LiMAx® test is impaired in patients with impaired Fontan hemodynamics and Fontan failure. Hence, the LiMAx® test represents a valuable complementary diagnostic modality for FALD and might be useful in evaluating the indication for combined heart and liver transplantation.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethikkommission der Charité, Berlin. The patients/participants provided their written informed consent to participate in this study.Conceptualization and formal analysis: AS, PK, and SO. Data collection: AS, NJ, MP, and PK. Investigation: AS, PK, FD, H-PM, TM, and HS. Supervision: FB and FT. Writing original draft: AS. Writing review and editing: PK and SO. All authors contributed to the article and approved the submitted version.Parts of the study were funded by Kinderherzen e.V., who also finance the open access publication of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.