The aims of the present study were to determine the subclinical coronary atherosclerosis and myocardial dysfunction in patients with non-alcoholic fatty liver disease (NAFLD), who were asymptomatic for cardiac disease.A total of 61 non-alcoholic fatty liver disease patients were enrolled in the study. The 10-year probability of cardiovascular events was evaluated according to the pooled cohort equation risk score (atherosclerotic cardiovascular disease). The coronary artery calcium score was measured. Conventional echocardiographic examination was followed by 2- and 3-dimensional speckle tracking echocardiography.P = .018), serum alanine aminotransferase (P = .002) and aspartate aminotransferase levels (P = .021), hepatic steatosis (P = .023), and fibrosis (P = .001) than non-alcoholic fatty liver disease patients.Patients with non-alcoholic steatohepatitis had significantly higher insulin resistance (The mean Atherosclerotic Cardiovascular Disease score was 7.5% ± 6.9% and 37% of the patients had medium and high cardiovascular disease risk. Cardiovascular disease (>1) was found in 30% of the patients. Interestingly, 56% had significant and extended atherosclerotic plaques. Among the patients with moderate-to-high atherosclerotic cardiovascular disease scores, 63% had significant atherosclerotic plaques and 21% had extensive plaque burden. The presence of non-alcoholic steatohepatitis did not significantly affect cardiovascular risk.P = .002). Mean E/e’ ratio was 8.1 ± 2.0. Submyocardial fibrosis detected had a slightly higher occurrence in non-alcoholic steatohepatitis patients than in non-alcoholic fatty liver disease patients (P = .530).Non-alcoholic steatohepatitis was deleterious on left ventricle diastolic functions. Mean A velocity in non-alcoholic steatohepatitis patients was significantly increased compared to non-alcoholic fatty liver disease patients (87.0 ± 17.5 cm/s vs. 72.3 ± 13.6 cm/s, NAFLD seems to be associated with an increased risk of subclinical cardiovascular disease and myocardial dysfunction in asymptomatic patients with cardiac disease. Coronary artery calcium is a sensitive and specific predictor to screen for early atherosclerosis.10 Increased calcification levels are indicative of a high total plaque burden and increased risk for prevalent CAD.10Studies have shown that NAFLD is associated with an increased risk of subclinical atherosclerosis including increased carotid intima-media thickness (CIMT), coronary artery calcium (CAC), arterial stiffness, and endothelial dysfunction.13 Both 2D and 3D speckle tracking echocardiography can be used to measure LV strain during the early diagnosis of structural and functional changes in the heart.13 Previous studies demonstrated that NAFLD was increased by 3 times the risk of mild-to-moderate LV diastolic dysfunction independently of other CVR factors.13 Cardiac magnetic resonance imaging (MRI) is a non-invasive imaging technique with high sensitivity and specificity. It provides detailed information about the morphology, myocardial structure, and tissue perfusion and function.15 Images of T1 mapping are obtained using the modified look-locker imaging (MOLLI) technique.15Non-alcoholic fatty liver disease may cause altered left ventricle (LV) structure and function and develop diastolic heart failure and cardiac dysfunction.In contrast to previous studies that evaluated the association between NAFLD and CVD in individuals with NAFLD diagnosed by abdominal sonography or computed tomography (CT), the present study aimed to determine the subclinical coronary atherosclerosis and myocardial dysfunction in biopsy-proven NAFLD patients, who were asymptomatic for cardiac disease.This is a prospective cross-sectional single-center study including biopsy-proven NAFLD patients, in the Ankara University School of Medicine, Department of Gastroenterology, Liver Diseases Outpatient Clinic between July 2017 and June 2019. The diagnosis of NAFLD was based on biochemical, radiological, and histological criteria, excluding other forms of acute and chronic liver diseases. Data were collected from outpatient visit charts. All patients provided their personal and familial medical history at the time of their recruitment into the study. Written informed consent was obtained from each patient. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the local ethical committee of the Ankara University School of Medicine.Biochemical and serological tests were conducted in the central laboratory of Ankara University School of Medicine. Laboratory tests were performed at the time of diagnosis, during the follow-up period, and during exacerbation of liver enzyme levels.All patients underwent abdominal sonography confirming the presence of fatty infiltration of the liver. Hepatic steatosis and liver stiffness were measured using a Vibration Controlled Elastography (VCTE) FibroScan 502 touch  with an M or XL probes with different body build types. The VCTE measured the controlled attenuation parameter (CAP) (dB/m) and liver stiffness (kPa) simultaneously.16All liver biopsy specimens were evaluated by 1 pathologist blinded to the clinical and biochemical data. Histological features of the samples were interpreted using the criteria of Kleiner et al.http://www.cvriskcalculator.com/.17 Those with a 10-year risk of <5% were considered low risk, those between 5% and 7.5% were borderline risk, 7.5%-20% were medium risk, and those of >20% were considered high risk.18 The ASCVD risk score does not apply to patients under the age of 40.18The ASCVD risk score was calculated for all participants according to the 2013 American College of Cardiology/American Heath Association Guideline on the Assessment of CVR by using the online calculator 2 and a peak intensity greater than 130. Computed tomography images were acquired with the following parameters: tube current of 300 mA, tube voltage of 120 kV, tube rotation time of 350 ms, section thickness of 3 mm, field of view of 200-220. All scans were analyzed by an experienced radiologist (CU). The CAC score was categorized into 0,1 to 10,11 to 100,101 to 400, and >400. Coronary artery calcification is defined as CAC > 1.19Coronary CT was conducted by a 64-slice CT scanner . The CT data were transferred to a remote workstation  for post-processing and subsequent evaluation. The CAC score was determined using the dedicated software Vitrea 2. The CAC scores were calculated applying the Agatston method, by summing calcium scores of each artery where coronary calcification was identified as a lesion, with an area greater than 1 mm20 Both 2D and 3D images were recorded for speckle-tracking echocardiography. By using a fully sampled 4 MHz matrix array transducer, the full‐volume acquisition was recorded from the cardiac apex for 3 consecutive cardiac cycles during a single breath-hold. The echocardiographic images were analyzed by a cardiologist (CT) blinded to the clinical condition of the subjects. The 2D global longitudinal strain (GLS) was measured using the 2D speckle-tracking Automated Function Imaging (AFI) . The offline analysis of 3D speckle-tracking was performed using the Echopac 4D Auto LVQ software package (GE Vingmed). First, the operator designated the long axis of LV in 3 different apical views . This software distinguishes the endocardial border of LV and tracks the border for an entire cardiac cycle. Finally, by using the standard 16‐segment model, the curves of peak strain are determined. The recorded 3D Speckle-Tracking Echocardiography (STE) parameters were LV end‐diastolic volume, end‐systolic volume, stroke volume, ejection fraction (EF), GLS, global circumferential strain (GCS), global radial strain (GRS), area strain, twist in degrees, and torsion degrees per second.The echocardiography was conducted by experienced cardiologists  using GE Vivid E95, with a 4 MHz 4V sector probe . Standard measurements of chambers and diastolic parameters were performed following related recommendations.21 E(early)/late(A) diastole peak velocity ratios are an indicator of LV diastolic dysfunction. The reference value of the E/A ratio is in the range of 0.8-2.E/A, ratio < 0.8 indicates increased filling pressure.21 The ratio of early trans-mitral velocity over the average of tissue Doppler-derived septal and lateral early-diastolic velocity (E/e’) is a determinant of LV filling pressures. The normal value of the E/e’ ratio is <8; the range of 8-14 was considered undetermined, and >14 is increased LV filling pressure that was considered to indicate abnormal diastolic function. Automated Function Imaging-derived 2D GLS measurement, an indicator of LV systolic functions, as well as 3D GLS, GCS, and GRS measurements, was calculated. The normal average GLS value is approximately −20%, but reference values might vary depending on the vendor. Global longitudinal strain values above −18% are generally considered normal, and the probability of systolic dysfunction increases when absolute values fall below −16% .20 Myocardial performance index (MPI) evaluates LV systolic and diastolic functions together, with a normal value of 0.39 ± 0.05, which is expected to be increased in the case of impaired LV functions.23 However, there is no normal range indicated in the guidelines for strain analysis of 3D speckle-tracking measurements.The most important indicators of LV diastolic dysfunction are deterioration in LV relaxation (velocity(é) decrease), decreased LV refilling forces, increased LV diastolic stiffness, especially an increase in LV end-diastolic pressure (increase in E/é ratio).Cardiac MRI was performed using Aera 1.5 Tesla Siemens . T1 mapping was conducted with the original MOLLI sequence (MOLLI 3(3)3(3)5). The variant (MOLLI 5(3)3) was acquired and followed by T2 mapping. Sequence parameters for MOLLI 5(3)3 were TE/TR/flip-angle:1.12 ms/279.8 ms/35°; voxel size 1.4 × 1.4 × 10 mm, bSSFP; GRAPPA: 2; half scan (7/8 Fourier). For the MOLLI 3(3)3(3)5, the parameters were TE/TR/flip-angle:1.64 ms/418.64 ms/50°; voxel size: 1.7 × 1.7 × 10 mm, bSSFP; GRAPPA: 2; half scan (6/8 Fourier). For standard T1 sequence, 1009 ± 59(±2 SD)ms and Siemens T1 sequence 1006 ± 56 (±2 SD)ms were accepted as mean reference values.The primary aim was to determine the subclinical coronary atherosclerosis and myocardial dysfunction in patients with NAFLD by comparing them with the NAFL and NASH patients.2 defining overweight and ≥30 kg/m2 defining obesity.24 Insulin resistance (IR) was calculated based on fasting plasma glucose and insulin values using the homeostasis model assessment (HOMA) and IR method.25 Percentage of body fat score was determined using a Tanita body composition analyzer.Obesity was defined based on the World Health Organization criteria using the body mass index (BMI) of 25-29.9 kg/mt-test or Mann–Whitney U test depending on the distribution of the data. Categorical variables were assessed with the chi-square test or Fisher’s exact test. Correlations between continuous and/or ordinal variables were calculated using Pearson’s correlation or Spearman’s rho analysis, where applicable. A P-value of less than .05 was considered statistically significant.Means, standard deviations, medians, ranges, and frequencies, and percentages were used for descriptive statistics. Comparisons between 2 groups were performed with Student’s 2 (range: 19.6-43.1 kg/m2), with 34.4% of the patients being overweight (25-29.9 kg/m2) and 55.7% obese (≥30 kg/m2). Body fat ratio was 33.5% ± 8% (range: 15.3%-49.6%). Among the patients, 42.6% had diabetes mellitus, 36.1% had hypertension, 21.3% had hyperlipidemia, 9.8% had been treated with statins, 9% were ex-smokers, and 5% were active smokers. The mean systolic and diastolic blood pressure was 134.4 ± 16.5 mmHg and 79.9 ± 8.1 mmHg, respectively. The mean waist circumference was 103.9 ± 11.0 cm and the hip circumference was 111.5 ± 10.6 cm. At the time of diagnosis, the median serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) levels were 41 U/L (range: 6-215 U/L), 31 U/L (range: 11-132 U/L), and 47 U/L (range: 12-204 U/L), respectively. The median total bilirubin level was 0.7 mg/dL (range: 0.3-2.7 mg/dL), and the median international normalized ratio was 0.95 (range: 0.8-1.2). The baseline characteristics of the patients are shown in A total of 61 NAFLD consecutive patients were recruited for the study. The median age was 54 years (range: 33-67 years), and they were predominantly females (66%).The median BMI was 30.4 kg/mP = .018), serum ALT (P = .002) and AST levels(P = .021), hepatic steatosis (P = .023), and fibrosis score (P = .001) than NAFL patients  and fibrosis was 1 (range: 0-3) . The VCTpatients .P = .675) and the presence of CAC .The mean ASCVD score was 7.5% ± 6.9% . Of the 61 patients, 47.4% (n = 27) had low CVD risk, 15.8% (n = 9) had borderline CVD risk, whereas 36.8% (n = 21) had medium and high CVD risk. Coronary CT was performed on 53 patients. Coronary artery calcium was not detected in 69.8% of the patients (n = 37), whereas it was found in 30.2% of the patients (n = 16). Interestingly, 56.3% (9/16) of them had significant and extended atherosclerotic plaques (CAC > 100) . Among tP = .986). Cardiac output was 3.9 ± 0.9 L/min. Mean GLS, GCS, and GRS strains were (−14.4%) ± 3.5%, (−14.0%) ± 3.0%, and (38.8%) ± 9.3%, respectively. Mean area was (−24.5%) ± 5.1%  diameter was 38.6 ± 4.6 mm. The mean LV end-systolic and end-diastolic diameters were 29.3 ± 4.1 mm and 48.6 ± 3.8 mm, respectively. Left ventricular systolic function reflected by LV ejection fraction was 56.8% ± 5.8%. The presence of NASH did not significantly affect the LV systolic functions  ± 5.1% .P = .002). The severity of fibrosis was significantly correlated with the A velocity . Mean E/e’ ratio was 8.1 ± 2.0. Of note, 44.2% (23/52) of the patients were undetermined (8-14). E/e’ ratio was slightly higher in patients with NASH compared to that of with NAFL patients . Of note, 53% (n = 9) of the patients with medium-to-high risk as defined by their ASCVD scores presented diastolic dysfunction (E/e’ ratio > 8).Non-alcoholic steatohepatitis was deleterious on LV diastolic functions. Mean mitral early and late velocities and E/A ratio were 71.4 ± 16.9 cm/s, 79.8 ± 17.2 cm/s and 0.93 ± 0.3. Mean A velocity in NASH patients was significantly increased compared to NAFL patients .Cardiac MR was performed in available 43 NAFLD patients. Mean routine T1 and Siemens T1 values were 1016.8 ± 27.9 and 1000.9 ± 31.4, respectively. Submyocardial fibrosis was slightly more common in NASH patients than in NAFL patients  study demonstrated that NAFLD is longitudinally associated with subclinical LV remodeling, abnormal LV geometry, impaired LV function, and early diastolic dysfunction.36 The investigators concluded that obesity is the cause of the association between NAFLD and LV function.36 In contrast to previous studies, 2D and 3D speckle-tracking echocardiography was used in the present study. The ventricular chamber, volume quantifications, and LV EF were within the normal limits in patients with NAFLD. The presence of NASH did not significantly negatively affect LV systolic functions, while it was deleterious on LV diastolic functions. Among the NAFLD patients, 44% presented an undetermined E/e’ ratio referring to the increased LV filling pressure. E/e’ ratio was slightly higher in patients with NASH compared to that of NAFL patients (P = .125). Mean A velocity in patients with NASH was significantly increased compared to patients with NAFL (P = .002). The severity of fibrosis was significantly correlated with the A velocity (r = 0.396). Of note, more than half of the NAFLD patients (53%) with moderate-to-high 10-year CVD risk determined by their ASCVD scores presented diastolic dysfunction.Diastolic heart dysfunction is considered a clinically important predictor of mortality in individuals with preserved systolic function.11 Previous limited studies with small samples demonstrated a significant relationship between the severity of NAFLD and LV systolic function in children and adults with NAFLD.38 In the CARDIA study, NAFLD participants presented deteriorating GLS over time, which was mostly attributed to obesity.36 In a recent study, patients with metabolic syndrome had a 2-fold increase in subclinical LV dysfunction risk if they had severe steatosis and a 1.7-fold increase if they had severe fibrosis.37 In the present study, the severity of fibrosis did not significantly correlate with diastolic dysfunction. However, NASH patients had numerically slightly lower 2D and 3D GLS levels than NAFL patients, which might suggest that subclinical LV dysfunctions begin at early stages, before liver fibrosis.Subclinical systolic and diastolic dysfunction in NAFLD patients can be attributed to myocardial steatosis and probably, fibrosis.15 Therefore, it has serious limitations in detecting diffuse myocardial fibrosis.15 T1 mapping has been developed to overcome this problem.15 T1 values are used to obtain information about the international structure of the myocardium. It has been reported that in patients with aortic stenosis, native T1 values and the histologically determined collagen volume fraction are correlated.40 However, similar to our study, although native T1 values were higher in the NAFLD patient, no significant difference was observed among the NAFL and NASH patients, in a study conducted in patients with diabetic cardiomyopathy.41Although late-gadolinium-enhanced images are widely used to detect ischemia-induced cardiac fibrosis, a contrast difference between fibrotic and normal tissue is required to detect the abnormality.In conclusion, based on the results of the present study, NAFLD seems to be associated with an increased risk of subclinical CVD and myocardial dysfunction in asymptomatic patients with cardiac disease. We suggest that the presence of NASH did not significantly increase the risk of CVD and subclinical myocardial dysfunction in such patients.


Introduction: Increasing survival of adult congenital heart disease (ACHD) patients comes at the price of a range of late complications—arrhythmias, heart failure, and valvular dysfunction. Transcatheter valve interventions have become a legitimate alternative to conventional surgical treatment in selected acquired heart disease patients. However, literature on technical aspects, hemodynamic effects, and clinical outcomes of percutaneous atrioventricular (AV) valve interventions in ACHD patients is scarce. Method: This is a descriptive cohort from CAHAL . ACHD patients with severe AV valve regurgitation who underwent a transcatheter intervention in the period 2020–2022 were included. Demographic, clinical, procedural, and follow-up data were collected from patient records. Results: Five ACHD patients with severe or torrential AV valve regurgitation are described. Two patients underwent a transcatheter edge-to-edge repair (TEER), one patient underwent a valve-in-valve procedure, one patient received a Cardioband system, and one patient received both a Cardioband system and TEER. No periprocedural complications occurred. Post-procedural AV valve regurgitation as well as NYHA functional class improved in all patients. The median post-procedural NYHA functional class improved from 3.0 (IQR [2.5–4.0]) to 2.0 (IQR [1.5–2.5]). One patient died 9 months after the procedure due to advanced heart failure with multiorgan dysfunction. Conclusion: Transcatheter valve repair is feasible and safe in selected complex ACHD patients. A dedicated heart team is essential for determining an individualized treatment strategy as well as pre- and periprocedural imaging to address the underlying mechanism(s) of AV regurgitation and guide the transcatheter intervention. Long-term follow-up is essential to evaluate the clinical outcomes of transcatheter AV valve repair in ACHD patients. Congenital heart disease (CHD) has an estimated prevalence of about 1% in the general population ,3. TransThis two-center observational, retrospective cohort study was performed at the departments of Cardiology of the Amsterdam University Medical Center and Leiden University Medical Center, united in the center of Congenital Heart Disease Amsterdam-Leiden (CAHAL). Consecutive ACHD patients with hemodynamically severe AV valve lesions  who underwent a catheter-based intervention to address the AV valve dysfunction between 2020 and 2022 were included in this cohort . All patDescriptive statistics were utilized to summarize data. Normally distributed continuous data are displayed as mean ± standard deviation (SD) and non-normally distributed continuous data are displayed as median and 95% and the first and third interquartiles [IQ1–IQ3]. Categorical data are presented as numbers. Statistical analyses were performed with IBM SPSS Statistics for Windows, version 28 .Five complex ACHD patients (two women), median age 52 years (44–74), with severe or torrential symptomatic AV regurgitation were included in this descriptive cohort; All procedures were performed under general anesthesia with transesophageal (TEE) and/or fluoroscopic guidance, except for one case, which was performed under local anesthesia. No periprocedural complications were reported. Post-procedural AV valve regurgitation improved significantly in all patients . The med2) and elevated levels of NT-proBNP . Despite pharmacological escalation, the patient remained in NYHA functional class III and experienced frequent recurrences of symptomatic AF. The severe functional TR due to annulus dilatation and progressive decline in systolic function of the overloaded right ventricle was deemed to be the cause. The perioperative risk of surgery involving a third thoracotomy in a septuagenarian was high, and therefore percutaneous options were evaluated. Given the malcoaptation and the dilated tricuspid valve (TV) annulus of 62 × 54 mm , presented to the emergency department with complaints of dyspnea and progressive weight gain. He was documented to have persistent AF with inadequate rate-control and signs of moderate left- and right-sided decompensation. He was treated with loop diuretics and underwent successful cardioversion to sinus rhythm after recompensation. Transthoracic echocardiography (TTE) revealed moderately reduced left and right ventricular function, normal function of the aortic bioprosthesis , trivial mitral regurgitation, and torrential tricuspid regurgitation (TR) with elevated filling pressures  A–D. Labo × 54 mm C, the heThe patient underwent a successful Cardioband annular reduction using right venous femoral access under general anesthesia with fluoroscopic (selective cannulation of the right coronary artery) and TEE guidance E–H. A toA 40-year-old female born with Ebstein’s anomaly of the TV who had previously undergone a surgical annuloplasty and a TV replacement with a bioprosthesis  and had two uncomplicated pregnancies afterwards was seen at the outpatient clinic with progressive complaints of reduced exercise tolerance, currently in NYHA functional class II. TTE revealed severe regurgitation and significant stenosis of the TVR bioprosthesis with progressively worsening right ventricular (RV) function and a giant right atrium (RA) partially compressing the left atrial compartment A–E. She This was successfully performed under local anesthesia, by means of right femoral access and fluoroscopy and TTE guidance. A temporary pacemaker wire was placed in the left ventricle and the AgilisTM steerable introducer  was used to safely access the RA, given the relatively sharp angle between the vena cava-RA and the RA-RV axis F. The Ed2) and elevated levels of NT-proBNP . TTE and TEE , mitral valve atresia, large ventricular septal defect (VSD), functionally univentricular heart with a hypoplastic left ventricle) was palliated using multiple Blalock–Taussig (BT) shunts. He had an abnormal systemic venous return with a hemiazygos continuation of the inferior caval vein (IVC) and a persistent left superior caval vein (SVC) A. The pa and TEE D showed As a result of the severely dilated annulus and tethering, the coaptation gap was large, and simultaneous grasping of both leaflets was challenging. The TriClip system has the advanced option of independent leaflet grasping. First, the anterior leaflet  was grasped and, subsequently, after minor device repositioning under TEE guidance, the septal leaflet was captured and the clip was released. The first clip was implanted near the commissure to narrow the coaptation gap so that the second clip could be implanted to treat the regurgitation C, which 2). Moderately reduced systolic and diastolic systemic ventricular function, severe atrial dilatation, and AV valve regurgitation were documented on TTE and TEE. Additional CT imaging showed a severely dilated functional mono-atrium in close proximity to the thoracic wall , pulmonary stenosis, hypoplastic left ventricle, a right-sided aortic arch, a persistent left SVC, and an interrupted IVC (azygos continuation). At the age of 30, he received a bilateral bidirectional Glenn shunt. The patient was now admitted with peripheral edema and permanent AF with adequate rate control and had preserved renal function . Furthermore, a transjugular approach was not feasible because of the bilateral Glenn connection. Therefore, it was decided that a hybrid procedure under general anesthesia with direct atrial access using a MitraClip delivery system  was the best strategy.The congenital cardiothoracic surgeon performed a right (mini) lateral thoracotomy in the fifth intercostal space to expose the giant mono-atrium. A double-purse string suture was placed and an incision was made to create an opening using a Safari wire for guidance and stability. The interventional cardiologist then placed two XTW clips under TEE guidance D, resultA 72-year-old female born with Tetralogy of Fallot (TOF) and having undergone three previous thoracotomies , numerous ablation procedures for atrial arrhythmias after which permanent AF was accepted, and a pacemaker implantation due to a high-degree AV block was evaluated at the outpatient clinic due to progressive complaints of dyspnea on exertion and a recent admission with right-sided decompensation. She was in NYHA functional class IV despite escalation in diuretic treatment.Echocardiography showed severe TR with a regurgitant jet directed towards the inflow of the inferior vena cava and a progressive dilation of the RV with preserved systolic function A,B. The Both procedures were performed in sequential order under general anesthesia, by means of right femoral access and fluoroscopy and transesophageal echocardiographic guidance C,D. A toIn this descriptive cohort, we report on the indication, methodology, and outcomes of transcatheter treatment of five consecutive ACHD patients with severe AV valve regurgitation in the setting of complex anatomical malformations: two patients underwent a TEER, one patient underwent a valve-in-valve procedure, one patient underwent a Cardioband system implantation, and one patient underwent a consecutive Cardioband implantation followed by TEER. In two out of five patients, the regurgitant AV valve was of the systemic ventricle . Post-procedural AV valve regurgitation as well as NYHA functional class improved in all patients. This cohort is illustrative of the feasibility and the wide range of applications of transcatheter techniques in addressing AV valve lesions in ACHD patients and highlights the necessity of an individualized and anatomy-tailored approach.All patients were discussed by a dedicated ACHD team and surgery was deemed to be too high risk for all patients reported. Lifetime rate of re-thoracotomies, extensive adhesions, unique anatomical challenges, hemorrhage prone collaterals, and multi-organ dysfunction are all recognized factors in this decision making favoring a transcatheter approach . Many ofHowever, despite the temptation of a less-invasive approach, it is important to recognize that data on procedural outcomes and long-term clinical results are scarce ,6,7. ThiThe Cardioband system addresses the annular dilatation pathophysiology in a minimally invasive catheter delivered approach. Nickenig et al. conducted the TRI-REPAIR study in thirty patients with moderate or greater functional TR who received a Cardioband system. The implantation of a Cardioband resulted in sustained and significant TR reduction at two years follow-up with substantial improvement in NYHA functional class . Gray etValve-in-valve transcatheter TV replacement has previously been reported to be a good alternative to surgery in patients with severe TV regurgitation and high operative risk ,13. In lFurthermore, three patients underwent a successful TEER, where one patient had a systemic left ventricle whilst the two other patients had a systemic right ventricle. In particular, one of those patients had a functional mono-ventricle with reduced systolic function in the setting of a very complex anatomy, in which the implantation of the clips was feasible and safe (patient D). Despite best efforts, the patient died 9 months after the procedure due to progressive heart failure and concomitant multi-organ dysfunction. Ott et al. previously reported that TEER in congenitally corrected TGA was feasible and safe  and SchaOf particular interest for further studies remain the patients with a failing systemic right ventricle and TR , as well as the growing group of Fontan circulation patients with functional AV-valve regurgitation (REF + REF). These groups are at specifically high surgical risk and the potential of percutaneous AV valve therapies would be a welcome development to mitigate the risk of re-operations ,16.The current series of patients illustrates the importance of a dedicated and experienced ACHD heart team in addressing AV valve dysfunction in this heterogenous patient group. Only after a thorough understanding of the mechanisms contributing to the valvular dysfunction, and careful consideration of the individual perioperative risks and the capability of a transcatheter technique in adequately addressing these mechanisms, can an individualized and weighted decision be made. Multidisciplinary expertise is essential and we advocate for all ACHD patients undergoing transcatheter AV valve repair or replacement to be discussed and treated in specialized centers by dedicated teams. As the vast majority of ACHD patients require a lifelong follow-up, the heart team can also be used as a forum to discuss treatment and follow-up strategies to ensure timely intervention .A comprehensive, multi-parametric, and multimodality approach is necessary to understand the underlying mechanism of AV valve regurgitation. This is essential to determine the optimal management strategy and timing of intervention. Given the current lack of robust data defining the optimal timing window for intervention for the vast majority of ACHD valvular lesions, and the often misleading seemingly “asymptomatic” status of the patients during long-term follow-up, serial imaging plays an essential role in timely detection of hemodynamic deterioration. Thorough review of patient records and focused imaging of the venous and arterial access and intracardiac connections is important, as many ACHD patients have concomitant vascular anatomy variants and venous return abnormalities and have undergone numerous vascular interventions, potentially compromising conventional vascular access routes. Patient C is illustrative of a transjugular venous access utilization and patient D required a hybrid procedure with surgical exposure of the functional mono-atrium and the common AV valve. Of note, several studies showed that pre-procedural planning using 3D modeling/virtual reality (VR) in pediatric cardiothoracic patients is feasible as there are some reports of the experience in ACHD patients ,18,19. VThis descriptive cohort is inherently limited by the small numbers of a heterogenous population and should therefore be interpreted in this context. It describes a two-center experience of an experienced ACHD interventional team and the techniques utilized might not be widely implemented in various settings. The follow-up period is limited and no data are available regarding the long-term  outcomes.In conclusion, novel (hybrid) transcatheter valve therapies, including transcatheter edge-to-edge repair using a TriClip or MitraClip, transcatheter annulus reduction using a Cardioband, and valve-in-valve replacement techniques are feasible and can address AV valve regurgitation in highly selected complex ACHD patients. Comprehensive multimodality imaging and a dedicated ACHD heart team are essential in successfully implementing patient-tailored transcatheter techniques and deferring high risk surgery in selected patients. Long term data on hemodynamic and clinical outcomes are essential in evaluating the efficacy and durability of transcatheter AV valve interventions in ACHD.


Hereditary and wild-type transthyretin-mediated (ATTRv and ATTRwt) amyloidoses result from the misfolding of transthyretin and aggregation of amyloid plaques in multiple organ systems. Diagnosis of ATTR amyloidosis is often delayed due to its heterogenous and non-specific presentation. This review investigates the association of musculoskeletal (MSK) manifestations with ATTR amyloidosis and the delay from the onset of these manifestations to the diagnosis of ATTR amyloidosis.This systematic review utilized Medline and EMBASE databases. Search criteria were outlined using a pre-specified patient, intervention, comparator, outcome, time, study (PICOTS) criteria and included: amyloidosis, ATTR, and MSK manifestations. Publication quality was assessed utilizing Joanna Briggs Institute (JBI) critical appraisal checklists.The search initially identified 7,139 publications, 164 of which were included. PICOTS criteria led to the inclusion of epidemiology, clinical burden and practice, pathophysiology, and temporality of MSK manifestations associated with ATTR amyloidosis. 163 publications reported on ATTR amyloidosis and MSK manifestations, and 13 publications reported on the delay in ATTR amyloidosis diagnosis following the onset of MSK manifestations.The MSK manifestation most frequently associated with ATTR amyloidosis was carpal tunnel syndrome (CTS); spinal stenosis (SS) and osteoarthritis (OA), among others, were also identified. The exact prevalence of different MSK manifestations in patients with ATTR amyloidosis remains unclear, as a broad range of prevalence estimates were reported. Moreover, the reported prevalence of MSK manifestations showed no clear trend or distinction in association between ATTRv and ATTRwt amyloidosis.MSK manifestations precede the diagnosis of ATTR amyloidosis by years, and there was substantial variation in the reported delay to ATTR amyloidosis diagnosis. Reports do suggest a longer diagnostic delay in patients with ATTRv amyloidosis, with 2 to 12 years delay in ATTRv versus 1.3 to 1.9 years delay in ATTRwt amyloidosis.These findings suggest that orthopedic surgeons may play a role in the early diagnosis of and treatment referrals for ATTR amyloidosis. Detection of MSK manifestations may enable earlier diagnosis and administration of effective treatments before disease progression occurs.The online version contains supplementary material available at 10.1186/s12891-023-06853-5. TTR gene lead to destabilization and dissociation of TTR from its native tetrameric conformation, and subsequent aggregation as amyloid fibrils [TTR gene sequencing in suspected patients [Systemic amyloidoses are protein-misfolding diseases characterized by the aggregation and deposition of amyloid plaques in multiple organ systems , 2. Tran fibrils . In ATTR fibrils . ATTRwt patients , 5.ATTR amyloidosis is a heterogeneous, multisystem disease in which a significant proportion of patients develop a mixed phenotype of polyneuropathy (PN) and cardiomyopathy (CM) , 5, 6. TThe typical patient journey before being diagnosed with ATTR amyloidosis is lengthy and involves consulting numerous physicians from different specialties , 11. ConThis systematic review was conducted to investigate the association between ATTR amyloidosis and MSK manifestations, and to investigate the temporal association between the onset of MSK manifestations and ATTR amyloidosis diagnosis.www.crd.york.ac.uk/prospero; protocol no. CRD42022310956), and the PRISMA statement was adhered to [The protocol for this systematic review is registered on the international prospective register of systematic reviews (PROSPERO) from the National Institute for Health Research Database , American Society for Surgery of the Hand (ASSH), European Society of Cardiology (ESC), European ATTR amyloidosis meeting (EU-ATTR), Federation of European Societies for the Surgery of the Hand (FESSH), International Federation of Societies for Surgery of the Hand (IFSSH), International Society of Amyloidosis (ISA), and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Conferences of interest that were not independently hand searched, given that the EMBASE electronic database search already captured their proceedings, included the American College of Cardiology (ACC), Heart Failure Society of America (HFSA), and the Peripheral Nerve Society (PNS).The inclusion and exclusion criteria were pre-defined in a patient, intervention, comparator, outcome, time, study (PICOTS) table during protocol development  using the most appropriate Joanna Briggs Institute (JBI) critical appraisal checklist. This assessment was conducted at the publication level .Following the JBI quality assessment of the 163 publications examining the association between MSK manifestations and ATTR amyloidosis, 51 publications were identified as being at low risk of bias . 87 publOf the 13 publications examining the temporal association, four were found to have a low risk of bias, seven had at least one quality domain that implied some potential bias, and in the remaining two publications, there was insufficient information reported to measure the potential risk of bias.The following information from each included publication was extracted: (1) publication characteristics: title, author, publication year, study design, objectives, country, and data collection period, 2) population characteristics: ATTR amyloidosis diagnosis, MSK manifestation subgroup, sample size, and demographic data such as age and sex, (3) the direction of the association relationship (ATTR amyloidosis outcomes in patients with MSK manifestations or MSK manifestations outcomes in patients with ATTR amyloidosis), (4) outcomes as defined in the PICOTS criteria  was narrower than the range reported for CTS, at 8.4–22.0% , 124 Ta, CTS wasSeveral studies investigated ATTR amyloidosis in OA –160, andThe publications reporting on the temporal association between MSK manifestation onset and a diagnosis of ATTR amyloidosis were limited to CTS, SS, and OA Fig. ; Table 8Across all CTS-focused publications, CTS symptom onset preceded a diagnosis of ATTR amyloidosis (ATTRv and ATTRwt inclusive) by up to 12 years , 134. InThree studies investigated the temporal association between SS and ATTR amyloidosis; one reported SS symptom onset preceding a diagnosis of ATTRv amyloidosis by approximately 2 years , while aA single publication reported on the temporal association for OA, reporting an average of 7.6 years delay before an ATTR amyloidosis with CM diagnosis was made from OA related surgeries, TKA, and THA .The ability to diagnose ATTR amyloidosis early in the disease course is critical to improving patient prognosis, and MSK manifestations may act as an early indicator of ATTR amyloidosis. This systematic review was conducted to investigate the association between ATTR amyloidosis and MSK manifestations, and to investigate the temporal association between MSK manifestation onset and ATTR amyloidosis diagnosis, in order to potentially aid clinicians in identifying and diagnosing the disease earlier. MSK manifestations, including CTS, SS, OA, among others, were found to be associated with a diagnosis of ATTR amyloidosis Tables , 6 and 7This systematic review is not all-encompassing, and caution should be exercised when drawing conclusions from such a heterogenous evidence base, including many studies reporting on a small number of patients. With the use of machine learning harnessing big data from registries and electronic health records and advanced statistical methodologies, it may be possible to enhance our understanding of the association between MSK manifestations and ATTR amyloidosis. For example, with the application of machine learning, Willis et al. determined which patients with heart failure were ‘at risk’ for developing ATTR amyloidosis; CTS and OA were highlighted as clinical predictive indicators of interest . The potThe included publications were highly heterogenous in terms of how the possible association of ATTR amyloidosis with MSK manifestations was demonstrated Tables , 6 and 7The current evidence supports that many MSK manifestations are associated with a diagnosis of ATTR amyloidosis. The MSK manifestation most commonly associated with ATTR amyloidosis is CTS; however, SS, OA, BTR, RCI, TF, among others, were also identified. The exact prevalence of CTS in patients with ATTR amyloidosis remains unclear, with both CTS and ATTR amyloidosis prevalence estimates reported bi-directionally having a broad range. Similarly, no clear trend was identified regarding whether the association with CTS is stronger  in patients with ATTRv or ATTRwt amyloidosis. Nonetheless, given the extent of the identified literature reporting a possible association between CTS and ATTR amyloidosis, patients with CTS may represent a population where targeted screening for ATTR amyloidosis would be valuable .SS was also often associated with ATTR amyloidosis, with similar prevalence estimates identified in patients with ATTRv and ATTRwt amyloidoses. Notably, where the prevalence of CTS and SS was explored in the same patient cohorts with ATTRv or ATTRwt amyloidosis, CTS was more prevalent than SS in all reports , 147.Finally, the identified evidence supports that ATTR amyloidosis may be prevalent in patients who previously underwent surgery (THA and/or TKA) for OA. TTR amyloid has been detected in the tissues from the joints of patients with OA, which may or may not be indicative of a diagnosis of ATTR amyloidosis, which was confirmed only in three publications. An interesting case series by Akasaki et al., found that all 12 OA patients who donated their knee articular cartilage for biopsy at autopsy had amyloid deposits in their tissue samples –155. AltThe current evidence highlights that CTS and SS symptom onset can occur months to years, or even decades, before the diagnosis of ATTR amyloidosis , 178.The exact length of time that MSK manifestations precede a diagnosis of ATTR amyloidosis is unclear, with great variation reported across publications. However, the current evidence offers insight into how the temporal association between CTS symptom onset and a diagnosis of ATTR amyloidosis might differ between patients with ATTRv and ATTRwt amyloidosis. According to the current review, CTS symptom onset appears to precede a diagnosis of ATTRv amyloidosis by a substantially longer period than a diagnosis of ATTRwt amyloidosis , 96, 134Care needs to be taken in the interpretation of the results from these studies given the variation in methodology. For example, at the time of MSK surgery, TTR amyloid deposition may not have occurred within the tissue taken for biopsy, which may confound clinical diagnosis in these patients , 175. CuIncreased awareness of the MSK manifestations associated with ATTR amyloidosis can enable earlier diagnosis and improve outcomes, given there are effective treatments for this rapidly progressive and fatal condition. Surgeons can play a critical role in early diagnosis of ATTR amyloidosis by recognizing associated MSK manifestations. Currently available data, summarized in this first systematic review conducted on the association between MSK manifestations and ATTR amyloidosis, demonstrates that MSK manifestations can be one of the earliest signs of ATTR amyloidosis; however, it should be kept in mind that the available data is heterogenous, and the extent of the causal relationship between MSK manifestations and ATTR amyloidosis should be further investigated.Additional file 1: Supplement 1. PICOTS criteria for study inclusion and exclusion in the SLR. Supplement 2. Ovid® search strategies for EMBASE and Medline . Supplement 3. Case studies excluded from the systematic literature with ATTR MSK manifestation


Those who had LOS < 5 days spent significantly less time sedentary and more time in light PA than those with LOS ≥ 5 days (p < 0.001 for both). Time spent sedentary or in light PA appears to be the most promising metric to associate with clinically relevant outcomes related to recovery following AECOPD. These findings can inform future clinical practice for the evaluation of inpatient PA to better establish its role in the clinical management of patients with AECOPD.People with hospitalised acute exacerbations of chronic obstructive pulmonary disease (AECOPD) exhibit low levels of physical activity (PA) and increased risks of future exacerbations. While methods to objectively measure and express PA are established for people with stable COPD, less clarity exists for people during AECOPD. Further, the relationship between PA during AECOPD and clinically relevant outcomes remains uncertain. The purpose of the study was to evaluate how much PA (step count and intensity) people accumulate during hospitalised AECOPDs, and the effect of accumulated inpatient PA (expressed via differing metrics) on length of stay (LOS), PA recovery, and readmission risk. This study was a secondary analysis of prospective observational cohort data collected with Actigraph wActiSleep-BT devices from patients with AECOPD in a Melbourne hospital from 2016 to 2018. Step counts and PA intensity throughout the hospital admission and at one-month follow-up were collected and analysed. Sixty-eight participants were recruited for inpatient measurement, and 51 were retained for follow-up. There were no significant changes in step count or intensity across the inpatient days, but 33/51 (65%) of participants demonstrated a clinically meaningful improvement in steps per day from 3817.0 to 6173.7 at follow-up. Participants spent most time sedentary and in light PA, with both PA metrics demonstrating significant influences on LOS and follow-up PA intensity, but with generally low explanatory power (R Reductions in muscle mass, exercise tolerance , and phyThe World Health Organisation recommends adults, including those living with chronic conditions, engage in at least 150 min of moderate-intensity PA and perform muscle-strengthening activities at least two days per week, and minimise periods of prolonged sitting . This caAn important technical evaluation of accelerometry-derived PA data from 389 hospital inpatients with AECOPD  suggesteThe present study, therefore, aimed to examine, among people with hospitalised AECOPDs, the patterns of PA accumulation across a range of relevant accelerometry metrics, and the clinical relevance of different approaches to express PA in order to clarify the potential impact upon future research and practice in this field.A prospective observational cohort study was conducted and reported in accordance with STROBE guidelines . The stuConsenting participants were recruited from respiratory units of a major tertiary hospital in metropolitan Melbourne, Australia, between 2016 and 2018 if they had a clinical diagnosis  of COPD, a smoking history of 10+ pack years, and were admitted to hospital due to AECOPD. Exclusion criteria comprised factors limiting participants’ ability to provide informed consent  or cooperate with test procedures , and/or those with a poor prognosis . A sequential convenience sample of 100 participants was planned as part of a broader exploratory cohort study from which data pertaining to this analysis were extracted. All participants received standard multidisciplinary care during their hospital admission, without the involvement of the researchers. Clinicians were not involved in data collection for this study.All Actigraph data were downloaded using ActiLife TM software v6.13.3 , converted from raw form (units of gravity collected at 30 Hz) into 60-second epochs, and cleaned to remove irrelevant times . A day was defined as occurring between 00:00 and 23:59, with all PA data collected during this time deemed eligible for inclusion as long as patients wore PA monitors for ≥8 h/day between the hours of 07:00 and 22:00 ,22, valiStata SE v17.0  was used for data analysis. Participant characteristics were described using descriptive statistics appropriate for the data type and distribution. Normality was inspected via histogram and Shapiro–Wilk tests. Alpha was set at 0.05 for all analyses.Patterns of PA accumulation across different accelerometry metrics were summarised via descriptive statistics pertaining and represented graphically by summary box plots (step counts) and 100% stacked column graphs (percentage time spent in various PA intensities) as well as individualised line graphs. Trends across the first 7 hospital days were examined via one-way ANOVAs.t-tests, Chi2 tests, and exploratory univariate regression or logistic regression analyses (depending on data type) were employed. Variables (and dichotomised subgroup thresholds) included (a) FEV1% predicted (GOLD stages 1–2 vs. 3–4), (b) LOS (≤/>5 days), (c) PA metrics at follow-up (and those who improved mean steps/day from discharge to one-month by a margin ≥1000—the minimum important difference threshold in stable COPD [p < 0.05. The proportion of variance (R2) explained by PA on the various outcome variables was noted for all regression analyses and is represented in The clinical relevance of inpatient PA accumulation metrics was evaluated by examining their relationship with clinically relevant variables and subgroups divided on the basis of dichotomizing these variables. For this purpose, a combination of unpaired ble COPD ), and . Participant demographics and inpatient management are summarised in p < 0.001 for all), with 33/51 (65%) participants achieving a gain in steps/day in excess of the minimally important different threshold for people with stable COPD (1000 steps/day [2 p = 0.072). Patterns of PA accumulation for mean steps/day (p > 0.05). Vast variability was observed, however, at the individual level (PA accumulation across both the inpatient and follow-up phases is summarised in teps/day ). No parteps/day  at any tteps/day  and timeteps/day  across ial level .t-tests (p = 0.004 between groups and 39.6 min (12.3); p = 0.004 between groups, respectively). Time (minutes) spent in MVPA was higher in those with mild COPD  compared to those with severe COPD .Unpaired t-tests  revealed2/pseudo R2 values ranging from 6% to 22%) with little difference apparent across the six different methods used to express each PA metric during the inpatient period  confers a relatively low impact on analysis findings. Time spent in sedentary behaviour and light PA, however, was high, and these metrics demonstrated a greater number of associations with clinical variables than other PA metrics . These mDetermining the best strategy to modify PA during AECOPD is a challenging and under-researched issue. Modifying time spent in light PA and/or breaking up bouts of prolonged sedentary behaviour seems attractive in terms of feasibility  but might necessitate greater dosages of sustained change in order to translate into health benefits. By contrast, increasing the duration of time spent in MVPA could be more difficult to achieve, but might elicit more potent effects on clinical outcomes in a shorter time . This maSeveral areas remain to be explored for future research. These include issues related to the precise patterns characterising PA accumulation during hospitalised AECOPDs , examination of the drivers underpinning PA behaviours , how clinical care can optimise PA accumulation, and how hospital environments can be better designed to promote more active inpatient stays. Such insight might plausibly lead to clearer opportunities to engage with interventions seeking to improve outcomes for this patient group.The present study represents an examination of an a priori hypothesis that sought to explore nuanced differences in the relationships between PA data and clinical outcomes in people admitted to hospital with AECOPD. Data collection and analysis were not planned to meet formal pre-specified sample sizes or power calculations. An example of how this limited findings was the inability to yield sufficient data relating to the proportion of participants who met international recommendations for daily PA  (which nPhysical activity can be accurately assessed via accelerometry during AECOPDs, but different PA metrics may confer differing levels of clinical relevance depending on the specific purpose of its evaluation. The present data suggest that no individual PA metric or method used to express PA during AECOPD appears more useful than another in terms of its relation to clinical outcomes. Further work is needed before routine measurement of PA during AECOPD is established in clinical practice.


Right heart failure can be defined as a clinical syndrome consisting of signs and symptoms of heart failure resulting from right ventricular dysfunction. Function is normally altered due to three mechanisms: (1) pressure overload (2) volume overload, or (3) a decrease in contractility due to ischaemia, cardiomyopathy or arrythmias. Diagnosis is based upon a combination of clinical assessment plus echocardiographic, laboratory and haemodynamic parameters, and clinical risk assessment. Treatment includes medical management, mechanical assist devices and transplantation if recovery is not observed. Distinct attention to special circumstances such as left ventricular assist device implantation should be sought. The future is moving towards new therapies, both pharmacological and device centered. Immediate diagnosis and management of RV failure, including mechanical circulatory support where needed, alongside a protocolized approach to weaning is important in successfully managing right ventricular failure. Right heart failure (RHF) can be defined as a clinical syndrome consisting of signs and symptoms of heart failure resulting from right ventricular dysfunction (RVD) .At its core is a progressive syndrome of systemic congestion when the right ventricle (RV) cannot meet blood flow demands without excessive use of the Frank–Starling mechanism . The funThe prevalence of RVF is often underestimated as it has been historically underdiagnosed. However, the most common causative etiologies are well documented. It is observed in 3%–9% of acute heart failure admissions, and the in-hospital mortality of patients with acute RV failure ranges from 5% to 17% .Patients are especially vulnerable to RVD if they are more likely to experience sudden changes in preload  or afterload  .Diagnosis of RV failure is more subtle than overt left ventricular dysfunction and is thus often delayed, which worsens the prognosis. The combination of clinical risk assessment and the use of existing diagnostic methods such as echocardiography, MRI (Magnetic Resonance Imaging), haemodynamic and biochemical markers are the key to accurate, early diagnosis and successful management.Treating RV failure should be targeted at correcting the underlying mechanism and therefore revolves around maintaining adequate perfusion pressure, optimizing the preload and reducing the afterload with the aim of improving the cardiac output. Methods for fulfilling these goals include respiratory and mechanical circulatory support in addition to medical therapy.Up until the second half of the 20th century, the study of the heart was disproportionally focused on the left ventricle (LV) with the RV being largely neglected. In the early 1980s, a growing interest in the study of the pathophysiology of the RV emerged, leading to the development of new imaging techniques, different surgical approaches, and an increase in the research of hemodynamic parameters and study of the ventricular interdependence . The appRecent advances in echocardiography and MRI have expanded the knowledge in the field of the anatomy and physiology of the RV and has shown how the mechanisms of left and right ventricular failure are very different. However, despite these advances there remain relatively few direct treatment strategies and few evidence-based interventions available than for its left-sided counterpart.The normal function of the right ventricle is the result of interplay between venous return (preload), PA pressures (afterload), right ventricular myocardial contractility, pericardial compliance and interventricular dependence . As suchAcute RV failure can therefore be divided based upon the underlying physiologic mechanism, and these are summarized in pressure overload, caused by either primary problems of the pulmonary vasculature  or as a result of acute left sided failure. The structure of the RV makes it poorly adapted to abrupt increases in upstream pressures and hence in the acute phase, the right ventricle cannot easily adapt in a homeometric fashion.Increased pulmonary pressures leads to The pulmonary vasculature is high-compliance  but low pressure. As LaPlace's law would suggest, the RV is well suited to these conditions by being thinner-walled and more compliant than the LV. This leaves it exquisitely sensitive to increased afterload. A small increase in afterload can cause a large reduction in stroke volume without an increase in pressure generation .Therefore, the RV does not cope well with acute increases in upstream pressures—and RV ejection fraction (RVEF) is inversely proportional to pulmonary arterial systolic pressure (PASP), and hence increased afterload, in a manner which is not replicated for the left ventricle . Adjustmvolume overload, progressive dilatation and dysfunction. However, in contrast to the response to pressure overload, the RV can adapt efficiently in a heterometric manner and hence copes well with volume overload. Examples of acute RV failure from volume overload include LVAD implantation or aggressive fluid resuscitation, especially in high output states such as sepsis.Increased venous return can cause reductions in contractility are often caused by myocardial damage, as seen in RV infarction or myocarditis, or a more global rhythm disturbance. This leads to reduced stroke volume and progressive RV dilatation, which can precipitate a negative spiral into tricuspid regurgitation, further dilatation and LV impingement due to interventricular dependence , increasing pulmonary pressures, as well as reducing myocardial contractility, and worsen RV function due to interaction between the left and right ventricles.The causes of chronic RV failure can be similarly subdivided by the causative mechanism.Any conditions causing chronic raised pulmonary pressures will increase the afterload. This includes primary causes of pulmonary hypertension as well as chronic left-sided heart failure. Patients with right heart failure secondary to increased pulmonary pressures have a poor prognosis .Volume overload as a cause of chronic right heart failure is often due to shunts, such as congenital heart disease, or right-sided valvular regurgitation. Chronic right heart failure due to either pressure or volume overload follows a similar course. There is initially a compensatory phase that involves hypertrophy and fibrosis. As the disease progresses there are various metabolic changes including mitochondrial dysfunction and fibrosis that leads to progressive RV dysfunction and dilatation .As the RV dilates and becomes dysfunctional, it impinges on the LV and causes reduced left-sided cardiac output. However, in chronic pericardial diseases the reduction in left sided cardiac output does not require RV dilatation; rather there is a competition for space within a fixed volume pericardium.Finally, several cardiomyopathies can lead directly to reduced RV function by directly affecting contractility, including arrhythmogenic right ventricular dysplasia (ARVD), dilated cardiomyopathies and the long-term sequelae of myocarditis.Early diagnosis is key in successful management of RV dysfunction, but it is often delayed or missed, possibly because the clinical signs can be more subtle than LV dysfunction. It is necessary to use a combination of clinical, echocardiographic, laboratory and hemodynamic parameters to accurately recognize the presence and underlying mechanism of RV failure.Echocardiography should be the first-line test in the assessment of acute RV failure because it is fast, non-invasive, and can identify life-threatening acute pathologies such as tamponade and PE.There are several parameters that can help with the assessment of the right ventricle.Tricuspid annular plane systolic excursion (TAPSE) is the most used and well-established parameter to evaluate RV systolic function, however, it only assesses longitudinal contraction, hence giving us only partial information about the RV function. For example, TAPSE is not suitable after tricuspid valve annuloplasty as it leads to an underestimation of RV systolic function . SimilarNew echo techniques are shifting from qualitative to quantitative evaluation . The mosAs discussed previously, pressure readings are crucial in diagnosis of acute RV failure. These include estimating PASP by utilizing a combination of peak TR velocity, right atrium (RA) size and inferior vena cava (IVC) dimensions, as well as pulmonary valve (PV) acceleration time.Visually, ventricular interdependence and septal bounce are important clinical signs, especially in the context of pericardial disease processes.Once right ventricle dysfunction has been diagnosed, echocardiography is also the most crucial tool in hunting for the underlying aetiology, specifically common left heart failure and valvular abnormalities. But it can also provide valuable information regarding evolution of the disease and the impact of treatment.As a 3-dimensional, tomographic imaging modality with good temporal and spatial resolution, MRI does offer advantages over echocardiography and hence has become the gold standard for assessing the morphological characteristics of RV function. It is more accurate than echocardiography in measuring these parameters, but this is only a marginal improvement because modern echo is accurate and is more sensitive at assessing pulmonary pressures. What sets cardiac MRI apart is the ability to accurately characterize tissue properties . TherefoApart from the myocardium, cardiac MRI also gives very detailed imaging to differentiate between conditions causing changes to the pre-and after load, such as congenital heart defects as a cause of pulmonary hypertension (PH), or chronically thickened pericardium. Velocity-encoded imaging adds to the structural information to calculate flow through valves or shunts , which cCardiac MRI does require expensive scanning equipment, dedicated radiographers, is unsuitable for claustrophobic patients or those who cannot breath-hold adequately, and patients with older pacemakers . HoweverTherefore, Cardiac MRI offers excellent characterization of tissue and overall cardiac structure. While MRI can assess flow through structures, it is best use as a complimentary adjunct to, rather than a replacement for, echocardiography.There are no specific biomarkers for the diagnosis of RV failure. The levels of frequently used biomarkers, such as B-Natriuretic Peptide (BNP) or cardiac troponins depend on the underlying pathology and clinical context in which RV failure is presented. New biomarkers more specific for the diagnosis of RV failure are currently under research .Invasive hemodynamic measurement with a pulmonary artery (PA) catheter is the most accurate method of assessing right-sided filling pressures, contractility, and afterload. It provides continuous, real-time data; however, it should be used for the shortest time possible.Parameters such as cardiac filling pressures, PA pulsatility index (PAPi), RV stroke work index (RVSWI), Pulmonary Vascular Resistance (PVR) and transpulmonary gradient (TPG) offer prognostic information in patients with RVF . PAPi, dRV stroke work index (RVSWI) is another prognostic hemodynamic parameter. It is calculated by the following equation: RVSWI = SVI × (mPA − mRAP) × 0.0136, where stroke volume index (SVI) is calculated by the [cardiac index/heart rate] × 1,000 , 24. A lAs discussed in the pathophysiology section, afterload is extremely important in assessing RV failure. However, pulmonary afterload is not a static process—as the RV contracts, the compliance of the pulmonary arteries exerts an opposing force.Hence pulmonary afterload encompasses both a “static” element (which is the PVR) and a dynamic component (which includes compliance (PC) and characteristic impedance) .Often, PVR has been used as a proxy for afterload. However, it only accounts for around 75% of pulmonary afterload . PVR is PC accounts for around 20% of pulmonary afterload and can be estimated by the ratio of stroke volume to PA pulse pressure measured by right heart catheterization . Loss ofTPG allows the determination of the cause of right heart failure if it coexists with pulmonary hypertension, where a high TPG (>12 mmHg) and a low PCWP (<15 mmHg) point to a pre-capillary cause and the reverse situation (TPG <12 mmHg and PCWP >15 mmHg) point to a left-sided aetiology. A high TPG and high PCWP co-exists in combined pre- and post-capillary PH  31)..31).Finally, the concept of RV-PA coupling unifies many of the points made above. The morphological adaptation of the RV to increasing pulmonary pressures can only compensate to a certain point (RV-PA coupling) before the RV can no longer compensate. Several studies combining invasive haemodynamics with echocardiographic markers of RV function have shown this combination to be more predictive than RV function alone , 33.1.Medical managementThe medical management of RVF encompasses a combination of pharmacologic and non-pharmacologic treatments to optimize preload, reduce afterload with the goal of enhancing RV contractility. Invasive monitoring via a Swan-Ganz catheter gives critical information to allow timely treatment titration and escalation RV infarction—treated with reperfusion and fluid resuscitation(ii)Pulmonary Embolus: anticoagulation and, if indicated, thrombolysis or clot retrieval(iii)Critically unwell patients: a homogenous group who require careful volume management with a high output state into a vasodilated system—can easily result in volume overload—see “Preload optimization” section below. If ventilated, high inspiratory pressures increase RV afterload, hence keep inspiratory pressure as low as feasible.2.Preload optimizationAlthough increases in afterload are often the primary cause of RV failure, preload optimization is the initial target for therapy because it is fast to initiate treatment, easy to monitor and has clear goal-directed targets and is effective due to its interaction and effect on RV afterload.Therefore, volume optimization is key, whether the patient requires volume initially (such as RV infarct) or is volume overloaded. At a minimum, care should be directed towards maintaining a central venous pressure of 8–12 mmHg .Historically, the RV was viewed as a passive conduction system and hence was often managed by increasing volume and right atrial pressures to increase pulmonary circulation. However, if the RV begins dilating, especially in the face of increased afterload, wall stress increases rapidly in such a thin-walled structure. This leads to further dilatation, reduction in systolic pressure generation, increased TR and impaired LV filling due to aforementioned interventricular dependence. Myocardial ischemia, due to both reduced CO and increased RV wall stress, and congestive multiorgan failure can ensue .The easiest and most effective method to reduce RV preload is using a high-dose furosemide infusion to reduce right atrial pressure to between 8 and 12 mmHg. The response must be rapidly assessed to allow escalation in therapy or addition of thiazides, which potentiate loop diuretics. Clearly, regular electrolyte monitoring is mandatory due to the possibility of rapid shifts. The addition of carbonic anhydrase inhibitors can improve any alkalosis resulting from loop and thiazide diuretics .Renal replacement therapy (RRT) is effective at removing excess fluid. Although commonly initiated in diuretic resistant patients, there is no clear evidence supporting their use in acute RV failure. Thus, RRT should not be considered first-line treatment but started after failure of diuretic therapy. It should be conducted at a rate that allows an adequate shift of extravascular to intravascular space .3.Afterload reductionSpecific afterload reduction therapies depend on the specific pathophysiology, such as in pulmonary emboli or increased ventilation, as discussed previously. In the absence of a specific reversible cause, pulmonary vasodilators decrease pulmonary vascular bed resistance leading to a decrease of RV afterload.In contrast, intravenous fluids are required in cases of associated hypovolemia to reach the above-mentioned target, for example in cases of RV infarction. However, if increased afterload is the primary cause of RV failure, even if the patient is volume deplete, this must be performed carefully and in small increments otherwise decompensation is likely.Intravenous agents such as milrinone (see below) are effective at both causing pulmonary vasodilation and increased contractility, although it causes both pulmonary and systemic vasodilation and hence can enhance hypotension.Selective pulmonary vasodilators include inhaled or parenteral epoprostenol , 37 or i4.RV contractility enhancementRegardless of the underlying cause of acute RHF, the endpoint is increased wall stress and reduced myocardial contractility due to both direct (such as overstretched myocytes) and indirect mechanisms (including reduced perfusion and reduction in LV function/output).They should not be administered in patients with postcapillary pulmonary hypertension and RV failure before the left sided problem  has been addressed. Increasing transpulmonary flow in patients with elevated left atrial pressure may induce pulmonary oedema.Inotropic agents, such as dobutamine or milrinone, that increase myocardial contractility and RV cardiac output are the two most frequently used. Milrinone has a more potent pulmonary and systemic vasodilator effect than dobutamine and is less likely to induce reflex tachycardia . As a reThe shorter half-life of dobutamine and its mild vasodilator effect may be consequently preferable in some patients. Exceptions to starting these would include situations where RV failure has been caused by myocardial ischemia and arrhythmia, which may be exacerbated by inotrope use.α1 receptor, causing vasoconstriction with limited β1 receptor stimulation and cardiac inotropy. However, the β1 effects on contractility have been shown to improve pulmonary artery/RV coupling in animal models of RV dysfunction , calcium channel blockers, phosphodiesterase type 5 inhibitors , prostacyclin analogues  and endotheline receptor antagonists .In Group IV patients suffering from chronic thromboembolic disease, lifelong anticoagulation followed by consideration of pulmonary endarterectomy by a specialist centre may be indicated. Despite their profound therapeutic differences, all these treatment approaches have the same goal, reducing RV afterload.2.DevicesWhen optimal medical therapy has not been effective, mechanical circulatory support (MCS) may be beneficial. There are several options that differ in the intensity and duration of support offered, the intended approach of implantation and the need for oxygenation. Current literature is limited to only small prospective randomized trials ((a)SHORT TERM SUPPORT. Considerations involved in choosing the most appropriate device depending on the clinical situation are shown in (i)Extracorporeal membrane oxygenation (ECMO): The first decision to make is deciding between using veno-venous (VV) ECMO and venoarterial (VA) ECMO. VV ECMO only oxygenates and returns blood to the venous system. Therefore, its use is limited to isolated RV failure due to acute hypoxemic respiratory failure. In contrast, venoarterial (VA) ECMO is the preferred option in situations of primary RV injury or RV failure with concomitant LV failure. VA ECMO supports the RV indirectly by reducing preload, reducing RV wall tension, and providing oxygenated blood to the coronary circulation (culation . ECMO is(ii)PROTEK DUO: This cannula-within-a-cannula device allows for percutaneous, single venous access at the right internal jugular vein. The double-lumen cannula consists of a 29 Fr outer cannula and a 16 Fr inner cannula with a length of 46 cm allowing for right atrium drainage. The inlet is positioned in the RA-SVC junction and the return in the pulmonary artery. It can be used with or without an oxygenator in case of respiratory failure ( failure  and it i(iii)IMPELLA RP:  is a minimally invasive percutaneous microaxial pump used to tackle RV failure. It is used after left ventricular assist device implantation, postcardiotomy or acute RV failure post myocardial infarction (farction  with FDAfarction . The posfarction  low survfarction . Howeverfarction .(iv)Extracorporeal magnetically levitated radial pump: Levitronix® CentriMag®  is a magnetically levitated centrifugal-flow pump designed for temporary extracorporeal support. It can also work with or without an oxygenator. It provides longer support than the devices above mentioned. It is easy to implant and has low risk of thrombosis, reduces pulmonary congestion, and allows for early mobilization. However, its implantation and explant usually require open surgery.(b)LONG TERM SUPPORT: There are limited options for long-term RV support and evidence is lacking. Devices implanted surgically such as HeartWare or HeartMate 3, Berlin Heart or extracorporeal magnetically levitated radial pump (Levitronix) require invasive surgery for both implantation and explantation.(i)RVAD: In June 3, 2021, Medtronic announced the withdrawal of the HeartWare Ventricular Assist Device (HVAD) from the global market (l market . Currentl market . These dl market .(ii)Total Artificial Heart (TAH): it is a biventricular pump that replaces both native cardiac ventricles and all cardiac valves. The SynCardia Total Artificial Heart  is the only biventricular cardiac replacement approved for bridge to transplantation by the FDA and which carries the European Union CE mark SHORHeart transplantation can be considered in cases of advanced refractory chronic heart failure in those situations in which optimized medical treatment, or any other management options have failed.Exclusion of all reversible causes and assessment of all comorbidities must be established before transplantation can be contemplated.There are not many situations in which HTx is needed due to pure RV failure. These can be summarized into arrhythmogenic right ventricular cardiomyopathy and extensive ischemia of the right territory.4.Special circumstances: LVAD implantationRV failure is one of the most encountered complications after durable left ventricular assist device (LVAD). More than 30% of patients experience acute RVF  are at high risk for post-LVAD RVF, similarly to patients with slightly increased INR, high NT-proBNP or leukocytosis. High CVP, low RVSWI, an enlarged right ventricle with concomitant low RV strain also identifies patients at higher risk .Post LVAD RFV is a challenging complication with high rates of morbidity and mortality. A minimally invasive approach to LVAD implantation, such as bilateral thoracotomy might play a role in protecting from RV failure , 63. ThiThe current management of RVF remains suboptimal and leaves much room for improvement. New therapies, both pharmacological and device-centered, should be sought.It remains of paramount importance to recognize RVF early, understand the underlying etiology and manage appropriately without delays.Molecular imaging is a developing method based on the existence of specific tracers that bind to molecules of interest. The potential of this method relies in combining targeted molecular imaging with quantification . PresentMoreover, research is focussing on specific biomarkers  for RV 2+ handling proteins, increased the threshold for Ca2+ and action potential duration alternans, decreased susceptibility to spatially discordant action potential duration (APD) alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with pulmonary hypertension-induced RHF  treatment attenuated RV structural remodeling, improved RV function, increased the conduction velocity, restored the expression of key Cauced RHF .Despite the great advances in MCS in the last decades, biventricular failure remains a challenge for physicians. Moreover, timing the implantation of the devices remains one of the most important targets in order to achieve good outcomes. Delays in the diagnosis and device implantation is associated with high rates of mortality mostly due to multiorgan dysfunction. Likewise, durable devices specific for the treatment of RVF with applicability to broader patient populations is urgently needed. A recent multicentre study advocates concomitant implantation of MCS for the RV at the time of LVAD implantation, associating it with improved 1-year survival and increased chances of RV support weaning compared to postoperative insertion .Whereas the right ventricle was once neglected and viewed as a passive player in the circulation, this is not the case anymore, and there has been an increased focus on the diagnosis and treatment of right heart disease over the last two decades. Research has focused on its unique structure and function and has led to the development of both medical and device therapies tackling preload, afterload and myocardial contractility. As with all conditions, the key to the successful management of acute right heart failure is prompt diagnosis to allow timely treatment initiation.The rapid development of short term MCS over the last decade has certainly facilitated the treatment of RVF. The evolution towards low profile-high output pumps allows the percutaneous treatment of right ventricular failure when medical management does not suffice. These include the minimally invasive percutaneously delivered devices like Impella RP, ECMO and Protek Duo.Long-term devices and heart transplantation should be reserved for those patients whose RV is unlikely to recover or are likely to require longer support. MCS related mortality is limited to bleeding and device complications, whereas the main morbidity and mortality driver of untreated right heart failure is multiorgan dysfunction . Therefo


Adverse changes in LV ejection fraction, LV cavity volume, LV mass index, and LV geometry were independently associated with an increased risk of HF hospitalization and death. Among adults with CKD, deleterious cardiac remodeling occurs over a relatively short timeframe and adverse remodeling is associated with increased risk of HF-related morbidity and mortality.Adults with chronic kidney disease (CKD) are at increased risk for developing heart failure (HF). However, longitudinal cardiac remodeling in CKD has not been well-characterized and its association with HF outcomes remains unknown. We evaluated the association between change in echocardiographic parameters between baseline and year 4 with the subsequent risk of HF hospitalization and death using Cox proportional hazard models in a landmark analysis of a prospective multicenter CKD cohort. Among 2673 participants, mean ± SD age was 61 ± 11 years, with 45% women, and 56% non-white. A total of 472 hospitalizations for HF and 776 deaths occurred during a median (interquartile range) follow-up duration of 8.0 (6.3–9.1) years. Patients hospitalized for HF experienced larger preceding absolute increases in left ventricular (LV) volumes and decreases in LV ejection fraction Reduced estimated glomerular filtration rate (eGFR) and proteinuria are independently associated with worse cardiovascular outcomes and a 2-to-threefold higher risk of incident heart failure (HF)3. Populations with CKD frequently have abnormalities in cardiac structure and function9, with evidence of adverse cardiac remodeling present even in asymptomatic patients and in those with early kidney disease10. We previously reported that among adults with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study, baseline echocardiographic findings including enlarged left ventricular (LV) cavity volumes, LV hypertrophy, abnormal LV geometry, reduced LV ejection fraction (LVEF), and/or an enlarged left atrium were associated with an increases risk of HF hospitalization or death11.Chronic kidney disease (CKD) is a growing public health burden affecting > 10% of the worldwide population representing > 800 million individuals13, but there are limited longitudinal data that describe serial echocardiographic changes in CKD populations over time. The timeframe over which cardiac remodeling occurs in CKD and whether echocardiographic changes are associated with HF-related morbidity and mortality remains unknown. Conversely, it is unclear whether the normalization of pathologic remodeling portends an improved prognosis. A complex interplay between neurohormonal dysregulation and fluid retention inherent to patients with CKD may alter the typical cardiac remodeling observed in HF. As the therapeutic armamentarium of neurohormonal antagonists targeting the cardio-renal axis continues to expand, understanding the complex interrelationship between kidney function and cardiac remodeling will be of paramount importance.Cross-sectional studies suggest abnormal cardiac remodeling becomes more severe as eGFR declinesThe CRIC study provides a unique opportunity to observe longitudinal echocardiographic changes and clinical outcomes in a large, diverse, and contemporary CKD population with a low rate of prevalent HF. The objectives of this study were (1) to describe the natural history of cardiac remodeling and (2) to assess the independent association between changes in echocardiographic parameters and subsequent risk of HF hospitalization and death in an ambulatory population of adults with CKD.2 were initially enrolled between June of 2003 and March of 2007 from seven centers across the United States 14. Patients were excluded for a history of polycystic kidney disease, use of immunosuppression within the previous 6 months, institutionalization, inability to consent, enrollment in other research studies, pregnancy, New York Heart Association (NYHA) functional class III/IV HF, human immune deficiency virus infection, cirrhosis, myeloma, renal cancer, recent chemotherapy, organ transplant, or chronic dialysis treatment within the last month14. Patients without at least 2 echocardiograms  were further excluded from the present analysis. All participants provided written informed consent, and the study protocol was approved by the Institutional Review Boards of the University of Pennsylvania-Renal Research, John Hopkin’s University ProHealth, University of Maryland, University Hospitals Case Medical Center, MetroHealth Medical Center, The Cleveland Clinic Foundation, University of Michigan Hospital and Health Systems, Wayne State University School of Medicine, University of Illinois at Chicago, Tulane Office of Health Research, Kaiser Permanente Northern California, and the University of California San Francisco. All methods were performed in accordance with the relevant guidelines and regulations.The CRIC study was designed to investigate the etiology, prognosis, therapy, health care services utilization, and quality of life among adults with mild-to-moderate CKD. A total of 3939 adult participants with an eGFR between 20 and 70 ml/min per 1.73 m15. All sonographers performing and physicians interpreting studies in the echocardiography core laboratory were blinded to the participant’s other clinical characteristics.Baseline and follow-up transthoracic echocardiograms were performed at years 1 and 4 after enrollment using a standardized protocol and transferred to an echocardiography core laboratory at the University of Pennsylvania  for systematic analysis. The median (interquartile range [IQR]) time between the year 1 and year 4 echocardiogram was 3.0 (2.9–3.1) years. Images were evaluated by a single physician according to contemporaneous guidelines from the American Society of Echocardiography (ASE)16 and indexed to body surface area using the Mosteller formula 17. LVEF was calculated as (LVEDV-LVESV)/LVEDV × 100 and further stratified into reduced (< 40%), mid-range (40–49%), and preserved LVEF (≥ 50%). LV mass (LVM) was calculated using the area-length method16 and indexed to body surface area (LVM index [LMVI]). LV geometry was categorized as normal, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy based on relative wall thickness and LVMI as defined by the ASE16. Prevalence of missing echocardiographic variables is provided in the supplement  and end-systolic volume (LVESV) were calculated using the biplane method of discs18. All covariates used in the analysis were obtained at year 4, except for B-type natriuretic peptide, which was only obtained at the time of enrollment.Demographic information, medical comorbidities, and medication use was ascertained via self-report questionnaires administered during annual in-person visits and updated during bi-annual telephone visits. Systolic and diastolic blood pressure, heart rate, height, weight, and urine/blood specimens were collected during annual in-person visits using standardized methods. An average of three seated blood pressure measurements was recorded. All laboratory testing was performed in a biomarker core laboratory, and eGFR was calculated using the 2009 Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration formula19. Deaths were also identified through death certificates or obituaries, review of hospital records, and from the Social Security Master File, as available. Participants were censored at the end of follow-up, study withdrawal, or death.The primary outcomes of hospitalization for HF and death were collected from the year 4 visit through November 30, 2018. CRIC study personnel screened participants or proxies for hospitalizations and death on a bi-annual basis via telephone interviews. All identified hospitalizations with International Classification of Disease 9th Edition discharge diagnosis codes related to HF  were reviewed by two physicians for evidence of documented symptoms, physical exam findings, chest radiographs, echocardiograms, and invasive hemodynamic monitoring if available. A HF hospitalization was considered to have occurred when both reviewers agreed it was “probable” or “definite” based on the modified Framingham clinical criteriahttps://www.r-project.org/). Baseline characteristics were collected at year 4  for this landmark analysis and were stratified by the presence or absence of HF hospitalization. Categorical variables are presented as frequencies with percentages and continuous variables as means with standard deviations. We describe the changes from year 1 to year 4 as both absolute and relative differences for continuous variables, and category changes for categorical variables. Differences between baseline characteristics and changes in echocardiographic parameters were compared using analysis of variance or Kruskal–Wallis tests for continuous variables and Chi-square tests for categorical variables.All analyses were conducted using SAS, version 9.4  and R, version 4.0.2 , medical history , vital signs , and laboratory values , and echocardiographic parameter value at baseline , and medical therapy for HF . We included a random effect for CRIC clinical center to account for within-center correlation and used a multiple imputation approach across 50 imputed datasets to account for missing data in echocardiographic and laboratory variables. Finally, an interaction analysis was performed between change in echocardiographic parameters and markers of kidney function (eGFR and urine protein-to-creatinine ratio) for the outcomes of HF hospitalization and death.Among 2,673 participants with serial echocardiograms, mean age was 61.7 ± 10.6 years, 45% were women, and 56% self-identified as non-white  of follow-up of 8.0 6.3–9.1) years, 18% of participants were hospitalized for HF  and 29% died . Kaplan–Meier curves of outcomes stratified by change  in LVEF, LVMI, LVESVI, and LVEDVI are shown in Fig. –9.1 yearAfter adjustment for clinical confounders, baseline echocardiographic parameters, and medical therapy for HF, adverse changes in echocardiographic measures were generally associated with an increased risk of HF hospitalizations and, to a lesser extent, death Table . DecreasIn this prospective study of 2673 adults with mild-to-moderate CKD at baseline, we observed significant cardiac remodeling over a 3-year time period with reductions in LVEF and increases in LV volumes, particularly LVESV. Participants with more severe baseline LV cavity dilation and systolic dysfunction experienced the greatest improvements  in echocardiographic parameters during the 3-year period. Participants subsequently hospitalized for HF experienced more adverse cardiac remodeling  over the preceding years. There was a trend toward increased LVMI in subjects hospitalized for HF and they were more likely to develop eccentric LV hypertrophy than those not hospitalized for HF. In fully adjusted models that accounted for baseline clinical characteristics and echocardiographic parameters, adverse changes in LV volumes, LVEF, and LVMI were all independently associated with increased risk of HF hospitalizations and death. These findings suggest serial echocardiograms over a timeframe of several years can detect cardiac remodeling in individuals with CKD, and that even modest changes in cardiac structure and function can be prognostically meaningful for outcomes of HF-related morbidity and mortality.21. Compared to our larger cohort, the 417 patients who progressed to ESKD had modest but significant declines in LVMI and experienced no change in LVEDVI, but other echocardiographic parameters were consistent with our findings. In a smaller study of 98 patients with stage 5 CKD, LVMI and LV geometry did not change appreciably over a 2-year study period22. The mean baseline eGFR of participants who developed ESKD during the CRIC study was predictably lower than the overall cohort (24.6 vs. 41.7 ml/min/1.73 m2). The discovery of distinct patterns of cardiac remodeling at different eGFR ranges within the same cohort suggests that the relationship between eGFR and cardiac remodeling may change as CKD progresses. Alternatively, other clinical circumstances associated with advanced CKD may influence cardiac remodeling in a manner that opposes the effect of CKD . For example, an elevated glycosylated hemoglobin is independently associated with abnormal cardiac remodeling23, but in advanced CKD, reduced insulin clearance contributes to lower glycosylated hemoglobin levels24. Data from cross-sectional studies, which are more vulnerable to this type of effect modification, are heterogenous but have generally shown that markers of deleterious cardiac remodeling worsen as eGFR declines12. Serial echocardiograms across a longer time horizon could detect non-linear changes in cardiac structure and function and provide a more comprehensive understanding of cardiac remodeling across a wide spectrum of eGFR.To our knowledge, this is the first study to prospectively report longitudinal echocardiographic changes in a large contemporary cohort with CKD. Serial echocardiographic measurements among the subset of participants in the CRIC study who progressed to ESKD has been previously reported, participants with seemingly favorable cardiac remodeling  consistently experienced higher crude rates of HF hospitalization and death than subjects with no change in their echocardiogram. However, after adjustment for baseline echocardiographic parameters, an improvement in LVEF category and normalization of LV geometry had strong favorable associations with subsequent HF hospitalization and death. Review of participant-level data reveals that subjects with lower baseline LVEF and larger LV volumes experienced more substantial improvement in echocardiographic measures. Measurement error may partially explain this finding, but a physiologic mechanism is also possible. A potential explanation is that adults with more abnormal baseline echocardiography were aggressively treated with guideline directed medical therapy for HF which had beneficial effects on cardiac remodeling. Regardless of mechanism, the ultimate consequence of this trend was that subjects with more favorable echocardiographic changes also had more abnormal echocardiograms and therefore appeared to have worse outcomes in analysis that did not account for baseline echocardiography. Our findings highlight the critical importance of interpreting changes in echocardiography within the clinical context of baseline values.In clinical practice, reversal of abnormal echocardiographic findings is typically interpreted as a favorable prognostic finding. Given this assumption, some of our findings may at first seem counterintuitive. In our Kaplan–Meier analysisOur study had several limitations. The CRIC study excluded subjects with NYHA functional class III/IV HF, which likely reduced participation among adults with prevalent HF and reduced systolic function and lowered the event rate for HF hospitalizations and potentially death. However, this decision allowed us to describe the natural history of echocardiographic findings in the setting of mild-to-moderate CKD patients with a low rate of prevalent HF which is unique. The protocol required echocardiograms at only two time points separated by a median of 3 years, potentially limiting our ability to detect non-linear associations between CKD progression and cardiac remodeling. Low rates of moderate to severe valvular heart disease at baseline precluded analyzing these findings. The approximately 20% of CRIC participants who did not have a year 4 echocardiogram were sicker than our analytical cohort normalization of echocardiographic parameters.Supplementary Information.