Heart failure (HF) is a cardiovascular disease defined by several symptoms that occur when the heart cannot supply the blood needed by the tissues. HF, which affects approximately 64 million people worldwide and whose incidence and prevalence are increasing, has an important place in terms of public health and healthcare costs. Therefore, developing and enhancing diagnostic and prognostic sensors is an urgent need. Using various biomarkers for this purpose is a significant breakthrough. It is possible to classify the biomarkers used in HF: associated with myocardial and vascular stretch (B-type natriuretic peptide (BNP), N-terminal proBNP and troponin), related to neurohormonal pathways , and associated with myocardial fibrosis and hypertrophy . There is an increasing demand for the design of fast, portable, and low-cost biosensing devices for the biomarkers related to HF. Biosensors play a significant role in early diagnosis as an alternative to time-consuming and expensive laboratory analysis. In this review, the most influential and novel biosensor applications for acute and chronic HF will be discussed in detail. These studies will be evaluated in terms of advantages, disadvantages, sensitivity, applicability, user-friendliness, etc. Cardiovascular diseases (CVDs) is a broad term covering heart and circulatory diseases and is listed in the literature as the leading cause of death worldwide. Management of CVDs, such as heart failure, hypertension, stroke, coronary heart disease, etc., is a huge economic burden for societies due to high incidence and mortality rates. Although the risk factors and underlying mechanisms for CVDs differ, advancing age, life and dietary habits, and genetic factors are the mainly evaluated parameters ,2,3. AmoIdentification, prediction, and diagnosis of HF is a compelling process; therefore, it is important to evaluate the clinical characteristics in terms of diagnosis and prognosis ,8. BiomaSelective, rapid, and sensitive determination of biomarkers that can be beneficial at every stage of HF management is also very critical. For this purpose, that the aim is for the biosensors to help with early-stage diagnosis and effective monitoring of the disease prognosis for HF by targeting the most suitable biomarkers ,14. The To the best of our knowledge, no studies in the literature solely focus on biosensor applications for acute/chronic HF biomarkers. This current review aims to be useful to researchers by filling this gap and evaluating the HF biomarkers for diagnosis and therapy and the biosensor applications. It will also offer perspective on future approaches, such as wearable biosensors.Heart failure is a global pandemic that affects ~26 million people worldwide. Age, genetic status, gender, environmental risk effects, smoking habits, hypertension, coronary artery disease, atrial fibrillation, and diabetes trigger the formation of the disease .HF occurs when the heart cannot pump enough blood to meet metabolic needs. If the left ventricle does not work enough, systolic HF and diastolic HF appear. The left ventricle cannot squeeze strongly sufficient in systolic HF, and therefore becomes stiff in diastolic HF. Right-sided HF can occur when the left ventricle is damaged due to a change in blood flow. Too much blood can collect in one place and cause swelling in the legs or abdomen. HF was evaluated as acute and chronic HF. Acute HF occurs very suddenly and requires immediate intervention. Chronic HF is observed gradually over time. HF symptoms are described as breathlessness, fast/irregular heart rhythm speed, weakness, nausea, and pain. The left ventricular ejection fraction (LVEF) leads the way in HF. According to the American Heart Association, LVEF levels should be within the range of 50% to 75% .The development and progression of HF result from many complex interactions of cardiovascular diseases that lead to neurohormonal activation, cardiac remodeling, inflammation, myocardial stretch, and myocyte injury .A biomarker is an indicator of the normal biological process, pathogenic processes, or pharmacological responses to a therapeutic intervention. An ideal biomarker should be non-invasive, low-cost, and easily reproducible, and should offer sensitivity and specificity. Many biomarkers have been identified for the clinical diagnosis of heart failure . They haBNP and NT-proBNP are referred to as gold-standard biomarkers in many published papers because they are used in the diagnosis of HF and contribute to the standard clinical HF diagnosis . The NT-Biomarkers and other investigations contribute to the diagnosis of HF. Chest X-ray and echocardiography are generally used as traditional clinical diagnosis techniques. However, echocardiogram testing can be difficult to perform in an emergency . In addiMolecular recognition mechanisms are based on the lock and key model, with the substrate and the receptor showing specific interactions without being ignored by complementary geometric shapes that fit into one another . The enzThe numerous electrochemical studies and biological detection of biomarkers often utilized in acute and chronic HF have been extensively examined over the past five years. When the studies in the literature were examined, primarily biosensor-based approaches were discussed. In addition, while reviewing recently published articles on diverse aspects of electrochemical techniques, there is substantial research into the application of electrochemical methods to detect acute and chronic heart failure biomarkers. In addition, Among the papers in In this study by Tang et al. , an effe2O2 reduction , with results that are in good agreement with those achieved by utilizing a traditional ELISA methodology. This new amperometric immunosensor’s promising analytical performance, ease of use, disposability, and the ability to use portable electrochemical transducers make it a very appealing alternative to widely used ELISAs for the development of automated POC systems for on-site detection of this HF disease biomarker.By combining a sandwich immunoassay with an HRP-labeled detector antibody and SPCEs transduction platforms built upon electrode modification with AuNPs, a disposable electrochemical-based immunosensor for the measurement of the BNP was created by Serafin et al. . Figure The survival rate is still low in HF patients, demonstrating the importance of early diagnosis with the determination of biomarkers. Regular measurement and monitoring of significant biomarkers can assist in the care of HF for patients ,86. The In addition to all these, the aim is to improve certain features of traditional biosensor devices and make them more useful. Researchers continue to work on objectives such as miniaturization, portability, less sample requirement, and simplification of the measurement process.HF is a significant type of CVD that requires a troublesome identification, prediction, and diagnosis process. Therefore, the selection, evaluation, and detection of significant biomarkers play a key role in disease management. In this review study, novel approaches to electrochemical biosensors for acute and chronic HF were explained by evaluating the most recent works in the literature. It was found that TNFα, CRP, cTnI, and miRNA are mainly studied analytes in electrochemical biosensors. To improve the properties of electrochemical biosensors, such as selectivity and sensitivity, hybrid systems modified with various materials, such as nanomaterials, have been preferred. The most frequently used electrochemical techniques are DPV and EIS. Immunosensors, on the other hand, have been mostly used due to their many advantages. Furthermore, it is seen that the applied samples are mostly biological samples such as human serum. In conclusion, it can be said that the researchers aim to develop sensors that will provide advantages and superiority in clinical and point-of-care applications.


Yes-associated protein  and its paralogue TAZ (with a PDZ-binding motif) are transcriptional coactivators that switch between the cytoplasm and nucleus and regulate the organ size and tissue homeostasis. This review focuses on the research progress on YAP/TAZ signaling proteins in myocardial infarction, cardiac remodeling, hypertension and coronary heart disease, cardiomyopathy, and aortic disease. Based on preclinical studies on YAP/TAZ signaling proteins in cellular/animal models and clinical patients, the potential roles of YAP/TAZ proteins in some cardiovascular diseases (CVDs) are summarized. According to the American Heart Association, although the mortality rate of cardiovascular diseases (CVDs) has decreased in recent years, it is still one of the major causes of death worldwide. In addition, the ageing of the population has led to increased CVDs and an increased cardiovascular burden in developing countries, resulting in socioeconomic damage ,2. ThereYes-associated protein  is a classic downstream effector in the Hippo signaling pathway and is an important factor that regulates cell proliferation and differentiation . The traMany recent studies have reported that YAP/TAZ plays a significant role in the development of CVDs, including pulmonary hypertension, atherosclerosis, aortic disease, and angiogenesis ,20,21,22An acute MI is myocardial necrosis caused by the acute and persistent ischaemia and hypoxia of the coronary artery, which can be complicated by arrhythmia and heart failure and is often life-threatening . DiffereCardiomyocytes are the main effectors of a myocardial contraction, and changes in the CMs proliferation or myocardial hypertrophy are an important part of the recovery of the cardiac function after an MI . The proIn addition, miRNA is also an important downstream effector of YAP. In addition, the forkhead box transcription factor (FoxP1) is a physiological mediator of the miR-206 function in CMs and is also an endogenous negative regulator of cardiac hypertrophy and survival. As an important downstream effector, the YAP upregulates the expression of miR-206 and regulates the CMs function by silencing the FoxP1 in CMs . NotablyYAP/TAZ can target some lncRNAs and miRNAs to mediate upstream and downstream targets or pathways to regulate the biological activity and cellular function; the increase in its nuclear translocation is conducive to the CMs proliferation ,46. HoweIn an endothelial hypoxia model, silencing the YAP impaired the hypoxia-induced ECs proliferation and angiogenesis, while the endothelial heat shock protein 12B (HSPA12B) bound to the YAP and acted as a target and coactivator of the YAP/TEAD4 to regulate endothelial angiogenesis after an MI, hypoxia makes HSA12B translocate to the nucleus, which is accompanied by the YAPs activation and increased nuclear translocation of endothelial cells. The interaction between the two synergistically regulates angiogenesis. The possible mechanism is that HSPA12B forms clusters with YAP/TEAD4, then the YAP is positively activated at the transcriptional level after hypoxia and the YAP degradation is eliminated . In factAngiogenesis after an MI is an important step in cardiac repair. As a shear stress-sensitive mechanical sensor, the YAP/TAZ activity changes with different blood flow patterns. The YAPs activation and nuclear translocation of ECs play a protective role in the function of ECs in the cardiac dysfunction after a myocardial infarction. Paradoxically, changes in the activity and location of the endothelial YAP/TAZ will affect the inflammatory microenvironment. Most studies believe that the increased nuclear translocation of endothelial YAP/TAZ will aggravate the progress of the inflammatory response.The YAP/TAZ may also be involved in cardiac repair after an MI through an endocrine mediation . Adult cIndeed, cardiac fibroblasts, which are the most prevalent cell type in the heart and the main source of the extracellular matrix (ECM), play an important role in regulating cardiac fibrosis after an MI. Studies have demonstrated that Erbb2 drives mechanotransduction signals during cardiac regeneration in mice and downregulates the YAPs activation signals based on cytoskeletal remodeling and phosphorylation, thereby promoting changes in the epithelial-mesenchymal transition (EMT), including the production of substantial amounts of ECM, cytoskeletal remodeling, and CMs migration . In addiUsually, ischemic or nonischemic CVDs pathologically manifests as the stress-mediated activation of innate immune signaling pathways in CMs , and stiIn conclusion, the increase in the YAP/TAZ protein levels and its nuclear translocation can have a positive effect on cardiac repair after an MI. Activating the YAP can promote a myocardial cell proliferation, reconstruct blood circulation, improve the cardiac function, and reduce cardiac fibrosis. However, in the same disease model, protective/injurious effects can be different due to different expression levels or the targeting of different cardiac cells. This is a direction worth exploring in future research. Hypertension, atherosclerosis, and coronary heart disease are common in CVDs, and their pathological features include the endothelial dysfunction caused by the impaired vascular function and structural abnormalities ,83. How The long-term poor control of blood pressure in hypertensive patients can increase the pressure on the arterial vessel wall, damage ECs, and easily enter the arterial wall, stimulating the proliferation of vascular smooth muscle cells (VSMCs) and causing atherosclerosis, thereby causing coronary heart disease ,85. HoweIn contrast, YAP/TAZ is closely related to the occurrence of the atherosclerotic inflammatory response, and inhibiting inflammation can delay the development of atherosclerosis . The rolIn the heart and vascular system, mechanical mechanics affects the shape and physiological function of the heart. Laminar flow plays an important role in maintaining endothelial cell homeostasis, while turbulent blood flow leads to atherosclerosis. Whether YAP/TAZ regulates changes in the cell morphology, cytoskeleton, and ECM by mediating hemodynamics or inflammatory factors needs further study. All these indicate that targeting the YAP/TAZ signaling protein may be a new strategy to improve atherosclerosis. Cardiomyopathy is a kind of heart disease with a complex etiology, and basic lesions occur in the myocardium, resulting in an abnormal contraction in the myocardium . CardiomHCM is an autosomal dominant disorder that causes a sudden cardiac death in young adults . This coDCM is characterized by a left ventricular or biventricular dilation and systolic dysfunction in the absence of a coronary artery disease or overload . Ankrd1 AC is a genetic disorder characterized by cardiovascular events following ventricular tachycardia or fibrillation . StudiesIn addition to primary cardiomyopathy, cardiomyopathy in a broad sense also includes specific cardiomyopathy with a clear etiology; it is also associated with systemic diseases. Diabetic cardiomyopathy, which is markedly characterized by cardiac hypertrophy and an impaired systolic and diastolic function ,115, hasIn cardiomyopathy, the YAP/TAZ is often overexpressed and leads to a poor prognosis, but the mechanism is complicated, and research on the YAP/TAZ in cardiomyopathy still needs more exploration. The largest artery in the human body is the aorta, and related diseases mainly manifest as a tumor-like dilatation, dissection, and developmental malformation. It is a complex disease caused by various factors, such as the environment, behavior, and genes . Aortic Inflammatory cells infiltrate blood vessels, while VSMCs change phenotype and secrete a large number of metalloproteinases to degrade the ECM. The phenotype of VSMCs plays an important role in the balance of the ECMs synthesis and degradation. In conclusion, YAP/TAZ protein signaling is important for maintaining the contractile phenotype of VSMCs.YAP/TAZ is involved in the regulation of many key physiological processes, such as cell proliferation and differentiation, embryonic development, and tissue regeneration. The treatment methods for the YAP/TAZ have been recommended for the treatment of various diseases. The mechanism of the YAP/TAZ is not only a single pathway, but the multiple targeted intervention of the YAP/TAZ is very attractive. Targeting the YAP/TAZ-TEAD complex, kinases, and the upstream and downstream signaling that regulates the YAP/TAZ are all ideal approaches ,131,132.Various upstream signals can regulate the YAP/TAZ localization by activating the MST-LATS kinase cascade. XMU-MP-1 is a reversible and selective MST1/2 inhibitor that activates the downstream effectors YAP/TAZ to promote cell growth. XMU-MP-1 attenuates a myocardial mitochondrial dysfunction and CMs necrosis in a mouse model of myocardial ischemia/reperfusion (I/R) injury and inhibits inflammatory responses by stimulating the I/R M2 macrophage polarization . In a moIn addition, the YAP/TAZs activity can also be interfered from a pharmacological inhibition and genetic inhibition. A new type of YAP chemical inhibitor CA3 has been proved to have strong anti-tumor activity against esophageal adenocarcinoma . In the 2+-activated channel [However, due to the specific structural properties of the YAP/TAZ, targeting the the YAP/TAZ-TEAD complex may be the better strategy. Verteporfin, for example, is a classic YAP inhibitor and autophagy inhibitor that disrupts the YAP-TEAD interaction and induces apoptosis ,143,144. channel . In rece channel ,155. TEA channel . VGLL4 c channel . In addi channel ; alterna channel .The latest research found that palmitoylation is an important protein modification mode of TEAD binding with the YAP/TAZ, and its unique binding mode makes the TEAD easy to target . VT3989 In recent years, scientific research on the complex molecular mechanisms of the YAP/TAZ and its related signaling pathways has grown exponentially, but the current research on the YAP/TAZ in CVDs is still in the exploratory stage . We beliSecond, the activation of the YAP/TAZ can be protective or damaging in different CVD models. Even in the same disease model, protective/injurious effects occur due to different expression levels. For example, studies have shown that the YAP can have a protective effect by promoting the CMs proliferation , while sFurthermore, different cell types may respond to the YAP/TAZ to varying degrees. Thus, what may be considered low YAP/TAZ activity in one particular cell type may be high activity in another cell type. The interactions between the different cells targeted by the YAP/TAZ should be further examined.It is reasonable to target the YAP/TAZ in heart disease, but there are still important considerations before it undergoes the transition to clinical application. These questions include the specificity of the cell type of conduction, the possibility of being out of target in non-heart organs or diseases under the condition that the physiological effects of YAP disease have been clarified, off-target effects, and the best way and duration of a YAP/TAZ intervention.It is worth noting that tumorigenic stimulation is a difficult problem in researching YAP/TAZ signaling. Elevated YAP/TAZ activity and YAP/TAZ nuclear enrichment have been reported in many types of human cancers, such as colon, lung, breast, liver, and gastric cancer ,173,174.The YAP/TAZ protein participate in the physiological process of cardiovascular disease by maintaining cell proliferation, transmitting mechanical stimulus signals, promoting angiogenesis, and regulating the immune response ,181. StuIn conclusion, the potential targeting of YAP/TAZ signaling for clinical indications of CVDs in the future has been fully described, and our understanding of the YAP/TAZ still needs a further exploration.


The tidal volume size was low in both groups (median (IQR), 7.2 (6.3 to 8.1) versus 7.0 (5.3 to 9.1) ml/kg PBW; p = 0.97). The median right ventricular MPI was 0.32  in the lower-PEEP group versus 0.38 (0.32 to 0.41) in the higher-PEEP group; the median difference was –0.03; 95% CI: −0.11 to 0.03; p = 0.33. The other systolic and diastolic parameters were similar. In patients without ARDS ventilated with a low tidal volume, a lower PEEP had no beneficial effects on the right ventricular MPI.The aim of this study was to investigate whether lower PEEP (positive end-expiratory pressure) had beneficial effects on myocardial function among intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) compared to higher PEEP. In this pre-planned substudy of a randomized controlled trial (RELAx), comparing lower to higher PEEP, 44 patients underwent transthoracic echocardiography. The exclusion criteria were known poor left ventricular function and severe shock requiring high dosages of norepinephrine. To create contrast, we also excluded patients who received PEEP between 2 cmH2O and 7 cmH2O in the two randomization arms of the study. The primary outcome was the right ventricular myocardial performance index (MPI), a measure of systolic and diastolic function. The secondary outcomes included systolic and diastolic function parameters. A total of 20 patients were ventilated with lower PEEP , and 24 patients, with higher PEEP (8 ± 1 cmH2O) (mean difference, −8 cmH2O; 95% CI: −8.1 to −7.9 cmH2O;  Mechanical ventilation, the most frequently applied strategy in the intensive care unit (ICU), is a potentially harmful intervention . ProtectPEEP is well-known to cause significant hemodynamic changes that could lead to a decreased cardiac index . A higheIt remains uncertain if ventilation with a PEEP of 8 cmH2O could negatively impact cardiac function in ICU patients without ARDS. Therefore, this study was conducted to compare lower versus higher PEEP on right and left ventricular function in patients without ARDS, assessed by echocardiography between 24 and 48 h after the start of invasive ventilation. We hypothesized that lower PEEP has beneficial effects on right ventricular systolic and diastolic function compared to higher PEEP with the use of low tidal volumes.clinicaltrials.gov accessed on 20 January 2022, trial number NCT03167580) was a national, multicenter, randomized clinical trial in invasively ventilated ICU patients without ARDS [The RELAx trial , and deferred informed consent was obtained from a legal representative for this substudy, as part of the parent study RELAx.The parent study enrolled patients who were expected to be ventilated for more than 24 h; the exclusion criteria included the presence of ARDS, COPD GOLD class III or IV, restrictive pulmonary disease, ongoing cardiac ischemia and severe untreatable anemia. The exclusion criteria were known poor left ventricular function , severe shock requiring norepinephrine greater than or equal to 0.5 µg/kg/min, and ventilation with PEEP greater than 2 cmH2O in the lower-PEEP group and less than 7 cmH2O in the higher-PEEP group.Transthoracic echocardiography images were recorded using a commercially available ultrasound system with a 2–5 MHz sector probe . The images were continuously and digitally stored according to the local standard protocol.2 or PaO2 dropped below 92%, or below 60 mm Hg for more than 5 min, the FiO2 was increased to the maximal 0.6 before the PEEP was increased in steps of 1 cmH2O up to 5 cmH2O (lower-PEEP group) or up to more than 8 cmH2O (higher-PEEP group).The full details of the study methods, including the ventilation strategies, have been described previously . BrieflyBefore the transthoracic echocardiography, the hemodynamic and respiratory data of the patients were recorded. All the ventilator settings and drug doses remained unaltered during the approximately 30 min required for transthoracic echocardiography. If arterial blood gas data were collected within 4 h of the transthoracic echocardiography, these data were obtained from the electronic patient data system. Skin electrodes were attached to generate a continuous cardiac rhythm on the echocardiogram with a minimum recording of three cardiac cycles in the case of a sinus rhythm, or five cardiac cycles in the case of atrial fibrillation according to guidelines .The right ventricular myocardial performance index was the primary endpoint of the study. The myocardial performance index was calculated from tissue Doppler imaging by adding the isovolumetric contraction time to the isovolumetric relaxation time and then dividing the sum by the ejection time. The secondary endpoints included the left ventricular myocardial performance index, and various systolic and diastolic echocardiographic parameters . Thereafter, the images were analyzed offline using automated function imaging software  by a blinded investigator.Based on the results of a recent study in a comparable patient cohort , we expet-test in the case of a normal distribution; otherwise, the Mann-Whitney U test was used. Categorical variables were compared between the PEEP groups using the chi-square test. Categorical data are reported as numbers with percentages in parentheses. Continuous data are reported as means with their standard deviations (SDs) in the case of a normal distribution; otherwise, medians with their interquartile ranges (IQRs) are provided. Comparisons are shown with the mean difference and the 95% confidence interval (CI) from the independent-samples t-test in normally distributed cases; otherwise, the Hodges-Lehmann estimate of the median difference and 95% CI were used.Continuous variables were compared between the PEEP groups using the independent-samples http://www.r-project.org, R version 3.3.1, accessed on 2 February 2022). A two-sided p value under 0.05 was considered statistically significant.All the analyses were performed in R through the RStudio interface , leaving 44 patients who underwent a transthoracic echocardiography examination. Data for the 44 patients, 20 patients allocated to lower PEEP and 24 patients allocated to higher PEEP, were analyzed .The baseline characteristics are presented in p < 0.01). Accordingly, the maximum airway pressure was lower in the patients ventilated with lower PEEP compared with those ventilated with higher PEEP . The tidal volumes were similar for the two PEEP groups. The mean pH was higher in the lower-PEEP group; the mean hemoglobin was higher in the higher-PEEP group. The hemodynamic parameters did not differ between the two PEEP groups.The respiratory and hemodynamic parameters are presented in p = 0.22), and 32 (17 to 160) % versus 23 (7 to 49) % (p = 0.21) in the lower- and higher-PEEP groups, respectively).Mitral or aortic valvopathy was present in none of the patients. There were no differences in the mean diameter of the vena cava inferior or in the distensibility index  in the patients ventilated with lower PEEP versus 0.45 (0.39 to 0.54) in the patients ventilated with higher PEEP; median difference, –0.02; 95% CI, –0.09 to 0.04; p = 0.35. No differences were found in any parameter for the systolic and diastolic function of the left or right ventricular between the PEEP groups  in the lower-PEEP group versus 0.38 (0.32 to 0.41) in the higher-PEEP group; median difference, –0.03; 95% CI, –0.11 to 0.03; P groups .This study shows that mechanical ventilation with lower PEEP in ICU patients without ARDS does not affect the right ventricular myocardial performance index compared to higher PEEP. The left ventricular myocardial performance index and other systolic and diastolic echocardiographic parameters were also not different between the two PEEP groups.2 values within the normal range, no hypoxia was observed, and the respiratory system was within normal ranges. In addition, there was sufficient time for the correction of a possible preload decrease in the higher-PEEP group as illustrated by the higher fluid balance. In this study, we observed that decreasing PEEP in patients without ARDS has minor effects on the right heart afterload and right and left systolic and diastolic function.The detrimental effects of PEEP on the heart have been assessed extensively in patients with ARDS ,19,20,21The effects of PEEP on cardiac function in this study should be considered within the context of ventilation with a lower tidal volume. In a recent study, performed in a similar patient group, the right ventricular myocardial performance index was lower during ventilation with a lower tidal volume versus a higher tidal volume (0.41 vs. 0.64) . In thatThe myocardial performance index, obtained using tissue Doppler imaging, was chosen in this study to assess right heart function for several reasons. The MPI is a straightforward, reproducible indicator of both systolic and diastolic function and is relatively independent of preload and afterload, and therefore, possible differences in the loading conditions, such as the fluid balance, will have limited effects on this parameter .Over the years, there has been a clear increase in the use of higher PEEP in patients with ARDS and in patients without ARDS , althougIn this study, we investigated if decreasing the PEEP from 8 to 2 cmH2O in ventilated patients without ARDS had beneficial effects on cardiac function. The vena cava distensibility index in this study indicates that the included patients were adequately volume resuscitated. This is supported by the difference in fluid balance of 900 mL between the two groups at the moment of echocardiography. One could suggest that this may have mitigated the detrimental effects of ventilation with a higher level of PEEP on cardiac preload.The strengths of this study are the fact that the effects of PEEP were evaluated in a heterogeneous population of ICU patients without ARDS, who were randomly divided into two PEEP groups. The protocol of this study was pre-published, and the transthoracic echocardiography data were analyzed by a blinded physician. The patients in both groups were well equilibrated, and the tidal volume was not different between the two PEEP groups. The examiners who performed the echocardiograms could not be blinded for group assignment, but the obtained images were further analyzed offline by a blinded investigator. This is the first clinical study to assess the effects of decreasing PEEP to the lowest possible level on cardiac function in invasively ventilated patients not having ARDS.This study also has some limitations. First, we only used transthoracic echocardiography to evaluate cardiac function. Future studies should include additional parameters of cardiac function to strengthen the current findings. Second, we did not perform serial transthoracic echocardiographies. A comparison from before intubation or shortly after intubation would have been interesting. However, this was not possible due to the design of the study; the randomization for the parent study was conducted within one hour of the start of ventilation in the ICU, the PEEP titrations were started immediately after randomization, and we required informed consent from the legal representative for this study before an echocardiography could be performed. Certainly, right ventricular function in patients requiring prolonged ventilation can be affected by several other factors . On the other hand, 24 to 48 h of mechanical ventilation is sufficiently long for studying the effects of PEEP without the risk of such confounders. Third, we did not measure the pulmonary artery pressure and therefore could not determine the effects with lower or higher PEEP on the pulmonary artery pressure and, with that, the afterload of the right ventricle. Fourth, the right ventricular myocardial performance index is relatively pre-load-independent; however, we cannot exclude the possibility that some patients may have had atrial pressures of more than 15 mmHg, causing a pseudonormalization of this index . FurtherIn patients without ARDS ventilated with a low tidal volume, ventilation with lower PEEP had no beneficial effects on the right ventricle myocardial performance index when compared to ventilation with higher PEEP.


Pericardial effusion may present clinically as pleuritic chest pain, dyspnea, or hemodynamic compromise and is a frequent finding in computerized tomographic pulmonary angiography (CTPA) exams. We hypothesized that CTPA-based analysis of the cardiac chamber volumes can be used to predict the hemodynamic significance of pericardial effusion (HsPE) as compared with echocardiography.Retrospective analysis of consecutive patients who underwent CTPA and echocardiography between January 2009 and November 2017 that ruled-out acute pulmonary embolism was included. Differences in cardiac chamber volumes were investigated in correlation to echocardiographic evidence of HsPE.p < .001) for predicting the presence of HsPE. An RA volume ≤86 ml yielded a sensitivity of 95.5%, a specificity of 64%, and a NPV of 99.2% for the presence of HsPE.The final cohort included 208 patients, of whom 22 (11%) were diagnosed with HsPE. The HsPE patients had much smaller right cardiac chamber volumes (Median 78.8 ml (IQR 72.4–89.1)) than patients without HsPE (Median 115.1 ml (IQR 87.4–150). A decision tree for the prediction of HsPE showed multiple cutoff values. Right atrium (RA) volume had the best accuracy (area under the curve 0.851, 95% confidence interval 0.776–0.925, CTPA-based volumetric information with focus on the RA volume may help predict the presence of HsPE.Pericardial effusion is a frequent finding in CTPA exams. Our study shows that CTPA-based volumetric information can predict the presence of HsPE with RA volume as the best indicator. The nonspecific symptoms associated with APE , that are prevalent in other etiologies, leads to only 10–20% of patients undergoing CTPA with confirmed with APE. Pericardial effusion is present in around 5% of CTPAs. Clinical significant effusion are most often caused by neoplastic, infectious (most commonly tuberculosis), and uremic. The clinical implication of the effusion is related not only to the size but also to the rate of accumulation. Effusions that develop slowly can be remarkably asymptomatic, while rapidly accumulating smaller effusions can present with tamponade. Clinical significant pericardial effusion occurs when the increase in pericardial pressure by the fluid impairs diastolic filling and thus decreases stroke volume and cardiac output. Although patients could be asymptomatic, many experience dyspnea, chest pain weakness, and in its most severe manifestation present with hemodynamic compromise. The most important aspect of the early evaluation of patients with pericardial effusion is the hemodynamic impact of the fluid, and echocardiography is the methodology of choice for detecting hemodynamic changes before the occurrence of a clinical cardiac tamponade.A computed tomography pulmonary angiogram (CTPA) is currently the modality of choice for the definitive diagnosis of acute pulmonary embolism (APE) Ohta et al reported that the combination of right ventricular outflow tract compression, IVC long and short axis diameter ratio, and effusion size had a sensitivity of only 81% in predicting the presence of cardiac tamponade. Their study did not include normotensive patients who were in a pre-tamponade state, which can be diagnosed by the presence of hemodynamically significant pericardial effusion (HsPE) on echocardiography.Several reports have shown non-specific imaging CT findings of cardiac tamponade, including coronary sinus compression, inferior vena cava (IVC) dilatation, and reflux of contrast material into the IVC.Since early diagnosis of an impending tamponade could lead to improved outcome, the aim of the present study was to assess the diagnostic value of automated volumetric analysis of the cardiac chambers based on CTPA images for the identification of patients with HsPE.This study is a retrospective analysis performed in a single university-affiliated tertiary-care hospital. It was reviewed and approved by the Institutional Review Board with a waiver of informed consent.The hospital’s database was used to identify consecutive patients who underwent CTPA between January 2009 and November 2017 and for whom echocardiography results were available. The electronic medical records of the patients were used to retrieve radiologic information as well as clinical information  and echocardiographic data. The inclusion criteria were inpatients older than 18 years of age with evidence of pericardial effusion on the CTPA examination. Patients whose CTPA examination was technically inadequate for volumetric analysis were excluded.All patients were scanned by a multidetector CT scanner  with 64 or 128 × 2 detector rows. The reconstructed slice thickness was 1.0 mm with increments of 0.5 mm. Scans were acquired according to our routine non-electrocardiographic-gated CTPA protocol with contrast injections of 70–100 ml of iodinated contrast material at a concentration of 300 mg iodine per mL  and at rates of 3–4 mL/second. To optimize visualization of the pulmonary arteries, an automated bolus-tracking technique was used with a region of interest placed within the main pulmonary artery. Scanning began 5 s after reaching a threshold of 100 Housefield Units at the region of interest. All scans were obtained in a caudal-cranial direction during a single breath-hold. The volume of each chamber was automatically calculated with additional computation of the ratios between the various cardiac chambers’ volumes: right ventricle (RV) volume to left ventricle (LV) volume , and right atrial (RA) volume to left atrial (LA) volume . Each exam was reviewed by an expert radiologist or cardiologist to assess the quality of the volume segmentation, and exams with inaccurate segmentation (n = 9) were excluded . When height and weight were available, each chamber’s volume was adjusted to the body surface area and reported as the patient’s index volume.Automated volumetric measurements were obtained retrospectively for research purposes by a fully automatic algorithm  that adapts an anatomic model of the heart chambers to the CT image volume. They included evaluation of the IVC and hepatic veins, evidence of right heart diastolic chamber collapse, increased respiratory variation in mitral inflow and left ventricular outflow tract outflow, and septal bounce. Patient were diagnosed as having HsPE if their echocardiographic findings were indicative, as per ASE 2013 consensus statement..Pericardial effusion was assessed by a comprehensive two-dimensional and Doppler echocardiographic study with multiple windows during the same examination according to the American Society of Echocardiography (ASE) clinical recommendations.P value was given for each branch. To increase the validity of the decision tree, a fivefold cross-validation procedure was applied with similar cutoff points. The discrimination ability was evaluated with the area under the receiver operating characteristic curve. All statistical tests were two-sided, and a P-value of <.05 was considered statistically significant. SPSS software was used for all statistical analysis .Categorical variables were reported as numbers and percentages, and continuous variables were reported as means ± standard deviation or medians with interquartile range. Continuous variables were evaluated for normal distribution with histograms and Q-Q plots. The Mann-Whitney test was applied to compare continuous variables between groups, and the Chi-square test was used to compare categorical variables. Each continuous cardiac chamber volume was divided into categories by means of a chi-squared automatic interaction detection model or a classification and regression model with a maximum tree depth of 3 levels, minimum of 50 cases in parent node and minimum of 20 cases in child node. The analysis selects the best predictor for splitting the data into child nodes according with association with the presence of HsPE. A The CTPA examination of nine patients was technically inadequate for volumetric analysis and they were excluded. Our final cohort included 208 patients, 106 patients (51%) with small while pericardial effusion, and 102 (49%) with moderate or large based upon CTPA assessment. 70% of the patients underwent echocardiography on the same 24 h as the CTPA exam. Twenty-two (11%) patients had HsPE per echocardiography, and 19 (9%) of them underwent urgent pericardiocentesis during their index hospitalization.p = .002), while those without HsPE were more likely to have a history of chronic lung disease , ischemic heart disease , atrial fibrillation , and chronic heart failure .P value). The areas under the ROC curves for the LV, LA, RV, and RA cutoff values were 0.713 , 0.782 , 0.833 , and 0.851 , respectively (ectively .p < .001) to sustain a HsPE compared to all other patients. Patients with an LA volume ≤59.4 ml had an OR of 11  compared with patients with LA volumes above 87.3 ml. Patients with an RV volume ≤82.7 ml had an OR of 6.5  compared with patients with an RV volume between 82.7 and 128.5 ml. Since no patient with an RV volume >130 ml had HsPE, the OR could not be calculated for that cutoff. An RA volume ≤64.1 ml had an OR of 66.2  compared with an RA volume >86.1. There was an OR of 16.2  for an RV volume between 64.1 and 86.1 ml compared with an RA >86.1 ml. The sensitivity, specificity, PPV, NPV, and accuracy of each cutoff value for the diagnosis of HsPE are presented in The major finding of this study is the ability of CT-derived cardiac chamber volumes to predict the presence of HsPE with a very good discriminative value. All cutoff values showed a high NPV, thus allowing the radiologist to safely rule out causes of a pending tamponade. PE is caused by the accumulation of fluid in the pericardial sac, with clinical manifestations ranging from asymptomatic, dyspnea, and non-specific chest pain to the most significant of them, cardiogenic shock. These patients could present to the emergency room with symptoms similar to APE and undergo CTPA that will rule out APE but diagnose the existence of the PE. The primary pathophysiology is compression of all cardiac chambers, especially the low-pressure right-sided chambers, as a result of the increased pericardial pressure. This process impairs diastolic filling that in turn decreases stroke volume and cardiac output.While the effusion size is an important parameter in evaluating PE, it does not evaluate the clinical and hemodynamic significance of the fluid in the pericardial sac. The relationship between the pericardial volume and pressure is non-linear, whereby a relatively small PE that accumulates rapidly may reduce cardiac filling, rapidly leading to hemodynamic shock, while a chronic very large PE may be observed as having minimal hemodynamic effectEchocardiographic assessment of PE is based mostly on the hemodynamic effect of the fluid, such as right heart diastolic chamber collapse when pericardial pressures exceed intracardiac pressure and inspiratory septum “bounce”. However, echocardiography lacks the ability to accurately determine the right chambers’ volumes. CTPA, on the other hand, allows simultaneous full visualization of all four chambers as well as the quantification of their volumes without the need for any geometrical assumptions. showed a method that allows an accurate assessment of the pericardial fluid by CT compared with autopsy report in a specific study population of patients with tamponade caused by rapid accumulation of the fluid  . The second by Liu J et al utilized a software that quantifies the pericardial effusion size and also gives an estimated HU density (for prediction of hemopericardium). Both studies are limited by the focus on the pericardial effusion size and not on the hemodynamic effect on the cardiac chambers.Two additional studies used volume analysis of CT scans in patients with pericardial effusion. The first by Ebert et al The RA is the chamber with the lowest pressure, especially during late diastole, making it relatively more susceptible to collapse from increased intrapericardial pressure. Thus, a small RA volume can be taken as a sign of significant pericardial pressure.Our study findings suggest multiple cutoff values for each chamber, with an RA volume ≤82 ml as being the best predictor of HsPE. The application of a four-chamber volumetric analysis tool is quick and can be executed automatically immediately following the CTPA scan, without any delay or need to transfer the patient to the echocardiography lab. Our results support the contention that an echocardiographic-based finding of RA collapse due to increased pericardial pressure is both a sensitive as well as an early sign of HsPE.This study had some limitations. First, the relatively small number of events limited our ability to perform a multivariate logistic regression analysis. Second, the nature of the retrospective analysis in a single tertiary hospital should be validated on a separate dataset. Third, we used non-gated CTPA for the assessment of cardiac volumes, a methodology that is inferior to gated procedures. Our purpose in doing so was to examine data obtained within routine clinical settings, which is currently based on non-gated CTPA scans. Also, volumetric analysis of non-gated CTPA is an accepted solution in other scenario such as assessing RV to LV volume ratio in patients with pulmonary embolism and is used to provide further prognostic information.In conclusion, our results suggest that small cardiac chamber volume, especially an RA of <86 ml which is based on automatic analysis of the CTPA scan, may predict the presence of HsPE in a patient with PE. Using automated software analysis, these data can be available soon after the completion of the exam and may allow more expeditious management of these patients.


The pathophysiological mechanisms underlying the development of the athlete’s heart are still poorly understood. To characterize the intracavitary blood flows in the right ventricle (RV) and right-ventricular outflow tract (RVOT) in 2 healthy probands, patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and 2 endurance athletes, we performed 4D-MRI flow measurements to assess differences in kinetic energy and shear stresses. Time evolution of velocity magnitude, mean kinetic energy (MKE), turbulent kinetic energy (TKE) and viscous shear stress (VSS) were measured both along the whole RV and in the RVOT. RVOT regions had higher kinetic energy values and higher shear stresses levels compared to the global averaging over RV among all subjects. Endurance athletes had relatively lower kinetic energy and shear stresses in the RVOT regions compared to both healthy probands and ARVC patients. The athlete’s heart is characterized by lower kinetic energy and shear stresses in the RVOT, which might be explained by a higher diastolic compliance of the RV. The morphologic remodeling in the so-called athlete’s heart and the RV alterations described in arrhythmogenic ventricular cardiomyopathy (ARVC) significantly overlap, although the underlying mechanisms significantly differ3. ARVC is a polygenic disease with different penetrance and degree of gravity involving desmosomal mutations4. There is evidence suggesting that intensive exercise may not only accelerate the development of an adverse RV remodeling in affected patients, but may also induce cardiac fibrosis and a pathologic RV dilation, leading to an increased risk for malignant arrhythmia even in healthy subjects5.Extensive training results in repetitive volume and pressure overloads, which are responsible for cardiac remodeling involving both ventricles. The right ventricle (RV) is particularly susceptible to exercise-related hemodynamic variations, thus leading to a structural, functional and electrical remodeling8.The analysis of fluid dynamics parameters such as mean kinetic energy (MKE), turbulent kinetic energy (TKE) and viscous shear stress (VSS) as measured by MRI have already been tested as hemodynamic indicators of severity in Tetralogy of Fallot, aortic valve stenosis and mitral regurgitationThe aim of this study is to better understand the hemodynamic differences of the blood flow in RV underlying the different RV remodeling pattern in endurance athletes and ARVC patients compared to healthy subjects.10. Athletes underwent MRI examination during their regular training and cardiopulmonary exercise testing showed a VO2peak of 37 ml/min/kg, corresponding to 339 W, 175% of theoretical maximal capacity, and a VO2peak of 43 ml/min/kg, corresponding to 412 W, 197% of theoretical maximal capacity, respectively. ARVC patient #1 was diagnosed during regular health check-up and presented with major imaging criteria and repolarization abnormalities. ARVC patient #2 presented initially with palpitation during sport activity and was diagnosed with major arrhythmia criteria due to the finding of ventricular tachycardia. Both ARVC patients did not perform high-intensity sport neither at the moment of ARVC diagnosis, nor before, but only moderate-intensity leisure activity11. Their functional capacity at exercise testing revealed a good functional capacity of 206 W, corresponding to 99% of the theoretical maximal capacity, and of 239 W, corresponding to 111% of the theoretical maximal capacity, respectively.In this observational study, male subjects were categorized into 3 groups as follows: healthy volunteers with mild daily activities , athletic male probands with endurance sport activity history , and patients with definite ARVC according to the 2010 Task Force Criteria All patient groups were screened and recruited for 4D flow MRI scans at the University Hospital of Zurich. Informed consent was obtained for all participants. The study conformed to the principles outlined in the Declaration of Helsinki and was approved by the local Ethical Committee of Canton Zurich (EK-Nr. PB_2016-02109).3, field of view 250 × 160 × 50 mm3. The velocity encoding (VENC) values were 40, 100 and 200 cm/s per direction. More technical details can be found in the previous publications of Gülan et al.13. The heart rate and cardiac output at the moment of the MRI analysis are reported in Table All subjects were scanned with a 3T Philips Ingenia System . For 4D Flow imaging, a spoiled gradient echo sequence with multipoint velocity encoding using 10 different velocity encodings  was applied. The imaging parameters were as follows: spatial resolution 2.5 × 2.5 × 2.5 mm13 as half of the blood density times the square of the phase averaged velocity:The anatomical segmentation was performed using an in-house algorithm in MATLAB. Four different hemodynamics parameters, namely velocity, mean kinetic energy (MKE), turbulent kinetic energy (TKE) and viscous shear stress (VSS) were utilized as an indicator of the hemodynamics performance in the circulatory system. The voxelwise total kinetic energy can be decomposed into mean kinetic energy (MKE) and turbulent kinetic energy (TKE). The mean kinetic energy (MKE) is calculated for each voxel for different phases of the cardiac cycle13.Finally, viscous shear stresses (VSS) are calculated as the gradient of the mean velocity profile:14.RV and LV end-diastolic diameters indexed for body surface area were measured in parasternal long axis according to current guidelinesThe baseline characteristics of the male subjects are summarized in Table 7 and a second peak in diastole due to the high velocity regions in the vicinity of the tricuspid region where the atrial blood flow fills the RV. Figure Temporal evolution of velocity magnitude spatially averaged over RV is shown in Fig. Temporal evolution of MKE averaged over the entire RV is shown in Fig. Similar to the MKE analysis, temporal evolution of TKE averaged over the entire RV was presented in Fig. Finally, the temporal trend of viscous shear stress is investigated. As shown in Fig. This study demonstrates time dependent, 3D blood flow patterns in the RV and RVOT as extracted using 4D-MRI flow measurements. To the best of our knowledge, this is the first study assessing the kinetic energy and shear stresses in the RV, and more specifically in the RVOT, by 4D-MRI in healthy probands, endurance athletes and ARVC patients.13. The present data show that these findings apply to endurance athletes, as well: RVOT has higher kinetic energies and shear stresses compared to the global averaging over RV in all population analyzed. This finding might explain the high incidence of idiopathic tachycardias originating from the RVOT even in absence of structural heart disease16.In this study, we compared fluid dynamics of both RV and RVOT in healthy probands, endurance athletes and ARVC patients. RV and RVOT flow patterns have already been investigated in a previous study both in vivo and in vitro, showing that healthy probands and ARVC patients are subjected to higher MKE and WSS levels in the RVOT regions as compared to the rest of the RV17.The diagnosis of ARVC is often challenging particularly at the early stages of disease, as it mostly involves young subjects. Furthermore, ARVC patients involved in both amateur and professional endurance sport activities are more likely to present with more severe clinical manifestations of ARVC. A better understanding of RV and RVOT fluid dynamics might help comprehend why genetically predisposed ARVC patients performing endurance activity develop a more severe phenotype and why otherwise healthy endurance athletes develop an ARVC-like phenotype even in absence of its corresponding genotypeContrary to healthy probands and athletes, we found that ARVC patients experience in particular a second peak in flow velocity even during the diastole in the subtricuspid region, which is one of the first regions presenting with structural anomalies during the early stages of the disease.18.Despite high RV and RVOT flow velocities, athletes had lower MKE values both along the whole RV and more specifically in the RVOT regions during both systole and diastole compared to ARVC patients. This finding likely reflects the differences in RV compliance, which is higher in athletes, whereas ARVC patients can develop RV diastolic dysfunction, which imply a negative prognosis8. We found that athletes constantly showed lower TKE levels both along the whole RV and more specifically in the RVOT regions during all heart cycle phases compared to healthy probands and ARVC patients. This finding was confirmed also when shear stress originating from viscous fluid was analyzed. Our group previously demonstrated that there are higher shear stresses in the RVOT regions in a similar fashion in both healthy probands and ARVC patients13.The analysis of blood stream turbulence was performed by assessing TKE, which has already been associated with adverse RV remodeling in patients with tetralogy of Fallot and relevant pulmonary valve regurgitation21. Despite a resting biventricular systolic ejection fraction on the lower normal range, early diastolic function is usually normal to enhanced23. The current findings about lower RV shear stress in athletes might be related to a higher adaptation capability of the athlete’s heart to dynamic intracavitary stress related to blood flow, leading to an increased ventricular diastolic compliance.Interestingly we found that endurance athletes had both global RV and locally in the RVOT area lower shear stress values not only compared to ARVC patients, but also to healthy probands. The athlete’s heart is defined as a set of structural, electrical and functional remodeling as response to repetitive intense or extensive exercise. Endurance athletes present with four-chamber enlargement and higher biventricular mass in response to repetitive volume challengesThe three groups investigated  are represented only by two subjects each. Thus, interindividual variability could not be taken into account and formal statistical analyses were not possible. The proposed study reflects the observation of different physiological and pathological flow mechanics in these 3 groups and did not aim to provide definite answers, also because statistical analyses were not possible due to the low numbers. Our study can rather be regarded as hypothesis generating.


Different regional depots of fat have distinct metabolic properties and may relate differently to adverse cardiac remodeling. We sought to quantify regional depots of body fat and to investigate their relationship to cardiac structure and function in Type 2 Diabetes (T2D) and controls.From the SCAPIS cohort in Linköping, Sweden, we recruited 92 subjects : 46 with T2D and 46 matched controls. In addition to the core SCAPIS data collection, participants underwent a comprehensive magnetic resonance imaging examination at 1.5 T for assessment of left ventricular (LV) structure and function , as well as regional body composition .P < 0.001), liver fat percentage (P < 0.001), thigh muscle fat infiltration percentage (P = 0.02), LV concentricity (P < 0.001) and LV E/e'-ratio (P < 0.001). In a multiple linear regression analysis, a negative association between liver fat percentage and LV mass  as well as LV end-diastolic volume  was found. Epicardial adipose tissue volume and abdominal subcutaneous adipose tissue volume index were the only parameters of fat associated with LV diastolic dysfunction (E/e'-ratio) . In a multivariate logistic regression analysis, only visceral adipose tissue volume index was significantly associated with T2D, with an odds ratio for T2D of 3.01  per L/m2 increase in visceral adipose tissue volume.Compared to the control group, the T2D group had increased: visceral adipose tissue volume index (Ectopic fat is predominantly associated with cardiac remodeling, independently of type 2 diabetes. Intriguingly, liver fat appears to be related to LV structure independently of VAT, while epicardial fat is linked to impaired LV diastolic function. Visceral fat is associated with T2D independently of liver fat and abdominal subcutaneous adipose tissue. Visceral adipose tissue (VAT) is associated with metabolic cardiovascular disease risk factors , 2, abovHow different fat depots affect cardiovascular risk factors is still unclear. Ectopic and visceral fat depots are thought to act through both local and systemic effects , and proper se is likely to affect cardiac remodeling .From the core SCAPIS data in Linköping, we had access to the following data:Demographic variables Self-reported cardiovascular morbidity and drug useAnthropometric measurements Routine clinical biochemistry Echocardiography .Echocardiography was performed using a GE Vivid E95 rev 201 or E9  according to current guidelines from EACVI/ASE  (see Sup1H-MRS) sequence, cardiac 3D cine balanced steady state-free precession (bSSFP) sequence and cardiac 3D Dixon sequence. After inclusion, all 92 participants underwent a comprehensive MRI examination at Linköping University Hospital between November 2017 and July 2018. Data were acquired in a single examination using a Philips Achieva dStream 1.5 T MRI-scanner  and included a neck-to-knee four-echo mDixon sequence, liver proton magnetic resonance spectroscopy  post-processing software. Briefly, the image analysis consisted of (1) image calibration, (2) fusion of image stacks, (3) image segmentation, and (4) quantification of fat and muscle volumes : the subcutaneous adipose tissue volume in the abdomen from the top of the femoral head to the top of the thoracic vertebra T9.Visceral adipose tissue (VAT): the adipose tissue volume within the abdominal cavity, excluding adipose tissue outside the abdominal skeletal muscles and adipose tissue and lipids within the cavity and posterior of the spine and back muscles.Fat-tissue free muscle volume (FFMV): the volume of all voxels with a fat fraction below 50%, i.e., “viable muscle tissue”, in the thighs.Muscle fat infiltration (MFI): the mean fat fraction in the FFMV of the right and left anterior thigh.Images from the neck-to-knee mDixon sequence were analyzed and automatically segmented using the AMRA volumes , 19, 20 VAT, ASAT and FFMV were indexed to height squared  and deno1H-MRS PRESS-sequence as described in previous publications  and 663 ms (water) and T2: 58.5 ms (fat) and 43.4 ms (water)  using MRS, which provides good precision on low fat concentrations and robustness toward artifacts. PDFF was measured using a ications , 23. Posications , 25. In  (water) , 26, 27.The epicardial adipose tissue (EAT) volumes were determined by analyzing the transversal image stacks from the cardiac 3D Dixon sequence. ROI-drawing was performed using the open-source software MITK (version 2018.04.2) . SegmentImages from the cardiac 3D cine bSSFP sequence were analyzed using software Segment CMR  , to acqu2) = (height (cm) × weight (kg)/3,600)1/2. Just as body composition variables, indexed cardiac parameters were denoted with the suffix “-i”.Stroke volume (SV) was calculated as: stroke volume = end-diastolic volume – end-systolic volume. Ejection fraction (EF) was calculated as: ejection fraction = stroke volume / end-diastolic volume. As a measure of concentricity, the ratio between LV mass and LV end-diastolic volume (LVEDV) was calculated for each participant, termed LV concentricity (LVC). Where applicable, cardiac parameters  were indexed to body surface area using the Mosteller method : BSA  was a simple linear regression between each fat parameter and each LV parameter. Model 1 was a multiple linear regression with each fat parameter deployed separately, adjusted for sex and diabetes. Model 2 was a multiple linear regression with liver fat, epicardial fat and visceral fat deployed simultaneously in a single model, adjusted for sex and diabetes. MFI data were missing in 25% of the participants and was therefore not used in Model 2. Liver fat distribution was skewed despite stratifying for sex and diabetes, and therefore logarithmically transformed for this analysis. For every model we calculated the overall R2-value as well as P-value and standardized beta coefficients for each independent variable.To test the associations between cardiac remodeling and fat infiltration, linear regression analyses were performed. Structural and functional LV variables were deployed as dependent variables and the metrics of fat as independent variables. Regression analysis was performed in three steps. The crude regression model , higher P-glucose , higher HbA1c  compared to the normoglycemic group. The T2D group also displayed significantly lower total cholesterol , lower LDL cholesterol  and higher self-reported usage of lipid-lowering medication   see .2, P < 0.001), higher liver fat percentage  and MFI percentage  (see As compared to controls the T2D group had a significantly higher VATi volume (1.94 vs. 1.35 L/m.02) see .P < 0.001), indicating impaired diastolic function, and increased LV concentricity, . There were no significant differences in ejection fraction, LVEDVi or LVMi , there was a positive relationship between liver fat and LVC . The association was still significant when including diabetes and sex , but not when including VATi and EATi (Model 2). The negative associations of liver fat to LVMi and LVEDVi were still significant in Model 2, P < 0.05 for both. All parameters of fat had a significant positive relationship with E/e'-ratio in the Crude model. When adjusting for diabetes, only EATi and ASATi were significantly related to E/e', P < 0.05 for both. VATi was positively associated with both LVC and E/e' in the Crude model, although these associations were non-significant when adjusting for diabetes and sex (Model 1). In general, liver fat was associated with structural LV parameters. In the Model 1 and Model 2, results were consistent when replacing diabetes status with BMI (not shown in tables). When adding adjustment for self-reported cardiac disease to sex and diabetes (not shown in tables), results in Model 1 and 2 were overall directionally consistent. Results in Model 1 persisted. Associations in Model 2 were slightly attenuated, as liver fat was borderline significant as predictor for LVMi  and LVEDVi .For P < 0.05 for all). In the multivariate model , only VATi remained statistically significant (P < 0.05), with an odds ratio (OR) increase for T2D of 3.01 for each L/m2 increment in VATi  and structural LV parameters. Neeland et al.  demonstrInterestingly, while liver fat was related to LV structural parameters in our study, it was not significantly associated with any functional LV measures after adjustment for sex and diabetes. Among the visceral and ectopic fat depots, EAT was the only parameter in model 1 that was significantly positively associated with E/e' ratio, an indicator of LV diastolic dysfunction. Although this association was non-significant in model 2, perhaps due to lack of power, our results support previous findings that epicardial fat relates to LV function without a significant association to structural remodeling. A meta-analysis stated that EAT was associated with LV diastolic dysfunction, but the associations between EAT and LV structure were found to be largely inconsistent and uncertain . There aDiastolic impairment was the main cardiac functional abnormality found in this study population, related to both diabetes and to increasing volumes of EAT (independently of diabetes), while there were no significant findings regarding ejection fraction between the groups or in the regression analyses. Moreover, lower LVEDV, lower LVM and higher LV concentricity in the left ventricle was associated with liver fat. Taken together, these findings closely resemble the cardiac phenotype seen in heart failure with preserved ejection fraction, where patients are typically seen with preserved or increased ejection fraction and low or normal LVEDV . The rolThe high proportion of individuals with T2D and matched design makes our study well suited to assess the relationship between individual regional fat depots and T2D using logistic regression. In the univariate models we found VAT as well as EAT, liver fat and MFI, but not ASAT, to be significant predictors of T2D. This is in line with the generally held view that ASAT and VAT have distinct metabolic and endocrine properties . And agaDue to the relatively small sample size, our data may lack statistical power to detect additional significant relationships between measures of fat, cardiac parameters and T2D. The rather small sample size limited the number of variables in the multiple linear regression analysis that could be adjusted for, in order to avoid overfitting. Moreover, we purposively limited the number of adjusting variables in the regression analyzes, in order to avoid adjusting for factors that potentially lie in the causal pathway between regional adiposity and cardiac remodeling. Finally, participants with previous or present cardiovascular disease were not excluded. As associations in model 2 were slightly attenuated when adjusting for self-reported cardiac disease, the observed associations between ectopic fat and LV remodeling could possibly be linked indirectly through various cardiac disorders.In the present study, the application of advanced MR-techniques permitted comprehensive characterizations of whole-body fat depots including liver fat, epicardial fat, visceral fat, abdominal subcutaneous fat, and skeletal muscle fat in participants with T2D and matched controls. Our findings show that epicardial fat is associated with LV diastolic dysfunction. The findings also propose that previously reported relations between visceral fat and LV structure could be interlinked by the levels of liver fat infiltration. On the other hand, visceral fat was associated with T2D independently of liver and abdominal subcutaneous fat. Larger follow-up studies are needed to establish these results.carl-johan.carlhall@liu.se.The raw data supporting the conclusions of this article can be made available by the authors, upon reasonable request. Requests to access the datasets should be directed to C-JC, The studies involving human participants were reviewed and approved by Linköping Ethical Review Board. The patients/participants provided their written informed consent to participate in this study.C-JC, JE, OL, PL, and TE conceived and planned the study. C-JC, CÖ, ES, JE, MK, OL, PL, and TE were involved in data collection. CE, MK, and TS analyzed the data. CE and C-JC carried out the statistics. CE, C-JC, ME, and OL interpreted the results. CE drafted the manuscript. All authors read and critically revised the manuscript and approved the final version.This work was funded by the Swedish Research Council, the Swedish Heart and Lung Foundation, and through ALF Grants Region Östergötland.Authors MK and OL are employees of AMRA Medical AB. Authors OL and PL are stockholders in AMRA Medical AB. Author ME reports personal fees from Advisory Board AMRA Medical AB. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


N = 14).This study quantitatively evaluated the phasic right heart morphology of candidate patients for a transcatheter tricuspid valve intervention (N=32) and of subjects with trace to no tricuspid regurgitation (Cardiac computed tomography angiography (CCTA) and transthoracic/transesophageal echocardiography (TTE/TEE) images were analyzed using dedicated research and clinical software. Using CCTA, the phasic right atrial and ventricular volumes, annulus dimensions, annulus-to-right coronary artery (RCA) distances, circumferential topography of the annular tissue shelf, vena cava dimensions (inferior and superior), vena cava positions, axis angles, and annular excursions were quantified. Using TTE/TEE, leaflet geometry, regurgitation, hemodynamics, and heart function were quantified. Measurements within and between groups were quantitatively compared with regression analyses to explore relationships between right heart features.The phasic position and orientation of the vena cava and the circumferential topography of the annular tissue shelf were quantitatively presented for the first time. The candidate patient group exhibited greater chamber dimensions, enlarged vena cava, distended vena cava positions, positional shallowing of the annular tissue shelf, geometric annular distortion, leaflet distention, moderate or greater regurgitation, and impaired ventricular function. Atrial volume correlated strongly with directional vena cava positions as well as with annular dimensions. Annulus-to-RCA distances and annular excursions were comparable between groups.This study provides new and further insight to the right heart morphology and functional characteristics of candidate patients for a transcatheter tricuspid valve intervention. These data provide a platform from which these patients can continue to be better understood for further improving transcatheter system design and use.The online version contains supplementary material available at 10.1007/s13239-021-00595-y. FTR is often diagnosed at a late stage and with comorbidities, making many patients ineligible to undergo an open-heart surgery. The long-term outcomes for these unmet patients are poor, even when treated with optimal medical therapy.19Functional tricuspid regurgitation (FTR) is the most prevalent tricuspid valve (TV) disease.26Less invasive transcatheter therapies have been proposed to treat these patients. These systems are designed to advance through the body’s venous vasculature, to maneuver within the beating heart, and to deploy implant(s) to the heart’s tissues. Currently proposed and developed systems have included edge-to-edge leaflet repair devices, TV replacement valves, heterotopic caval valve implants, leaflet spacers, annuloplasty systems, and devices to reshape the right heart chamber dimensions.27 These data however have been unable to capture other critical features for transcatheter therapies, including the position of the vena cava with respect to the TV, vena cava delivery axis angles and heights, the topography of the tissue encircling the TV annulus, annulus excursion, and their correlation to other right heart features.3A large influence on the design of the device delivery systems, implants, patient-implant sizing, and procedures is the phasic morphology of the right heart. Recent research has quantified phasic right heart chamber dimensions and volumes, tricuspid annulus dimensions, annulus-to-right coronary artery (RCA) distances, and inferior vena cava (IVC) dimensions in FTR patients.22 Computed tomography and magnetic resonance imaging can quantify these missing features but require time-intensive manual approaches significantly limiting their routine quantification.6 A more comprehensive knowledge of these right heart morphological features, their variation, and complexities exhibits both possibility and promise for aiding transcatheter system design, sizing, and device-procedure development.These knowledge and data gaps are attributed to several factors. Echocardiography is the cardiac imaging modality of choice but restrictions in right heart imaging windows limit the measurements that can be recorded.N = 32). Cardiac computed tomography angiography (CCTA), transthoracic echocardiography (TTE), and transesophageal echocardiography (TEE) images were analyzed using dedicated research and clinical software. The phasic right atrial and ventricular volumes, annulus dimensions, annulus-to-RCA distances, topography of the annular tissue shelf, dimensions of the vena cava (inferior and superior), vena cava positions, axis angles, annular excursions, tricuspid regurgitation, leaflet geometry, hemodynamics, and heart function were quantified. As many measures are being reported for the first time, all measurements were repeated in subjects with trace or no regurgitation (N = 14) to explore the impact of right heart disease and range of values that may be seen clinically.This study quantitatively evaluated the phasic right heart morphology of transcatheter patient candidates . The studied groups included thirty-two candidate patients for a transcatheter TV intervention with moderate or greater FTR (≥ 3 + TR group) and fourteen patients with trace to no TR (≤ 1 + TR group). The inclusion criteria for all patients consisted of no previous TV procedure, the availability of TTE and TEE imaging, and a multi-phase CCTA scan. Further inclusion criteria for the medical images included no major imaging artifacts and adequate right sided CCTA contrast for morphological measurements.Transthoracic and transesophageal echocardiography images were analyzed as a means to provide clinical context to the studied patient groups and to provide measures of tricuspid leaflet geometry, tricuspid regurgitation, and cardiac function to supplement the phasic CCTA-based morphological measures. Comprehensive echocardiography imaging was available for all patients and analyzed using syngo  and QLab .12 including RV basal and mid-dimensions, RV length, fractional area change, and RV systolic tissue Doppler velocity. The 4-chamber tenting height and tenting area of the leaflets were also determined. TR grading was performed using multiple methods according to guidelines and quantitative Doppler methods.28 RV outflow tract and TV stroke volumes were determined from cross-sectional areas and velocity time integrals. For the left heart, multiple measurements of regurgitation severity, atrial volume index, and ejection fraction were performed according to guidelines.12Measures of right ventricular (RV) size and function were performed according to the American Society of Echocardiography guidelines,23 A transcatheter aortic valve planning protocol was followed for the ≤ 1 + TR group.9 All scans were reconstructed with a slice thickness of 0.5 mm in 5% increments across one full R-R electrocardiogram interval (20 phases of the cardiac cycle). Per the patient inclusion criteria, all scans exhibited sufficient right sided contrast for the morphological measurements.All patients previously underwent an electrocardiographically gated CCTA using a 320 detector-row system . A contrast-enhanced tri-phase protocol was followed for the ≥ 3 + TR group.CCTA data was analyzed using CI Vision . This research software provides a highly automized workflow for CCTA data processing and analysis. This software was utilized over commercially available software to permit a more comprehensive quantification of the right heart features for which other software do not include within their workflows or alternatively require prohibitive, time-intensive manual approaches. This software was used to quantify the phasic right heart morphology as follows:Fully automatic volumetric reconstructions of the heart for each phase of the R-R electrocardiogram interval were completed Fig. A. The enFor both phases, a semi-automatic segmentation of the tricuspid annulus at the leaflet hinge was completed with the annular area, 3D perimeter, maximum diameter, minimum diameter, and eccentricity (minimum/maximum diameter) automatically determined Figs. C and 2. The topology of the tissue shelf encircling the TV was then automatically quantified at ten rotationally symmetric positions around the segmented annulus Figs. E and 2. The maximum diameter, minimum diameter, area, and perimeter of the inferior vena cava (IVC) and superior vena cava (SVC) at the cavoatrial junction were then quantified Figs. F and 2. r), 95 % confidence interval, and p values, respectively.CI Vision is a research software not yet available for commercial use. The precision and agreement of select measurements by CI Vision were therefore compared to commercially available software packages that included Materialise Mimics , 3Mensio , and HeartNavigator . Annular area, perimeter, maximum diameter, minimum diameter, and the basal distance of the SVC from the TV annulus were determined in two phases of the R-R electrocardiogram interval  from thirty-eight patients by expert users and compared using Bland-Altman reporting the mean bias and 95% limits of agreement. Measurements from each software and metric were also assessed using correlation, reporting the Pearson correlation coefficient , 95% confidence interval (CI), and p values, respectively. Multiple regression was used to evaluate relationships between anatomical features and annulus-to-RCA distances as well as the morphology of the annular tissue shelf.All statistical analyses were completed using Minitab . Normality for continuous variables were assessed by the Anderson-Darling test and expressed as a mean ± one standard deviation (SD) and range. Intergroup comparisons for parametric data were assessed using two sample p = 0.519), body surface area , and sex  vs. N = 18 (56%), p = 0.332). Subjects within the ≥ 3 + TR group exhibited a transvalvular pacemaker lead (N = 3), mitral annuloplasty ring (N = 2), and mitral replacement (N = 6). One subject of the ≤ 1 + TR group had a prior mitral replacement. The echocardiography measurements from the studied patient groups are tabulated in Table There was no difference between the ≤ 1 + TR and ≥ 3 + TR groups for age . The phasic RA and RV volumes were observed to exhibit only a moderate degree of correlation .End-systole was most frequently observed in the 35–40% phases whereas end-diastole most frequently occurred in the 90–100% phases . The ≥ 3 + TR group annuli were more circular but maintained a preserved degree of ovality. The annular dimensions were generally observed to reduce from end-diastole to end-systole, whose mean reductions were found to be similar between groups.Tricuspid annulus measurements are summarized in Table The tricuspid annular dimensions were observed to strongly correlate with RA volume Figure . Some ovFor all patients and phases, the mean annulus-to-RCA distance was 7.9 ± 3.8 mm with a range of 0.5–23.2 mm .The topography of the annular tissue shelf for the differing phases and patient groups is schematically represented in Figure In the ≥ 3 + TR group, the coronary sinus was located more towards the valve plane, resulting in a wider shelf and shallower tissue angle in the posteroseptal region Figure . SimilarThe IVC size, axis, and position relative to the tricuspid annulus center is tabulated in Table r = 0.27, 95% CI 0.07–0.45, p = 0.010; basal vs. posterior: r = 0.12, 95% CI − 0.09 to 0.32, p = 0.247; posterior vs. septal: r = 0.10, 95% CI − 0.12 to 0.30, p = 0.376).Of all measures, the RA volume was found to correlate most strongly with the directional positions of the IVC  whereas weak to no correlation was observed between the other directional components .The directional positions of the SVC were observed to strongly correlate with RA volume. The RA volume exhibited strong correlations with the basal and anterior SVC distances, with no correlation in the lateral direction , or towards various points within or around the annular perimeter . For planning a delivery system’s approach, it is important to consider operator technique and the differing ways and routes by which the system may be positioned to the target location. Access site location and restrictions imposed on the device by the vasculature may also influence a device’s course, and therefore several strategies for achieving a given position may wished to be considered. Knowledge in the maneuverability of the device’s delivery system helps in this regard and is beginning to be included within select device’s instructions for use. Importantly, the multiple phases of the CCTA scan provide an ability to predict the dynamic range occurring during the procedure, further aiding this evaluation.Circumferential quantification of the annulus tissue shelf morphology was reported for the first time in this study. The mean results from the ≥ 3 + TR group exhibited a relatively unchanging shelf from the anterior to posterior region, a shallowed shelf near the coronary sinus, and a shelf verticalization at the aortic continuity. Select similarity in the tissue shelf was observed between the studied groups, with ≥ 3 + TR being most associated with a shallowing of the posteroseptal aspect of the shelf at or near the coronary sinus. Assessing the potential range in shelf lengths and angles was limited by the fully automatic quantification of the shelf measurements based on a 5-mm atrial height to the annular plane Figure . While lQuantifying the shelf morphology can inform device design, delivery system development and testing, and procedural development. TV replacement valves for example must expand into the annular perimeter, secure themselves partially or fully to the annular shelf tissue, and seal off the annular shelf space to prevent perivalvular leakage. For repair and annuloplasty devices, the tissue shelf morphology helps by defining the appropriate delivery system articulations that would be required to achieve a desired anchor, suture, or attachment orientation to or within the shelf tissue. A shorter or vertically oriented shelf may be a challenge for anchoring systems which require a perpendicular angle of insertion from either the atrium or the ventricle. The ability to achieve these required angles of insertions are undoubtably influenced by the vena cava positions as well as delivery system maneuverability as previously described.1,718,21 A wide range of annular dimensions were observed in this study with overlap between the studied groups .27 The sample size of this study is however lesser in size than a control arm of one study, in which the annulus-to-RCA distances and IVC dimensions were quantified in subjects with < 3 + TR (N = 210).27 In a subset of patients, the annulus-to-RCA distance was unable to be determined in the posterolateral and posterior segments due to the RCA diameter decreasing to or below the spatial resolution of the CCTA images, insufficient intraluminal contrast, or both. Some measures used in select transcatheter therapies were not quantified, including IVC-hepatic vein measures, TV-to-RV measurements, and outflow tract geometry. Interested readers may consider using the RV measurements taken by echocardiography to supplement the CCTA data, as applicable (Table ). The tricuspid leaflets were not analyzed using CCTA, although this is possible in some cases and is improving with technology. Echocardiography remains the primary modality for this purpose.5The study was retrospective. The study sample size is small relative to clinical trials but exceeds or is comparable in size to studies evaluating right heart anatomical features in patients with moderate or greater FTR .Below is the link to the electronic supplementary material.


Overall, 13.1% deteriorated to LVEF ≤ 40%, 5.9% were upgraded to cardiac resynchronization therapy device, and 14.4% developed new-onset atrial fibrillation, with no significant differences between the groups. This study demonstrated a high risk of PICM despite normal pre-implant left ventricular systolic function with no significant difference between CT-verified RV septal or non-septal lead position.Prospective studies applying fluoroscopy for assessment of right ventricular (RV) lead position have failed to show clear benefits from RV septal pacing. We investigated the impact of different RV lead positions verified by computed tomography (CT) on the risk of pacing-induced cardiomyopathy (PICM). We retrospectively included 153 patients who underwent routine fluoroscopy-guided pacemaker implantation between March 2012 and May 2020. All patients had normal pre-implant left ventricular ejection fraction (LVEF). Patients attended a follow-up visit including contrast-enhanced cardiac CT and transthoracic echocardiography. Patients were classified as septal or non-septal based on CT analysis. The primary endpoint was PICM (LVEF < 50% with ≥10% decrease after implantation). Based on CT, 48 (31.4%) leads were septal and 105 (68.6%) were non-septal. Over a median follow-up of 3.1 years, 16 patients (33.3%) in the septal group developed PICM compared to 31 (29.5%) in the non-septal group ( It is well known that right ventricular (RV) pacing may lead to pacing-induced cardiomyopathy (PICM) and heart failure . The detFluoroscopy is the main imaging modality for guiding pacemaker lead implantation. However, reliable implantation in the intended position is challenged by shortcomings of fluoroscopy. Importantly, RV lead position determined using fluoroscopy has previously been shown inaccurate and poorly reproducible compared with cardiac computed tomography (CT) ,9. The lThe aim of the present study was to investigate the effect of different CT-verified RV lead locations on the risk of PICM in chronically paced patients with advanced atrioventricular (AV) block. We screened consecutive patients undergoing routine dual-chamber pacemaker implantation due to advanced AV block at Aalborg University Hospital between March 2012 and May 2020 for study eligibility. This was a retrospective study with active clinical follow-up. Patients were eligible for study inclusion if they had a baseline transthoracic echocardiogram (TTE) documenting a left ventricular ejection fraction (LVEF) ≥ 50% prior to pacemaker implantation and frequent RV pacing (≥40%). Exclusion criteria were inability to attend a study-specific follow-up visit , competing cause of decreased LVEF , device complications with replacement of the RV lead ≥3 months after implantation, contraindications to iodinated contrast agents for cardiac CT, and unable or unwilling to provide informed written consent to participate. The primary outcome was PICM defined as a ≥10% decrease in LVEF resulting in LVEF < 50% at any timepoint between implant and the end offollow-op. Secondary outcomes were cardiac resynchronization therapy (CRT) device upgrade, new-onset atrial fibrillation, and absolute change in LVEF. Echocardiographic outcomes were obtained by analysis of follow-up TTEs. The remaining characteristics were obtained by review of electronic medical records and pacemaker interrogation reports. Advanced atrioventricular block was defined as second-degree AV block Mobitz type II, 2:1 AV block, higher degree AV block with ≥2 consecutive P-waves not conducted, and third-degree AV block. Severe IHD was defined as acute myocardial infarction confirmed by coronary angiography, requiring revascularization, or having confirmed significant stenosis in ≥2 epicardial arteries requiring revascularization. Severe VHD was evaluated using guideline-recommended quantitative and semi-quantitative measures . The. The8]. All patients had a 2-dimensional TTE performed prior to pacemaker implantation, and a study-specific TTE was repeated at follow-up. Furthermore, all TTEs performed after pacemaker implant and until study follow-up were retrieved. All TTEs were recorded using a 2.5 MHz transducer on a commercially available ultrasound system  and analyzed using EchoPAC software . LVEF was calculated by two experienced cardiologists blinded to RV lead position using the Simpson’s biplane method and global longitudinal strain (GLS) was based on speckle tracking .t-test or Mann–Whitney test as appropriate. Categorical variables are reported as absolute numbers and percentages and compared using Fisher’s exact test. Modified Poisson regression analysis with robust variance estimation was used to estimate relative risks between groups. For continuous variables, regression was used to estimate differences in means between groups. To overcome potential non-normality and variance inhomogeneity, standard errors were calculated using bootstrap with 5000 replications. No adjusted analyses were performed, as the RV lead was regarded as implanted at random. Hence, confounding through association with both exposure and outcome was considered unlikely. A two-sided p < 0.05 was considered statistically significant. STATA version 17 was used to perform all of the statistical analyses. Descriptive statistics are reported as mean and standard deviation (SD) or median and interquartile range (IQR) as appropriate for continuous variables. Differences were compared using unpaired Student’s Of the 1384 patients screened for study eligibility, 608 patients met the inclusion criteria. Subsequently, 181 patients were excluded at baseline due to known severe VHD, severe IHD, contraindications to CT contrast agents, or terminal illness at time of pacemaker implantation, leaving 427 eligible for longitudinal follow-up. Of these, 274 were excluded after baseline due to development of severe VHD, severe IHD, contraindication to CT contrast agents, terminal illness, device complications, unable or unwilling to consent to study participation, or deceased at time of study follow-up. Finally, 153 patients were included for study participation.A study-specific CT scan was performed in 111 patients, as 42 patients had prior thoracic contrast-enhanced CT scans performed for other clinical reasons. Determined from CT, 48 (31.4%) had a septal RV lead position and 105 (68.6%) had a non-septal position. Detailed analysis of RV lead position showed 74 (48.4%) leads located in the apex, 31 (20.4%) leads located on the free wall, 37 (24.2%) leads located on the anterior septum, and 11 (7.2%) leads located on the posterior septum. Only one lead was implanted in the RV basal segment , the remaining leads were implanted in the mid or apical segments . p = 0.003).Differences in patient characteristics between the septal and non-septal groups are summarized in p = 0.63), CRT upgrade , or new-onset atrial fibrillation  between the non-septal and septal groups  developed PICM. Nine (5.9%) patients were upgraded to CRT and 22 (14.4%) developed new-onset atrial fibrillation during the study period. There were no statistically significant differences in risk of PICM . Among those with PICM, a 19% LVEF reduction (95%CI 17–22%) was observed, and 20 (13.1%) deteriorated to LVEF ≤ 40%. There was no significant difference in LVEF reduction between the septal (10% [95%CI 7–13%]) and non-septal (ΔLVEF = 8% [95%CI 6–9%]) group (p = 0.21).Overall, a significant 8% reduction in LVEF following pacemaker implantation was observed . Also, the greatest reduction in LVEF was observed in the posterior septum group (15%). However, this again was not statistically significant (p = 0.33). Furthermore, no relevant difference in negative GLS reduction (p = 0.88) was observed between the groups. PICM, reduction in LVEF and reduction in negative GLS compared between RV lead implantation in the anterior septum, posterior septum, apex, and free wall are shown in This is the first study, to our knowledge, investigating the risk of PICM using study-specific contrast-enhanced cardiac CT for the detailed assessment of exact RV lead position. When using cardiac CT as reference, no benefit of septal pacing over non-septal pacing was observed. The study demonstrated an overall high risk of PICM (30.7%) over a median follow-up of 3.1 years despite normal pre-implant LVEF. Clinically relevant, 13.1% had a follow-up LVEF ≤ 40%, 5.9% were upgraded to CRT, and 14.4% developed new-onset atrial fibrillation. Routinely, fluoroscopy has been applied to guide pacemaker lead implantation and determine final RV lead position in studies comparing RV lead positions ,14. HoweRecently, Hattori et al. conducted a retrospective study including pacemaker patients who had an incident thoracic CT performed after pacemaker implantation. RV lead position was classified as septal or free wall and they found an increased risk of cardiac death and heart failure related hospitalizations with RV free wall implantation during 41 months follow-up . HoweverPrevious retrospective studies show a wide variation in reported risks of PICM. This is partly due to discrepancies in PICM definition and may also be related to differences in study designs, duration of follow-up and inclusion criteria . Among pThis was a retrospective observational study performed in a single center with a relatively small sample size. Patient selection may have limited the external validity and induced unknown bias, which is why this study can merely be considered hypothesis generating and not conclusive. Importantly, post-treatment selection is not a limitation only for our study. Many of the larger retrospective studies investigating the effect of RV pacing are also limited and likely biased by post-implantation patient selection ,17,19,20To answer the question of optimal RV lead implantation site, new methods beyond fluoroscopy are needed to ensure intraprocedural accuracy when implanting the RV lead, thus enabling true randomization of RV lead position in prospective studies. It is important to establish a true clinical benefit from RV septal pacing to justify the potential increased procedure duration and the additional fluoroscopy time required for RV septal implantation . Also, the simplistic approach used in the current study and previous studies, dividing the RV lead position into arbitrary segments without consideration of individual electroanatomical differences may have limited clinical relevance. Perhaps, the search for an optimal RV lead implantation site needs to move towards physiological pacing including His bundle pacing and left bundle branch pacing . HoweverThis study demonstrated an overall high risk of PICM despite normal pre-implant left ventricular systolic function with no significant difference between CT-verified RV septal and non-septal lead position.