We hypothesize that both increased myocardial steatosis and interstitial fibrosis contributes to subclinical myocardial dysfunction in patients with increased body mass index and diabetes mellitus.Increased body weight and diabetes mellitus are both individually associated with a higher incidence of heart failure with preserved ejection fraction. However, it is unclear how increased myocardial steatosis and interstitial fibrosis interact to influence myocardial composition and function.A total of 100 subjects  were prospectively recruited to measure left ventricular (LV) myocardial steatosis (LV-myoFat) and interstitial fibrosis (by extracellular volume [ECV]) using magnetic resonance imaging, and then used to determine their combined impact on LV global longitudinal strain (GLS) analysis by 2-dimensional (2D) speckle tracking echocardiography on the same day.On multivariable analysis, both increased body mass index and diabetes were independently associated with increased LV-myoFat. In turn, increased LV-myoFat was independently associated with increased LV ECV. Both increased LV-myoFat and LV ECV were independently associated with impaired 2D LV GLS.Patients with increased body weight and patients with diabetes display excessive myocardial steatosis, which is related to a greater burden of myocardial interstitial fibrosis. LV myocardial contractile function was determined by both the extent of myocardial steatosis and interstitial fibrosis, and was independent of increasing age. Further study is warranted to determine how weight loss and improved diabetes management can improve myocardial composition and function.The online version contains supplementary material available at 10.1007/s10554-022-02723-8. There is a worldwide growing epidemic of obesity and diabetes. Both conditions are associated with mitochondrial dysfunction , myocardCardiac magnetic resonance imaging (MRI) technique such as water and fat separated imaging with variable projection (VARPRO) to calculate myocardial fat (LV-myoFat) content can quantify myocardial steatosis . SimilarTherefore, the present study aimed to evaluate the pathophysiological mechanisms linking myocardial steatosis and interstitial fibrosis secondary to increased BMI and diabetes with LV-GLS. We hypothesize that: (1) increased BMI and diabetes are independently associated with increased myocardial steatosis; (2) increased myocardial steatosis is independently associated with increased myocardial interstitial fibrosis; and (3) both increased myocardial steatosis and interstitial fibrosis are independently associated with LV-GLS.100 volunteers randomly recruited from the community were divided into 3 groups:2);Group 1 included 27 healthy volunteers with normal BMI (< 25.0kg/m2);Group 2 included 21 healthy volunteers with increased BMI , inability to undergo a cardiac MRI, and inadequate echocardiographic images for speckle tracking analysis.Exclusion criteria included age < 18 years, pregnancy, rhythm other than sinus rhythm, known underlying severe coronary artery disease, previous myocardial infarction, LVEF < 50%, moderate/severe valvular stenosis or regurgitation, pre-existing hepatic or renal disorders  was measured at the time of echocardiography. As LV-GLS is load dependent and correlated with both heart rate and BP, rate pressure product  was therefore used in the multivariable models. RPP was calculated as the heart rate multiplied by systolic BP during echocardiography.Blood samples were collected to measure hemotocrit, fasting lipid profile, plasma glucose, glycated hemoglobin (HbA1c), and insulin . The homeostatic model assessment index of insulin resistance (HOMA-IR) was computed using the HOMA calculator that utilizes the HOMA2 model .Cardiac MRI examinations were performed using a 1.5T Siemens Magnetom Avanto system . See Supplemental Appendix for cine imaging parameters. LV end-diastolic mass, LV end-diastolic volume (EDV) and LV end-systolic volume (ESV) were measured, and LVEF was calculated. Images were analyzed using MASS V2010-EXP . We have previously published the intra- and interobserver measurement variabilities for LV-myoFat and ECV .We quantified both the proportion  and the total amount of LV myocardial steatosis . Our group has previously validated LV-myoFat fraction by VARPRO against the gold standard proton spectroscopy . See SupThe LV basal and mid-ventricular short-axis slices by the VARPRO sequence were obtained at identical LV levels as quantification of interstitial fibrosis by ECV. During analysis, epicardial and endocardial contours were deliberately drawn in the mid-myocardium to avoid partial volume effects from epicardial adipose tissue and LV blood pool Fig. 2]. LV-. LV-2]. This equation is identical to the quantification of intramyocardial triglyceride (TG) content by spectroscopy . Total LThe MOLLI T1 mapping sequence was used to quantify the burden of interstitial fibrosis by ECV . See Supwas calculated and expressed as a percentage :\documenTotal myocardial interstitial volume was calculated as previously published :\documenTransthoracic echocardiography was performed using commercially available system and images were analyzed offline . See Supplementary Appendix for the Doppler measurements.LV-GLS were derived from 2-dimensional images in the apical 2-, 3- and 4-chamber views, at 50–70 frame/s. During analysis, the endocardial border was manually traced at end-systole and the region of interest width adjusted to include the entire myocardium. Our group has previously reported the intra- and interobserver measurement variability for LV-GLS in patients with increased BMI .See Supplemental Appendix for sample size calculation. All continuous variables were tested for Gaussian distribution. Continuous variables were presented as mean±1 SD unless, and categorical variables were presented as percentages. Chi-square and Fisher’s exact test were used as appropriate to compare categorical variables between groups. One-way analysis of variance (ANOVA) was used to compare the 3 groups of patients for continuous variables, and pairwise comparisons (by unpaired Student’s t-test and Mann-Whitney U test as appropriate) for significant results by ANOVA were performed with Bonferroni corrections. Pearson correlation was used to determine the association between 2 continuous variables. Multiple linear regression analyses were performed to identify independent variables associated with LV-myoFat fraction, total LV-myoFat volume, ECV-fraction, total myocardial interstitial volume, and LV-GLS using the backward elimination method. In each multivariable model, significant univariables with p < 0.05 were entered as covariates. In addition, age was forced into multivariable analyses due to significant differences between the 3 groups of patients. A tolerance of > 0.5 was set to avoid multicollinearity. RPP was used in the multivariable models instead of heart rate and BP due to its higher correlation coefficient and to prevent overfitting of the multivariable models. A 2-tailed p value < 0.05 was considered significant. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 21.0 .TableThere was no difference in LV-myoFat fraction between men vs. women , but there were significant differences in LV-myoFat fraction between the 3 groups  and HOMA-IR  remained independent determinants of LV-myoFat fraction (model R = 0.78). The supplemental appendix showed the determinants of total LV-myoFat volume.There was no difference in ECV-fraction between men vs. women . TableNext, age and hypertension were forced into the multivariable model to determine if they were associated with ECV-fraction. However, the results did not change and LV-myoFat fraction remained the only significant independent determinant. Similarly, to determine if diabetic patients had higher ECV-fraction with increasing BMI compared to non-diabetic patients, the presence of diabetes*BMI interaction term was also included in the multivariable model together with age and hypertension. However, the results did not change and LV-myoFat fraction remained the only significant independent determinant of ECV-fraction.The supplemental appendix showed the determinants of total myocardial interstitial volume.There was a trend towards lower LV-GLS in men than women . FigureTo further explore the role of LV myocardial steatosis and interstitial fibrosis on LV-GLS, the presence of diabetes and BMI variables were replaced with LV-myoFat fraction and ECV-fraction Table, model 2Next, LV-myoFat fraction*ECV-fraction interaction term was added to the multivariable model together with LV-myoFat fraction, ECV-fraction, age, RPP, plasma TG and LV mass Table, model 3Supplementary Table3 shows that when LV-myoFat fraction and ECV-fraction were replaced by total LV-myoFat volume and total myocardial interstitial volume respectively, the only independent determinants of LV-GLS were total LV-myoFat volume*total myocardial interstitial volume interaction term and RPP (model R = 0.64).The present study showed that presence of diabetes, BMI and insulin resistance were independently associated with increased myocardial steatosis. Furthermore, there was an interaction between diabetes and BMI, indicating that diabetic patients had a greater degree of steatosis with increasing BMI compared to non-diabetic patients. In turn, increased myocardial steatosis was independently associated with a higher burden of interstitial fibrosis. Finally, diabetic patients had more impaired LV-GLS with increasing BMI compared to non-diabetic patients, and both the extent of myocardial steatosis and burden of interstitial fibrosis were independently associated with LV-GLS.Quantifying myocardial TG by the gold standard proton magnetic resonance spectroscopy is challenging and time consuming due to the need to perform double respiratory and cardiac gating . In contPrevious validation study showed that VARPRO overestimates myocardial TG concentration due to its T1 bias from the high flip angle . HoweverBoth the associations between diabetes and myocardial steatosis, and increased BMI without diabetes and myocardial steatosis, have previously been well documented , 18. HowThis study showed that increasing BMI was correlated with a higher burden of myocardial interstitial fibrosis on univariable analyses, and diabetic patients had significantly more myocardial interstitial fibrosis compared to non-diabetic patients. However, post-hoc subgroup analysis corrected for multiple comparisons suggested no significant difference in myocardial interstitial fibrosis between normal weight vs. increased BMI in non-diabetic healthy volunteers. On multivariable analysis, myocardial steatosis was independently associated with myocardial interstitial fibrosis. As the healthy volunteers with increased BMI in Group 2 had no underlying cardiac comorbidities could have potentially confounded the LV-myoFat and ECV measurements, the results suggested that isolated increased BMI without other cardiac comorbidities was not associated with increased myocardial interstitial fibrosis.Increasing age is often assumed to be associated with increased interstitial fibrosis and myocardial dysfunction. However, age was not independently associated with ECV-fraction or total myocardial interstitial volume in the present study. This was consistent with a previous MRI study that similarly showed no correlation between age and ECV in healthy volunteers .Previous study showed that increased fat content can bias native T1 mapping . SpecifiPatients with obesity and diabetes are more likely to develop HFpEF , 23. In We recently showed that both diabetes and increased BMI had an additive detrimental effect on LV-GLS . The preThe present study did not show an independent relationship between age and LV-GLS. This was consistent with other publications including the Framingham study that failed to show any age-related changes in LV-GLS , 29. In Although we have previously validated VARPRO against spectroscopy in normal healthy volunteers of varying BMI, it has not been validated in diabetic patients .It is well accepted that LV-GLS is superior to LVEF in detecting subclinical myocardial dysfunction, and is prognostic for long term adverse clinical outcomes , 33. TheThe present study demonstrated that diabetes, increased BMI, and insulin resistance were independently associated with increased myocardial steatosis. In turn, the extent of myocardial steatosis was independently associated with the burden of myocardial interstitial fibrosis. Finally, both increased BMI and diabetes were independently and incrementally associated with more impaired LV-GLS. Multivariable analysis suggested that LV-GLS was determined by myocardial steatosis and interstitial fibrosis. The changes in myocardial steatosis, interstitial fibrosis and LV-GLS were independent of age.We demonstrated that both increased BMI and diabetes are independently associated with increased myocardial steatosis, which in turn is related with a greater burden of interstitial fibrosis. Together, both increased myocardial steatosis and interstitial fibrosis is correlated with impaired LV-GLS. This study provides insight into the mechanism in which patients with increased body weight and patients with diabetes can develop heart failure with preserved ejection fraction.Tissue characterization by cardiac MRI can provide novel insights into the pathophysiological mechanisms that predispose patients with increased body weight and patients with diabetes to develop heart failure with preserved ejection fraction. More studies are needed to determine how weight loss and improved glycemic control can alter myocardial composition and function.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2


Worsening chronic heart failure (HF) is responsible for recurrent hospitalization and increased mortality risk after discharge, irrespective to the ejection fraction. Symptoms and signs of pulmonary and systemic congestion are the most common cause for hospitalization of acute decompensated HF, as a consequence of increased cardiac filling pressures. The elevated cardiac filling pressures, also called hemodynamic congestion, may precede the occurrence of clinical congestion by days or weeks. Since HF patients often have comorbidities, dyspnoea, the main symptom of HF, may be also caused by respiratory or other illnesses. Recent studies underline the importance of the diagnosis and treatment of hemodynamic congestion before HF symptoms worsen, reducing hospitalization and improving prognosis. In this paper we review the role of integrated evaluation of biomarkers and imaging technics, i.e., echocardiography and pulmonary ultrasound, for the diagnosis, prognosis and treatment of congestion in HF patients. Most of the patients hospitalized for worsening heart failure (HF), 60% in the EURObservational Research Programme of the European Society of Cardiology, have dyspnoea and signs of congestion . The indIn HF registries one in five patients hospitalized have residual clinical or hemodynamic congestion at discharge . The perThe clinical evaluation of congestion has many limitations. Physical examination has a low sensitivity and specificity to identify pulmonary congestion, and auscultation of the lung poorly correlates with left ventricular (LV) filling pressures ,14,15. AAll these data underline the importance of non-invasive detection of congestion in patients with HF, in order to reduce re-hospitalizations, to improve the prognosis, and to decrease mortality by optimizing HF treatment. Several imaging and biochemical markers have been proposed for the assessment of congestion. The ultrasonographic evaluation of the heart, veins and lung provides useful information about congestion and has been validated as prognostic markers, both in acute and chronic settings . In the Echocardiography has a crucial role in the diagnosis of HF, providing structural and functional information and becoming an integral part of the clinical examination nowadays .Cardiac ultrasound has the unique ability to non-invasively estimate LV filling pressures using a comprehensive, stepwise approach, together with associated structural cardiac abnormalities in patients with unexplained dyspnoea or with clinical manifestations of heart failure, irrespective to the EF .The early rapid filling wave (E) velocity and the late filling wave due to atrial contraction (A) velocity are related to the transmitral pressure gradient. When there is a suspicion of myocardial disease, a mitral flow pattern with E/A ratio >2 due to high E and low A wave peak velocities and short E-wave deceleration time (<160 msec) is a restrictive mitral filling pattern consistent with increased LV filling pressures. If the E/A ratio is ≤0.8 and the E velocity is <50 cm/s, as a consequence of a small transmitral pressure gradient, the filling pressures are considered to be normal . For valE/e’, the ratio between E wave peak velocity and mitral annular early diastolic velocity, e’, is widely used for the estimation of LV filling pressures and it has been shown to correlate with invasive measurements of LV filling pressures . In myocE/e’ has a good correlation with LV filling pressures in patients with HF with preserved EF (HFPEF). However, in patients with HF with reduced EF (HFREF), on resynchronization therapy or with dilated hearts, there is only a moderate correlation between septal E/e’ > 15 and invasively measured LV filling pressures ,24. The increase in sPAP is another criterion for the estimation LV filling pressures, if other non-cardiac causes of pulmonary hypertension or pulmonary arterial hypertension are excluded. sPAP is calculated as the sum of systolic tricuspid pressure gradient using peak TR velocity and the estimated right atrial pressure, based on the inferior vena cava (IVC) measurement. A peak TR jet velocity >2.8 m/s is strongly indicative of elevated filling pressures. However, TR jet cannot be accurately recorded in about half of the patients, mainly with preserved EF ,26 The sAlso, in patients with acute pulmonary embolism, right ventricular infarct, or severe right ventricular dysfunction, the markedly increased right atrial pressure will lead to a low peak TR velocity, regardless of left-sided filing pressures.2 by 2D echocardiography is integrated in the algorithm for the estimation of LV filling pressures and it is associated with higher cardiovascular risk in HFPEF , and RVSI is defined as the ratio between duration of absent venous flow divided by the duration of the cardiac cycle.The changes in IRVF patterns reflect the elevated right-side pressures transmitted backward, leading to increased interstitial and tubular hydrostatic pressure within the encapsulated kidney and lowering the glomerular filtration rate. The parenchymal vessels are compressed, and the venous flow becomes pulsatile, being dependent on the cardiac cycle, due to increased compliance of the congestive renal parenchyma. There are similar changes in hepatic venous flow ,39. In a recent study, in several patients with stable chronic HF the IVRF pattern became discontinuous after volume loading, even without change in IVC size, suggesting that changes in IVRF pattern could be an earlier index of systemic congestion . More recent data bring important evidence supporting the use of IRVF pattern as a congestion marker. Under decongestive therapy the normalization of the discontinuous IRVF patterns occurs in approximately one-half the patients hospitalized with decompensated HF, most of them (87%) showing impaired IRVF patterns at admission. No changes in the IRVF patterns were noted in patients with renal dysfunction at baseline . Serial evaluation of IRVF patterns in stable ambulatory HF patients demonstrated that discontinuous patterns during the follow-up period, rather than those at baseline, were associated with poor outcomes . Moreover, persistent discontinuous pattern was associated with renal impairment progression . The abnormal IVRF patterns are non-specific markers of systemic congestion, as it may occur in other conditions associated with increased pressure in the renal parenchyma, such as obstructive uropathy, or increased intra-abdominal pressure .The clinical examination of neck veins for the assessment of central venous pressure in right ventricular failure if often limited in obese patients and has an intra- and intraobserver variation. The evaluation of the internal jugular vein (IJV) compliance using ultrasound could be a useful parameter for the assessment of systemic congestion. Due to the curvilinear shape of the relationship between intravenous pressure and volume, the venous compliance is high at low venous pressures and decreases when the venous pressures become elevated. The dimension of IJV should be measured at rest (at end-expiration) and during Valsalva manoeuvre, which acutely increases the right atrial pressure. When right atrial pressure is normal, there is a substantial increase in IJV dimension during a Valsalva manoeuvre. For the measurement of the dynamic changes of IJV two methods can be used: the diameter and cross-sectional area of the vein. The JV distention (JVD) ratio is calculated as the ratio between the maximal diameter during Valsalva manoeuvre to the diameter at rest . Since tThe cross-sectional area of IJV will increase by 20–30% during Valsalva manoeuvre in patients with normal right atrial pressure. An increase in IJV cross sectional area >17% during Valsalva manoeuvre effectively ruled out patients with elevated right atrial pressure invasively measured by right heart catheterization ,47. The evaluation of congestion using the IJV compliance by ultrasound is limited in patients unable to perform a Valsalva manoeuvre.The overt complete clinical picture of pulmonary congestion is a late manifestation of interstitial and alveolar oedema. However, in most instances, in patients with imminent acute HF, there is a transition subclinical period in which a gradual accumulation of extravascular water occurs . IdentifSeveral clinical, imaging  and non-imaging methods have been proposed in order to depict and quantify increased lung water.Chest radiography (CxR) is a widely available and inexpensive method for assessing causes of dyspnoea especially in the emergency room . A sequeThoracic computer tomography can identify pulmonary fluid accumulation however, its use as a marker of pulmonary congestion in the very prevalent HF population is refrained due to cost, availability, and radiation exposure . Intrathoracic impedance falls as the amount of fluid in the lungs increases therefore, implantable or non-invasive lung impedance monitors have been proposed for assessing pulmonary congestion and guiding HF therapy ,55. HoweIn the past 10 years, lung ultrasound (LUS) has emerged as a non-invasive imaging biomarker of pulmonary congestion with diagnostic, monitoring, therapeutic and prognostic value in the management of HF patients ,57,58,59LUS behaves as a densitometer accurately evaluating the progressive decrease in lung aeration ,58. In aLUS is a quantitative, simple and rapid method of assessing lung congestion. The main diagnostic findings suggestive of interstitial syndrome (caused by increased extravascular transudate or exudate) are the B lines ,60. ThesEvaluation of the presence and number of B lines on LUS as a marker of interstitial syndrome has shown good correlation with clinical, radiological, invasive, and post-mortem markers of lung congestion and has shown prognostic and therapeutic value . B lines are very useful in establishing the cardiac cause of acute dyspnoea in the emergency room ,58. DataThe B lines assessed with LUS are dynamic and their number and location can change rapidly after decongestive therapy making them an attractive biomarker that could help in the management of pulmonary congestion . Acute cTherefore, B lines assessment is a promising marker of pulmonary congestion and decongestion. In a single center small trial, LUS helped in tailoring diuretic therapy of patients with acute HF and was able to accelerate the discharge time . Three rOther biomarker-guided strategies have been evaluated in the follow-up and management of HF patients. However, the main advantage of the LUS strategy is its non-invasiveness and the negligible associated cost ,75,76. Pulmonary congestion as reflected by B lines assessed with LUS has an important prognostic role in ambulatory or admitted HF patients ,77. The In hospitalized HF patients, LUS-detected pulmonary congestion was found to be an independent predictor for short-term mortality and HF hospitalization . The cutThe prognostic value of LUS is preserved in ambulatory, chronic, HF patients. It was shown that a higher number of B-lines on LUS identified patients at risk for urgent HF visits, HF hospitalizations, or death from any cause over 6 months, independent of age, sex, NYHA class, and clinical congestion score . LUS is an important prognostic marker both at rest as well as when assessed during stress. B lines development or worsening during exercise is associated with higher levels of natriuretic peptides at baseline, higher pulmonary artery pressures, worse functional impairment and poor outcome ,68,69. AIn end stage chronic kidney disease patients undergoing dialysis, subclinical pulmonary congestion is frequent. LUS is able to detect increased lung water content which was shown to predict poor outcome . PatientLUS is a very sensitive technique for assessing lung congestions however B lines are not specific for cardiogenic pulmonary edema. B lines appear in any pulmonary interstitial syndrome such as interstitial pneumonia, acute respiratory distress syndrome, COVID-19 lung disease interstitial fibrosis ,85. A seLUS is a very feasible echographic technique even though it can be challenging to obtain acceptable image quality in patients with morbid obesity, subcutaneous emphysema, soft tissue edema or large wound dressings . LUS is a near-ideal imaging marker of lung congestion and its value it’s complemented by additional clinical, laboratory and imaging markers. Its inclusion in a multiparametric congestion score will likely improve the diagnostic and prognostic value. As such, currently, the Heart Failure Association of the European Society of Cardiology recommends an integrative evaluation of congestion in HF patients including LUS .The most commonly used clinical scores and the cardiac, vascular and pulmonary ultrasound parameters of congestion in HF are depicted in Biomarkers can be measured objectively as indicators of physiological or pathogenic processes, as well as responses to therapeutic interventions, with no inter-observer variability . SeveralNPs have been discovered few decades ago and extensively studied thereafter, proving to be the gold standard biomarkers for the diagnosis, prognosis, monitoring and treatment in patients with HF. NPs have also added prognostic value for HF risk screening in other cardiovascular diseases.BNP and atrial-type natriuretic peptide (ANP) are neurohormones synthesized and released into the bloodstream exclusively by ventricular and atrial cardiomyocytes in response to increased end-diastolic wall-stress due to volume or pressure overload. NPs are synthesized as pre-prohormones, then cleaved as prohormones and subsequently cleaved into active hormones, BNP and ANP, and the inactive NT-proBNP and mid-regional proANP (MR-proANP). BNP and ANP play adaptive counter-regulatory roles, by binding to NP-receptors at several levels and causing vasodilation, natriuresis and diuresis. BNP and ANP have short circulating half- lives , being actively cleared from the circulation due to NP receptors and plasma endopeptidases. NT- proBNP si MR-proANP have longer circulating half-lives (around 90 min) and their clearance is primarily renal. They are useful molecular targets for biochemical measurement, being used as surrogates for plasma levels of BNP and ANP ,94.Although NP are continuous variables, the heart failure guidelines currently recommend cut-off values of NP plasma concentration to “rule-out” or “rule-in” the diagnosis of HF in patients with dyspnoea and clinical suspicion of HF . BNP andThe value of BNP and NT-proBNP as biomarkers have been more extensively investigated than ANP and MR-proANP. However, MR-proANP proved to be a more sensitive and specific and also a prognostic biomarker of HFPEF than NT-proBNP, as high plasma levels of MR-proANP were associated with increased 10-year all-cause mortality in patients with HF ,100,101.NPs might be able to detect very early stages of congestion in HF and may estimate risk of readmission . The decIn HF patients, the de-congestive treatment with diuretics and the long-term treatment with beta-blockers, renin-angiotensin-aldosterone system inhibitors and cardiac resynchronization therapy, due to their beneficial effects on cardiac remodelling and reducing ventricular wall stress, would lead to a reduction in NP concentrations. Of note, the plasma levels of NP would transitorily increase during early treatment with non-vasodilator beta-blockers. The treatment with sacubitril-valsartan, due to the neprilysin inhibition, also tends to increase the BNP levels in HF patients, especially in those with higher baseline values .In summary, NP values are very useful tools for assessing the congestion in HF patients, but always in relation with clinical data. Their inherent limitations stimulated further research aimed to validate other biological and imaging markers of congestion. Cardiac troponins (cTn) are routinely measured in patients with acute HF in order to rule out an acute coronary syndrome. Actually, cTn are often elevated in patients with acute HF due to acute or chronic cardiomyocyte death or injury in the absence of ischemia, possibly caused among other mechanisms by elevated intracardiac filling pressures, increased wall stress, subendocardial ischemia ,112. ConWhen measured with a conventional assay, elevated cTn in the absence of a type 1 myocardial infarction on admission for acute HF associates an increased risk of death during hospitalization or post discharge and also for HF readmission . MoreoveHigh sensitivity cardiac troponin (hs-cTn) assays have also been proven useful for prognosis in patients with acute HF. Very low levels of hs-cTn predict a good prognosis whereas any elevation is associated with an increased risk of death or HF readmission . Serial Besides their utility in prognostic evaluation, cTns may be as well useful in guiding therapy in acute HF. Several studies demonstrated that cTn levels change with adequately applied medical therapy. The use of angiotensin converting enzyme-inhibitors (ACEIs) and angiotensin receptor blockers was associated with undetectable levels of cTn, whilst the absence of beta-blocker use was associated with higher levels of cTn . TreatmeAlthough initially classified as a marker of myocyte stress, the expression of soluble suppression of tumorigenesis-2 (sST2), the circulating form of the interleukin-33 membrane receptor, is largely a response to vascular congestion, mechanical stretch and to inflammatory and pro-fibrotic stimuli in extracardiac tissues ,121,122.Cardinal requirements for clinically useful biomarkers are met by sST2, providing information additive to a thorough clinical examination, complementing the prognostic value of natriuretic peptides and, in chronic HF, to hs-cTn T . The comHigh levels of sST2, as a biomarker of fibrosis, have been linked to a higher risk of sudden cardiac death, therefore the decision for an ICD could be based on them . In righThe limitations of using sST2 as a cardiovascular diagnostic marker include its vulnerability to concomitant inflammation, such as autoimmune diseases, liver failure, asthma, sepsis ,126. TheOverall, while sST2 is a powerful outcome predictor, the question remains whether a sST2-guided management of acute or chronic HF could optimize disease progression and symptoms.Carbohydrate antigen 125 glycoprotein has been used for a long time as biomarker for ovarian cancer surveillance. Recent evidence showed CA125 as a possible marker of congestion of cardiac origin, as it was positively correlated with fluid overload, increased atrial and pulmonary pressure, right-ventricular dysfunction, and also with the risk of adverse events . Soluble CD146, known as a marker of endothelial function, was linearly correlated to the severity of pulmonary congestion evaluated by chest radiography, and also to LV function and congestion in acute HF ,130.Adrenomedullin acts as a circulating hormone but has also local autocrine and paracrine actions with vasodilatory and natriuretic properties within cardiovascular, renal, pulmonary, cerebrovascular, gastrointestinal, and endocrine organs . It has proved prognostic value, superior to both BNP and NT-proBNP in predicting 14-day mortality in acute setting and additive to BNP and NT-pro BNP in predicting 90-day mortality ,132. ExpElevated central venous pressure in HF may contribute to worsening kidney and liver function. Abnormalities in liver and kidney function tests are common findings in patients with HF, with an incidence varying between 25% and 75% .Venous congestion has been shown to be the most important hemodynamic contributor to worsening renal function in patients with decompensated HF patients. Therefore, during hospitalization the blood urea nitrogen to creatinine ratio can be useful as a marker of congestion or it may suggest decongestion ,134. AltIncreased central venous pressure with subsequent high right atrial pressure transmitted to the hepatic veins, may alter hepatocyte function, resulting in cholestatic liver injury . MoreovePlasma volume may be indirectly estimated by several formulas using haemoglobin and/or haematocrit level, which seem useful for monitoring congestion and decongestion both in acute in chronic setting. Plasma volume variation can be evaluated using Strauss formula: % change in plasma volume = 100 × haemoglobin before/haemoglobin after × (1 − haematocrit before)/(1 − haematocrit after) − 100. Instantaneous plasma volume estimation can be calculated using Duarte’s formula: 100 × (1 − hematocrit)/hemoglobin . Several other biological parameters that are routinely determined in patients with HF, such as serum protein, albumin, hemoglobin, and hematocrit have been associated with prognosis, being proposed as alternate markers for monitoring congestion. However, their utility as de-congestion biomarkers is limited by the fact that small changes may be caused by other HF-associated conditions and also they do not reflect the absolute change in plasma volume .The value of biomarkers in HF management is strengthened by their availability in a short time, which became possible through the Point-of-Care Testing (POCT) devices development. POCT can be performed next to or very close to the patient’s bed, both sample collection and analysis, testing results being available within minutes (about 20 min). Besides this remarkable time advantage as sample transport and processing are not necessary, compared to conventional testing, requiring centralized laboratory settings and trained personnel, POCT can be very easily performed by any user. Moreover, POCT devices do not necessitate sophisticated equipment, the technique being simplified due to advancements in the area of microfluidics and nanotechnology . Hence aIdentification of biomarkers in cardiovascular disease through POCT has been available for many years, the first implemented technique delivering qualitative results. Although POCT for cardiac troponin measurement is available for twenty years, the performance of most commercial devices is far beyond the high sensitivity assays performed within the central laboratories . CurrentOn the contrary, POCT devices can determine NP levels just as accurate as central laboratory platforms . Most POAlthough POCT systems offer several advantages to healthcare, there are limitations to their widespread use in clinical practice: the discrepancies between POCT and central laboratory results, as well as between different POCT models, lack of appropriate training for test performing and device maintenance, economic and local infrastructure issues that delay the implementation of these devices ,151.Thereby, there are limited data from studies supporting the role of point-of-care NP serial testing in ambulatory care as a tool for monitoring patients with HF and there are no established guidelines recommendations in this regard. The POC-HF (Point-of-Care in heart failure) is a pilot study conceived to demonstrate the usefulness of serial NT-proBNP measurements using POCT in patients hospitalized for acute decompensation of HF ,153. However, larger prospective trials should confirm the possible positive results of this study. Presumably, POCT sustained by clinical examination and ultrasound imaging might improve the management of patients with HF in ambulatory setting.Congestion, the most common cause of HF decompensation, is responsible for recurrent hospitalizations, accelerating disease progression and worsening the prognosis. Therefore, the evaluation of the congestion severity, monitoring its course during treatment, and early detection of subclinical congestion after discharge are important targets of the management of patients with heart failure. In addition to conventional imaging tools, among which echocardiography plays a central role, more and more studies sustain the advantages of lung ultrasound in assessing pulmonary congestion and de-congestion. Complementary to natriuretic peptides, the gold standard biomarkers for the diagnosis, prognosis, and treatment monitoring in patients with heart failure, a large amount of evidence supports the value of several other biochemical markers for the diagnosis of congestion In summary, the evaluation of congestion in HF implies a comprehensive, multiparametric approach using imaging and circulating biomarkers in different algorithms adapted to the clinical setting of the patient with heart failure.


Cardiovascular failure is one of the most relevant causes of death in pulmonary hypertension (PH). With progressive increases of right ventricular (RV) afterload in PH patients, both RV and left ventricular (LV) function impair and RV–LV dyssynchrony develop in parallel. We aimed to analyze the balance between the left and right ventricular deformation to assess the outcome of patients with pulmonary hypertension by means of speckle tracking echocardiography. In this prospective study, 54 patients with invasively diagnosed pulmonary hypertension, and 26 healthy volunteers were included and underwent a broad panel of noninvasive assessment including 2D-echocardiography, 2D speckle tracking, 6-minute walking test and BNP. Patients were followed up for 338.7 ± 131.1 (range 60 to 572) days. There were significant differences in |LVGLS/RVFLS-1| and |LASc/RASc-1| between PH patients and the control group. During the follow up, 13 patients experienced MACEs, which included 7 patients with cardiac death and 6 patients with re-admitted hospital due to right ventricular dysfunction. In the multivariate Cox model analysis, |LVGLS/RVFLS-1| remained independent prognosis of markers (HR = 4.03). Our study findings show that |LVGLS/RVFLS-1| is of high clinical and prognostic relevance in pulmonary hypertension patients and reveal the importance of the balance between the left and right ventricular deformation. Pulmonary hypertension (PH) is a group of diseases characterized by persistent progressive pulmonary arteriolar wall thickening, luminal stenosis and elevated pulmonary vascular resistance. Continuously excessive afterload of the right ventricle and right heart failure induced by the increased pulmonary artery resistance is the main cause of death in most patients with end-stage pulmonary hypertension ,2. RightCurrently, echocardiography is the most widely available technique for evaluating the performance of the RV. Patients with PH can benefit from the speckle tracking echocardiography for risk stratification by evaluating RV systolic function ,7,8. HowThe study population consisted of 54 patients with pulmonary hypertension diagnosed by right heart catheterization in the East and South Renji Hospitals affiliated to Shanghai Jiao Tong University School of Medicine from September 2018 to July 2020. The enrollment criteria for the pulmonary hypertension group included: aged 18–80 years old, with a resting mean pulmonary artery pressure (mPAP) ≥ 25 mmHg. Exclusion criteria included pulmonary hypertension due to left heart disease, hypoxic pulmonary hypertension, patients with severe complications (such as tumors) and atrial fibrillation, pregnancy, poor quality echocardiographic images and inability to complete follow-up. Another 26 healthy volunteers who were age and gender matched were recruited as the control group. All PH patients also underwent a 6-minute walking test and B-type natriuretic peptide (BNP) measurement.Echocardiography examinations in PH patients were performed on the same day of the 6-minute walking test and BNP measurement. Two-dimensional and four-dimensional (4D) echocardiographic images were acquired by an experienced physician using Vivid E9 scanner , equipped with 4V and M5S ultrasound probes (1.5 to 4.5 MHz) and synchronously connected ECG. The EchoPAC 201.0 version software  was used for offline analysis for the stored images by two physicians who were blinded to the patients’ condition. All parameters were the mean measurements of three consecutive cardiac cycles during a single breath-hold.Echo recordings and measurements followed the current guidelines ,16. MeasTwo-dimensional speckle tracking echocardiographic analysis was performed from apical four-chamber view with the clear ventricular or atrial wall. Measurements of two-dimensional speckle tracking echocardiography included left ventricular global longitudinal strain (LVGLS), right ventricular free-wall longitudinal strain (RVFLS), left atrial reservoir function (LASr), left atrial conduit function (LASc), left atrial pump function (LASp), right atrial reservoir function (RASr), right atrial conduit function (RASc) and right atrial pump function (RASp). The endocardial boundary is delineated manually, and the width of spot tracking is adjusted appropriately to match the thickness of the ventricular wall or atrial wall. Images with more than two tracking-failed segments will be discarded.The 6-minute walking test was conducted according to American Thoracic Society guidelines . The tesAll patients were followed up by phone or outpatient clinic every three months to record the occurrence of the endpoint events. A major adverse cardiac event (MACE) was defined as all-cause death and readmission due to right heart failure, pulmonary arterial hypertension complications or clinical deterioration.p < 0.05 by Cox proportional univariate hazard model were re-evaluated using a Cox proportional multivariate hazard model for determine of the independent predictor of the endpoint events in PH patients.Continuous variables were expressed as the mean ± SD for normally distributed data and as median with interquartile range when variables were skew distributed. An independent samples t-test was used for comparison between two groups with normal distribution. The Mann–Whitney U test was used to compare the data with the skewed distribution. Correlation between two variables was assessed by Pearson correlation coefficient. Variables that achieved a significant level of Moreover, we introduced the new parameters |LVGLS/RVFLS-1|, |LASr/RASr-1|, |LASc/RASc-1| and |LASp/RASp-1|, which were the absolute values of the ratio of left and right ventricular or atrial motion parameters minus 1 to represent the deviation of LVGLS/RVFLS, LASr/RASr, LASc/RASc and LASp/RASp from 1 to evaluate the motion balance between left and right heart.p value of <0.05 was considered statistically significant. All statistical analysis was performed using IBM SPSS 19.0.A The follow up duration in all PH patients was 338.7 ± 131.1 (range 60 to 572) days. During the follow-up period, 13 patients had MACE, which included 7 patients with cardiac death and 6 patients with re-admitted hospital due to right ventricular dysfunction.p = 0.60–0.97).The demographic, etiology, clinical characteristics and invasive hemodynamics of the patients are noted in p = 0.000) and FAC , which were significantly decreased in PH patients compared to controls, but not in LVEF  (p > 0.05). Compared with the control group, LVGLS  vs. −15.70 , p = 0.004) and RVFLS  were significantly decreased in PH patients . Both left and right atrial reservoir and conduction were markedly reduced with the numerically largest difference in conduct function. Although left atrial pump function in PH patients was slightly lower than controls, there was no significant difference in right atrial pump function between PH patients and the control group.Echocardiography-derived conventional parameters included TAPSE  vs. 16.00 , = 0.195) . LVGLS ap < 0.05). Although the difference between patients with both preserved or both impaired and patients with LVGLS impaired or RVFLS impaired was not significant because of the small sample size of the LVGLS impaired group and RVFLS impaired group, it can be seen from the K-M survival curve of each group that survival rate of patients reduced whether LVGLS alone or RVFLS alone decreased. Additionally, when both decrease, the survival rate of patients will decrease more significantly.Based on the trend shown in As p < 0.0001) and BNP , RASr , RASc , RVSP  and FAC . However, there was no significant relation between |LVGLS/RVFLS-1| and 6MWD.As Univariate analysis demonstrated that BNP, 6MWD, NYHA, FAC, RVSP, LVGLS, RVFLS, LASc, RASr, |LVGLS/RVFLS-1| and |LASp/RASp-1| were the most significant predictors of the MACE . The HazKado et al. reported that the four-chamber longitudinal strains in patients with cardiac amyloidosis were significantly associated with increase of major adverse cardiovascular events, with an incremental value over traditional echocardiographic parameters, and the relative preservation of both LV LS and RA LS values may better than the reduction in one or more strain values on prognosis of the patients . AccordiIn our study, compared to the control group, the parameters reflecting right and left ventricular and atrial function of pulmonary hypertension patients were decreased except right atrial systolic function and LVEF, and both right and left atrial conduit function were severely decreased. Decreased RA conduit function may result from RV delayed relaxation and diastolic dysfunction because of the RV afterload increment and hypertrophy of the RV myocardium. Reduced reservoir function and increased systolic function can be explained by the Frank-Starling law : With thp = 0.195), LVGLS  vs. −15.70 , p = 0.004)). These studies demonstrated that there is a close relationship between the left and right heart, and echocardiographic speckle tracking is more sensitive than LVEF in early detection of left ventricular impairment.We always consider the right heart and left heart as two independent chambers, but this distinction is somewhat artificial. Not only does the circumferential myocardium on the superficial right ventricular wall extend to the left ventricle, but also both ventricles share ventricular septum and pericardium, completely synchronized electrophysiological properties. As we all know, electrical dyssynchrony which leads to remodeling of ventricles with a faster increase of radial and axial fiber growth . It willAt first, we conducted a Kaplan–Meier survival analysis for MACEs among four groups of PAH patients stratified by the median value of LVGLS and RVFLS. The curve showed that not only the survival rate of patients with impaired right ventricular function will decrease, but also the survival rate of patients with impaired left ventricular function, and MACE-free survival was similarly worse in patients if either LVGLS or RVFLS was below the cutoff values, which is similar to Kado’s study . TherefoThus, we introduced a few new parameters including |LVGLS/RVGLS-1|, |LASr/RASr-1|, |LASc/RASc-1| and |LASp/RASp-1| to represent the balance between left and right ventricular global longitudinal strain and left and right atrial functions. In PAH patients, similar to RVGLS, LVGLS and RASc, LASc, |LVGLS/RVFLS-1| and|LASc/RASc-1| were significantly increased, representing a greater deviation between left and right ventricular global longitudinal strain and atrial conduit function.Furthermore, the results showed significant correlations between |LVGLS/RVGLS-1| and BNP, NYHA, FAC and RVSP, but |LVGLS/RVGLS-1| did not have relationship with 6MWD, which has shown a prognostic effect in previous studies. 6MWD is an indicator that can reflect the activity tolerance of patients, while |LVGLS/RVGLS-1| represents the biventricular movement balance. We speculated the reason of this result is that the left and right ventricular motion began to be unbalanced before the 6MWD was decreased, and the changes of the two were not synchronous.Our small sample study showed that |LVGLS/RVFLS-1| and |LASp/RASp-1| were an important ratio in outcome of patients with pulmonary hypertension, especially |LVGLS/RVFLS-1|. |LVGLS/RVFLS-1| was associated with a 4.03-fold increase in MACE in Cox univariate regression. After adjustment for age and the variables with significant difference by Cox univariate regression, |LVGLS/RVFLS-1| increases were continuously related to MACE in the multivariate Cox analysis. The |LVGLS/RVFLS-1| increase was associated with a 3.15-fold increase in MACE. The Hazard ratio of |LVGLS/RVFLS-1| (HR = 3.15) was significantly higher than 6MWD (HR= 0.995). The results showed that the balance between the left and right ventricular longitudinal strain was important in patients with pulmonary hypertension. If the patient loses the balance, the prognosis of the patient will be worse. Our study was the first presented the impact of |LVGLS/RVFLS-1| in patients with pulmonary hypertension, which provided us a completely new, simple and great predictor for the evaluation of patient’s outcome. We hope that this parameter could be used not only in pulmonary hypertension patients, but also in any patients with the disease caused unbalanced left and right ventricular movements, such as electrophysiological remodeling mechanisms.Univariate and multivariate COX regression analysis showed that only 6MWD and |LVGLS/RVFLS-1| were independent prognostic factors for death or re-admission. Although RV longitudinal peak systolic strain has been to be a significant determinant of all-cause mortality ,36, anotIn a few patients, we observed that the decrease of LVGLS is more obvious than RVFLS because of the compression of right heart, which is different from PAH patients with RVFLS decreased as the main manifestation. These patients were often neglected in previous clinical studies focusing on the right heart function of PAH patients, but their survival rate is also affected by pulmonary hypertension. The new composite index we introduced can include not only the patients with decreased right ventricular function, but also these patients, which may be one of the reasons why the index is more sensitive in the multifactor prognosis analysis.The results of our study remind us that the interaction and regulation of left and right ventricles in the structure, function, electrophysiological mechanisms and neuroendocrine regulatory system may be more than we expected. We should pay attention to protect left heart function in PAH patients, and preservation and balance of left and right ventricular function may benefit patients more.There are several limitations of this study that need to be pointed out. First, we could not perform subgroup analysis according to PASP, NYHA and so on because of the small sample population. Second, the follow-up time was not long enough, and the number of patients with positive results was small. Third, atrial strain measured by speckle tracking has some deviations due to thin atrial wall. Meanwhile, due to the enlargement of the right heart in patients with pulmonary hypertension, it is difficult to include two ventricles in one section, which may lead to deviation of ejection fraction measured by four-dimensional ultrasound. Lastly, myocardial strain includes longitudinal strain and circumferential strain, but only longitudinal strain was measured in this study, and two-dimensional speckle tracking can only reflect myocardial movement in the same plane, so our results need to be confirmed by three-dimensional speckle tracking.Previous studies on the prognosis of pulmonary hypertension patients have focused on right ventricular systolic function or left ventricular diastolic function. Our study revealed that the motion balance between left and right ventricular may be one of the important indexes to evaluate the prognosis of PH patients. The interaction and regulation of left and right ventricles in the structure, function, electrophysiological mechanisms and neuroendocrine regulatory system may be more than we expected.


However, the fluid mechanics of feHLHS is not well-characterized. Here, we conduct patient-specific echocardiography-based flow simulations of normal and feHLHS left ventricles (LV), to understand the essential fluid dynamics distinction between the two cohorts. We found high variability across feHLHS cases, but also the following unifying features. Firstly, feHLHS diastole mitral inflow was in the form of a narrowed and fast jet that impinged onto the apical region, rather than a wide and gentle inflow in normal LVs. This was likely due to a malformed mitral valve with impaired opening dynamics. This altered inflow caused elevated vorticity dynamics and wall shear stresses (WSS) and reduced oscillatory shear index at the apical zone rather than mid-ventricle. Secondly, feHLHS LV also featured elevated systolic and diastolic energy losses, intraventricular pressure gradients, and vortex formation numbers, suggesting energy inefficiency of flow and additional burden on the LV. Thirdly, feHLHS LV had poor blood turnover, suggesting a hypoxic environment, which could be associated with endocardial fibroelastosis that is often observed in these patients.In cases of fetal aortic stenosis and evolving Hypoplastic Left Heart Syndrome (feHLHS), aortic stenosis is associated with specific abnormalities such as retrograde or bidirectional systolic transverse arch flow. Many cases progressed to hypoplastic left heart syndrome (HLHS) malformation at birth, but fetal aortic valvuloplasty can prevent the progression in many cases. Since both disease and intervention involve drastic changes to the biomechanical environment, The online version contains supplementary material available at 10.1007/s10439-022-02990-5. FAV involves introducing a needle through the mother's abdomen into the fetal LV and inflating a balloon catheter at the stenotic aortic valve to relieve the stenosis.18 Elevated LV pressure often leads to severe MR, which can cause left atrial pressurization and dilation, and consequently, premature narrowing or closure of the foramen ovale.31 Further, LV ejection fraction and myocardial strains are severely depressed.9 After the intervention, de-pressurization of the LV can be achieved, decreased LV end-diastolic volume and acute improvements in diastolic function and ventricular strains.38 Furthermore, there is evidence that such changes in hemodynamics after FAV, such as that seen aortic arch and foramen ovale, allowed for increased growth of the AV and mitral valves (MV).25 Unfortunately, there is currently little data on the biomechanical environment of feHLHS hearts before or after the intervention.In both critical aortic stenosis and fetal aortic valvuloplasty, there were drastic changes to the biomechanical environment of the heart. During feHLHS, outflow obstruction caused high pressures in the LV, which can be inferred by the maximum instantaneous peak gradient from the aortic valve (AV) or mitral regurgitation (MR) velocities, estimated by the simplified Bernoulli equation.39 while left atrial ligation in chick embryo has led to hypoplastic LV29 and evidence of fibroelastosis.22 For this reason, an improved understanding of LV biomechanics during feHLHS may help develop future strategies for better prognosis or to improve intervention outcomes.The above clinical evidence for feHLHS progression to HLHS, and for interventions to reduce risks of this progression, has led to the prevailing thought that the biomechanical stimuli of the heart exert influence on the growth and development of the heart, and can determine morphological outcomes. Large and small animal experiments have corroborated this notion, the occlusion of lamb fetal foramen ovale was shown to lead to the underdevelopment of LV chamber and aortic and mitral valves,via subject-specific computational fluid dynamics (CFD) simulations based on 4D echocardiography images and characterized essential differences against those in normal human fetal LVs.Thus, in this study, we conducted a study of the blood flow mechanics in human fetal LVs with feHLHS, 1 and underwent the intervention later, and their characteristics are listed in Table 36Data for 5 healthy fetuses and 5 feHLHS were prospectively gathered, from the National University Hospital, Singapore, and the Kepler University Hospital, Austria, with ethics approval from both , and written consent from all participants. All feHLHS cases were within the selection criteria for aortic valvuloplasty intervention37 Briefly, 4D B-mode ultrasound images were acquired using the Vivid-7®, Vivid E9®, or Vivid E95®  ultrasound system via the Spatio-Temporal Image Correlation (STIC) mode. The STIC sweep took 10–15 s, with an image capture rate of 70–90 frames per second, thus giving 40 volumes for 1 cardiac cycle. Subsequently, images were exported as a stack of 2D cine images with 0.5mm spacing between consecutive planes. The lumen cavity of the left and right ventricle , and left and right atrium  were segmented with a custom-written semi-automatic lazy-snapping algorithm,14 reconstructed via Vascular Modeling Toolkit , and smoothed with Geomagic Studio .Imaging and image processing methods were as established in our previous studies.35 This algorithm fits a global motion model of spatial b-splines of temporal Fourier onto results of a set of pair-wise image registrations between different time frames, thus enforcing the cyclic nature of motions. Segmentation was performed at a particular time point, as it could be animated with the motion model to all other time points. The stroke volume of cardiac chambers could then be calculated based on their re-animated motions.A validated cardiac motion estimation algorithm was used to track the motion of the patient-specific reconstructed LV, RV and LA endocardial wall over the cardiac cycle.37 and utilized ANSYS FLUENT 2019 R2 . LV luminal blood space was meshed into at least 1–1.5 million tetrahedral elements, which was shown to exceed mesh convergence requirements.36 A user-defined function was used to control the wall motions according to the motion model from motion tracking. Blood viscosity was modelled with the Carreau-Yasuda model as we previously reported,13 while density, ρ, was prescribed as 1060 kg/m3. Dynamic mesh CFD simulations were conducted to solve the 3D Navier Stokes equation with 400 time steps per cardiac cycle for at least three cycles, and only the last cycle was used for analysis to minimize artefacts of the stagnant initial condition. Convergence criteria were set to be less than 10−4 for all scaled residuals.Methods for image-based CFD simulation were adapted from our previous studies,Inlet and outlet boundary conditions were idealized as instantaneous opening or closing of valves, by converting surfaces between openings and walls. When opened, inlets and outlets were prescribed with pressures that were calculated based on a Windkessel lumped parameter model, described below. In the feHLHS cohort, mitral valve insufficiency was modelled by having a regurgitation orifice that was modelled as a permanently open orifice, located within the mitral orifice zone on the model’s surface. The sizes of all the aortic outlet, mitral inlet, and mitral regurgitation orifice were iteratively adjusted until CFD simulations produced valve velocities that matched clinical patient-specific Doppler scans satisfactorily, including aortic outflow velocity, peak E- and A-wave inflow velocities and peak mitral regurgitation velocity. Due to the low resolution of echo images, the valve morphology and orifice shapes and sizes could not be discerned. Orifices were thus approximated to be at the centre of their likely location, for example, the aortic orifice was assumed to be at the centre of the aortic valve, while the mitral regurgitation orifice was assumed to be at the centre of the mitral valve.et al.21 who proposed a methodology for allometric scaling of the lumped parameter from 38 weeks gestational age (GA) to other GA, as briefly explained in supplementary section S1 (which includes Table S1). However, we recalibrated it to fit more recent human fetal clinical measurements,34 in contrast to some of its original fit to fetal lamb measurements. To do this, all resistances were scaled by an age-dependent factor, while all compliances were scaled by another. The original value of the inertances and valvular dissipative coefficients were retained from Pennati et al.21A Windkessel lumped parameter model was used for ventricular-vascular coupling in our flow simulations. During the coupling of the model to the CFD boundary conditions, the model was run for 10 cardiac cycles to ensure a steady and periodic state was achieved. The lumped parameter model was adapted from Pennati 8 the fetal abdominal aortic pulse pressures,34 and fetal LV systolic and diastolic pressures10 at the matching GA. Subsequently, a 5th order and 6th order polynomial fit were calculated for the resistance scaling factor and the capacitance scaling factor, respectively. We interpreted Johnson et al.’s data as indicating that the minimum diastolic LV pressure was 5 mmHg regardless of age, rather than diastolic pressure increasing with age, as the latter would lead to excessively high diastolic pressure when extrapolated to the near-term fetus. Figure The age-dependent scaling factors at specific ages between 22 and 38 weeks gestation were first determined by fitting literature values of LV and RV volume clinical measurements ,28 Secondly, aortic stenosis was modelled by iteratively adjusting the aortic orifice in the CFD simulations to match Doppler measurements. Third, mitral regurgitation was modelled in the CFD simulation for feHLHS cases if present. Fourthly, to emulate elevated LA pressures observed in many fetal aortic stenosis cases, we modelled LA pressure , which was approximated using the atrial length, width and the ellipsoid method.ε, was given as,12From the CFD results, the normalized energy loss across time, −9 m2/s which minimized mixing and enabled better differentiation of the two fluids.To evaluate blood turnover within the LV chamber, we performed simulations with two different fluids, existing blood in the chamber and fresh blood from inflow, using an arbitrary but low diffusivity coefficient 10t was the duration of either the E or A wave, whichever was higher, or the entire diastolic duration for monophasic flow, and 3To further characterize diastolic vorticity, we calculated the formation time  was performed using a 31The peak local valve velocities of our simulations were successfully tuned to achieve a satisfactory match with Doppler velocity measurements at the valves, as demonstrated in Supplementary Table S2. We report a velocity error of − 0.005 ± 0.049 m/s or a percentage error of 4.5% ± 4.3%. Table 13 where wide diastolic vortex rings, corresponding to E- and A-wave flow were observed to propagate from the mitral towards the apex. These vortex rings occupied the entire width of the LV and propagated to various extents towards the LV apex. The rings merged and interacted with endocardial walls, bringing about elevated WSS along the way and creating complex secondary vorticity structures that did not dissipate completely but were ejected during the subsequent systole.Flow patterns within the fetal LVs from CFD simulations are shown in Figure Flow patterns in feHLHS were drastically different. Here, MV inflow occurred as a narrow jet with typically high velocity, generating a small-diameter vortex ring that propagated quickly towards the apex and impinged on the apical endocardium. In our simulations, narrowed mitral inlet orifice was necessitated so that the simulation can yield inflow velocities that matched with high Doppler measurements (Supplementary Table S2). This suggested mild MV stenosis, which consequently resulted in the observed fast and narrow inflow jets. Table Due to chamber dilation and narrow inflow jet, the inflow vortex rings in feHLHS LVs had minimal interaction with the endocardial walls before impinging at the apex. The jet impingement stirred up secondary vortices and elevated wall shear stresses (WSS) around the impingement location. The strength and complexity of secondary vortices and magnitude of WSS depended on the MV inflow velocity. These vortices were weak for feHLHS-1, 2 and 4, and moderate for feHLHS-3, but in feHLHS-5, chaotic flow structures erupted from the high-speed impingement and spread throughout the LV, elevating WSS over a substantial surface area.15 Only feHLHS-1 and 5 demonstrated a discernible biphasic mitral inflow profile, which was likely linked to better diastolic ventricular function.5 This further contributed to the difference in vorticity pattern complexity between these subjects and the other diseased subjects. Overall, feHLHS LVs had distinctive flow features apart from normal LVs, but there was also considerable variability between individuals within the diseased cohort.Contrary to normal fetal hearts, feHLHS LVs mostly demonstrated monophasic inflow, which was frequently reported for this disease.Flow stresses and energy dynamics results from the CFD simulations are provided in Table Furthermore, systolic and diastolic energy loss and systolic work done showed a marked increase for all feHLHS cases. Due to aortic stenosis, there was elevated aortic velocity and narrowed outflow channel, leading to high fluid stresses and excessive energy losses in the flow convergence zone of the outlet. A high amount of energy expenditure was thus needed by the LV wall to overcome high frictional energy losses to force fluid through the AV. Diastolic energy losses were substantially elevated from the normal ranges as well. This was likely due to the elevated inflow velocity and the concentration of fluid forces at the impingement point that led to high viscous dissipation. Overall, we observed high-pressure gradients, energy losses and work done in LVs of the feHLHS cohort.36 Mid-ventricular WSS elevation was likely caused by the more significant interaction between the diastolic vortex rings and the endocardial walls in this zone, while outlet WSS elevation was likely caused by the systolic flow convergence at the outlet, where there were elevated velocities within the narrowed flow channel. These zones of high WSS magnitude were also the zones where OSI was low, which demonstrated the consistent directionality of velocities at these walls.The spatial distributions of TAWSS and OSI are shown for the feHLHS cohort and two representative cases from the healthy cohort in Figure In the feHLHS cohort, high WSS and low OSI were also observed at the outlet region, likely caused by systolic flow convergence as well. however, WSS was generally elevated not at the mid-ventricle zone, but at the site of diastolic inflow jet impingement and its immediate vicinity, near the apical region. With increased strength of the secondary vorticity structures after impingement, such as in the case of feHLHS-5, WSS elevations could extend further up the LV towards the base. OSI was observed to be low at this impingement point but was higher elsewhere in the LV.Figure Table 23 and an improved understanding of disease fluid dynamics may lead to optimization of the intervention.We conducted image-based flow simulations in LVs of feHLHS, to understand essential fluid dynamics differences from normal LVs. Our cohort of disease patients was from a pool of patients fitting the selection criteria for FAV and eventually underwent the intervention. Our focus on this cohort of patients is due to evidence that such interventions have the potential of improving medium-term survival for the cohorts,We find that in the disease cohort, there was substantial variability in flow patterns and forces, but there were unifying features. The most distinctive feature in the feHLHS cohort was that of a narrow and fast inflow jet that moved quickly from the mitral inlet to impinge on the apical region, which led to excessive dynamics at the apical region but allowed the basal region to be more quiescent. In contrast, in normal LVs, the inflow vortices were slower and interacted more substantially with the mid-ventricular endocardial walls, leading to elevated vorticity dynamics at the mid-ventricular and basal region, but more quiescent flow at the apex.The elevation of mitral inflow velocity was somewhat surprising, as one would expect the high LV pressure in the diseased LV to oppose mitral inflow and lead to decreased rather than increased inflow velocities. Our analysis suggested that this elevated inflow velocity was not due to a hypoplastic mitral annulus but was more likely associated with the impaired mitral valve opening dynamics because the inflow jet diameter was small despite a normal-sized mitral annulus. Since these velocities did not show acute improvement after aortic valvuloplasty intervention, it was likely that the mitral valve was malformed and had impaired opening function. However, further studies to validate this notion and understand the details are warranted.7 We noted with interest that the vortex formation times in healthy LVs were close to that reported in normal adult hearts, which had a range of between 2 and 7.6 This suggested similar vortex characteristics between pre-and post-natal LVs. In feHLHS cases, however, formation times were considerably higher, due to greater blood inflow velocities and smaller MV diameters. This suggests that diastolic vortex generation in feHLHS LVs was energy inefficient, which corroborated with observations of higher diastolic energy losses.Since the mitral inflow was observed to be abnormal, we computed the formation time of diastolic inflow vortex rings Table , as thisA second distinctive feature of feHLHS LV was that both the mitral inflow and the aortic outflow were associated with elevated IVPG and energy losses. Aortic outflow energy losses per unit volume of flow were found to be one order of magnitude higher, but this was not surprising, given the severity of the stenosis. These excessive energy losses seemed likely to impose an excessive burden on the LV and could be contributing factors to the progression of HLHS at birth.22 A plausible mechanism for this was the hypoxia-induced endothelial-to-mesenchymal transition (EndMT), as fibroelastosis was shown to be related to EndMT,40 which hypoxia was shown to induce.41The third distinctive feature was a reduced blood turnover in feHLHS LVs, where the renewal of blood within the LV was 66% slower on the average. This was likely to induce hypoxic stress in the endocardium. In a chick embryonic model of HLHS induced by left atrial ligation, histology demonstrated increased regions of hypoxia consequent to altered LV hemodynamics, and at the same time, elevated deposition of collagen I. This bore similarity to clinical endocardial fibroelastosis (EFE) that could often be observed in feHLHS LVs as hyper-echogenic endocardium.19 and as such is important to understand. A previous study suggested that flow disturbances such as stagnant intracavity flow and aortic regurgitation led to the development of EFE.26 Our disease LVs matched this description, having stenotic mitral inflow. While WSS patterns were qualitatively different in feHLHS cohort, we did not find consistent trends in the overall spatially-averaged WSS magnitude, due to large variability between cases, which dampened the notion that specific WSS characteristics could have caused EFE or impairment on the growth of the left heart. However, further investigations on these issues seemed warranted here as well.EFE has been associated with diastolic dysfunction in feHLHS. LVs with severe EFE are associated with bad diastolic dysfunction and greater impairment in LV growth after FAV,Since the overall WSS magnitude did not demonstrate clear differences between normal and feHLHS LVs, we suggest that this may not be a consequential factor in determining the progression of feHLHS LVs towards HLHS at birth. It seemed more likely that the drastic elevation of LV pressure and thus stresses on the myocardium and valves, and the lack of myocardial deformational motion and leaflet dynamics were more closely related to the lack of growth of these cardiac structures.17 The post-intervention LV fluid dynamics was thus likely to be quite different from both the pre-intervention feHLHS LV, and the normal LV, and detailed investigation seemed warranted.Further, it seemed that some of the essential differences between feHLHS and healthy LVs were resolvable with FAV. In the post-intervention data from our patient cohort, a large proportion of fetuses developed a biphasic mitral inflow profile and improved stroke volumes as demonstrated in Table Our current study provides a baseline disease characterization, such that when post-intervention fluid dynamics data is available, we can compare pre-and post-intervention to understand the effects of the intervention. We can also use the same approach to understand the effects of growth and remodelling changes to cardiac fluid dynamics, such as if there was a regression of the aortic stenosis after the intervention or weakening of cardiac contractility, and we can also study the relationship between fluid mechanical stimuli and cardiac growth and gestational development. All of these may lead to an improved understanding of the effects of the intervention and of how the flow of mechanical stimuli affects outcomes, which can inform clinical decisions such as the suitability of specific patients for the intervention, when to conduct the intervention, and whether novel medical devices such as fetal transcatheter replacement aortic valve can be beneficial.33 However, the main flow phenomena such as the inflow jet vortex ring and its interaction with ventricular walls were likely to be retained. Secondly, we approximated the locations for the valve orifices as we could not imagine their exact location, and this could have led to errors. Thirdly, due to limited imaging resolution and image noise, there are likely to be some errors in our segmentation and cardiac motion estimation.There are some limitations to our study. Firstly, our simulations did not account for the fluid-structure interaction between fluid and the mitral valve and were simplified as an effective inlet orifice area, due to an inability to observe valve morphology as images had poor resolution and high noise. This was likely to have altered the resulting flow patterns, as the presence of the mitral valve would increase vortex penetration, wall shear stress and viscous dissipation.In conclusion, we performed patient-specific 4D flow simulations of normal and feHLHS LVs and found essential differences. There was wide variability observed in feHLHS cases, but also unifying features. Firstly, in feHLHS LVs, an abnormally fast and narrow diastolic mitral inflow jet was observed, likely due to a malformed mitral valve with impaired ability to open. This inflow jet impinged at the apex, causing elevated vorticity dynamics and WSS at the apex region, rather than the mid-ventricle region as was the case for normal LV. Secondly, in feHLHS LV, there were further elevated intraventricular pressure gradients, and higher systolic and diastolic energy losses, due to both AV and MV stenosis. Thirdly, feHLHS LV had low blood turnover, suggesting a hypoxic environment, which may be linked to EFE that is frequently observed in such patients.Supplementary file1 (DOCX 591 KB)Supplementary file2 (MP4 290 KB)Supplementary file3 (MP4 436 KB)Supplementary file4 (MP4 543 KB)Supplementary file5 (MP4 640 KB)Supplementary file6 (MP4 1034 KB)Supplementary file7 (MP4 742 KB)Supplementary file8 (MP4 1072 KB)Supplementary file9 (MP4 1675 KB)Supplementary file10 (MP4 1141 KB)Supplementary file11 (MP4 1077 KB)Below is the link to the electronic supplementary material.


Prior to recommending exercise, assessment of safety to engage in PA along with self-efficacy and motivation in patients with heart failure is essential.The aim of this study was to explore the readiness for physical activity (PA) and its related factors in patients with heart failure. This cross-sectional study included 163 patients with heart failure . The ability to safely engage in PA was assessed with the PA Readiness Questionnaire (PAR-Q). Psychological readiness was measured using two questionnaires, namely: Exercise Self-efficacy Scale and the Motivation for PA and Exercise/Working Out. A multivariate analysis of covariance was conducted to test the effect of background variables on readiness for PA. 64% (n = 105) of patients reported not being able to safely engage in PA, 80% (n = 129) reported low self-efficacy, and 45% (n = 74) were extrinsically motivated indicating external factors drove their motivation. Factors that positively influenced the PA readiness included lower age ( Heart failure (HF) is a chronic syndrome with a prevalence and incidence on the rise due to an ageing population and increased survival from ischemic and non-ischemic causes ,2. An esSelf-management strategies, such as physical activity , can opEducation is an essential component of nearly all management programs for patients with HF. Although education typically addresses the changes in PA necessary to control signs and symptoms and improve outcomes, failure to adhere to recommendations continues to be a common reason for hospital readmission for patients with HF ,10. EducSelf-efficacy, according to the Social Cognitive Theory, refers to an individual’s confidence in his or her ability to engage in a behavior, even when barriers occur . A higheReadiness in PA, as a combination of the ability to safely engage in PA  and psychological readiness to engage in PA , has not been previously explored in patients with HF. Therefore, the primary purpose of this study is to explore the readiness for PA in patients. The secondary aims were to assess daily PA in patients with HF and its association with readiness for PA. Additionally, we explored factors associated with readiness for PA in this population.This is a cross-sectional study. Patients diagnosed with HF (regardless of their ejection fraction), free from major psychiatric or neurocognitive conditions, and older than 18 years of age were eligible for participation. Exclusion criteria were inability to understand Spanish and/or cognitive impairments that would make it impossible to fill in the study questionnaires.The present study complies with the Declaration of Helsinki and was approved by the Regional Ethics Committee (H1510342565432).All patients with HF that visited the cardiology department in a university hospital in Spain  between January–July 2018 were invited by research staff to participate. Patients provided oral and written informed consent before filling out the questionnaires. Help was provided for filling in the questionnaire when needed.Demographic and clinical characteristics including age, gender, time since diagnosis, New York Heart Association Classification (NYHA-class), body mass index (BMI), and comorbidities ) were collected from the patients’ medical charts. Information on marital status and educational level was assessed using a questionnaire. Readiness for PA was assessed with: (i) the ability to safely engage in PA; and (ii) psychological readiness in becoming more physically active.The ability to safely engage in PA was assessed with the PA Readiness Questionnaire (PAR-Q) . This quPsychological readiness in becoming more physically active was measured with the Exercise Self-efficacy Scale (ESES) and motivation with the Motivation for PA and Exercise/ Working Out questionnaire (RM 4–FM). The ESES included 9 items and assessed the participant’s confidence to perform exercise under different conditions or constraints. For each condition or constraint such as being tired, weather conditions, afraid of being hurt, lack of motivation, etc., participants responded on a 7-point scale, ranging from “very sure” (1) to “not at all sure” (4). A score of 15 and higher was seen as having exercise self-efficacy. This scale has been tested for its validity and reliability . The RM The amount of physical activity was measured with the short form International Physical Activity Questionnaire (s-IPAQ)). The s-IPAQ contains seven items for identifying the frequency and duration of light, moderate, and vigorous PA, as well as inactivity during the past week. The answers to the questions were transformed into Metabolic Equivalent of Task (MET-minutes), a physiological measure expressing the energy cost of physical activities. The patients were classified into three PA categories: low, moderate, and high. The s-IPAQ is a valid and reliable instrument to measure PA ,26.p-value < 0.01 was considered significant. The basic assumptions to fit the linear model were met. Data were analyzed using SPSS (version 25).In the descriptive analyses, means and standard deviations were calculated for continuous data, and absolute numbers and percentages were computed for nominal variables. The normal distribution of the data was tested by the Kolmogorov–Smirnov test. Correlational analyses were done to explore the relationship between the ability to safely engage in PA and psychological readiness and the total amount of MET-minutes. A multivariate analysis of covariance (MANCOVA) was done to test the effect of categorical variables on PA readiness. Factors that were tested in the model were age, gender, time after diagnosis (months), body mass index (BMI), marital status (married/in a relationship or single), educational level , NYHA-class, and the presence of diabetes and COPD. A In total, 163 patients participated (response rate 82%), with 35 % (n = 57) reporting low PA level (<600 MET-minutes a week) and 65% (n = 106) reporting moderate PA level (between 600–3000 MET-minutes a week). Participants had a mean age of 66 (±16) years, 50% were female, 82% were married, 63% NYHA I, and 37% NYHA II .Of the patients included, all patients were taking medication for their heart condition. In our analysis, when this question was discarded, 64% reported not being able to safely engage in PA (n = 105); 43% (n = 70) experienced balance problems, 34% (n = 55) experienced chest pain, and 20% (n = 32) experienced problems in their joints.Eighty percent of the patients reported low self-efficacy for exercise (n = 129). In total, 45% (n = 74) were extrinsically motivated for PA and 55% (n = 89) reported primarily internal motivating factors to be physically active.p = 0.09) and identified regulation  were not correlated.Most components  of PA readiness were correlated with each other ; only inHigher ability to safely engage in PA, higher motivation, and higher self-efficacy were positively associated with the amount of physical activity that patients with HF performed.p < 0.01), male gender (p < 0.01), less time since diagnosis (p < 0.01), higher educational level (p < 0.01), being married (p < 0.01), and being in NYHA-class I compared with NYHA-class II (p < 0.01), lower BMI , and not having COPD (0.022). Having diabetes did not influence the PA readiness   .A prudent and important first step in the fitness assessments and exercise prescription process in patients with HF is the determination of PA readiness. Along with screening for the ability to safely engage in PA, it is also important to screen for psychological readiness for engaging in PA. Higher ability to safely engage in PA and higher psychological readiness were found to be associated with higher PA in patients with HF.In our study, not taking medication use in consideration as all patients were on HF medication, more than half of the patients (64%) experienced the inability to safely engage in PA. Commonly reported physical limitations included the experience of balance problems (43%), chest pain (34%), and joint problems (20%). Our findings agree with prior studies. A previous study  on patieIn analyzing psychological readiness, we found that half of the participants were extrinsically motivated for PA and exercise and the other half experienced internal factors that motivated them to be involved in their PA. Although the strength of the motivation was not strong (mean score of 0.30), this indicates that while one-half of the patients were driven to perform PA for the sheer pleasure that was derived from engaging in PA, the other half was motivated for extrinsic reasons, such as valuing the importance of PA for their health condition, to impress others, attaining a reward, or for fear of punishment. Motivations towards exercise are important in patients with HF, as self-determined patients are more likely to maintain exercise behavior . It is iMotivation to be physically active is important but not sufficient. In addition to a high level of motivation to be physically active, it is important that patients with HF have a high degree of self-efficacy . PatientOur study shows that the ability to safely engage in PA and psychological readiness are highly correlated with each other, meaning that they influence each other, confirming our study’s outcome measure of PA readiness. We found the inability to safely engage in PA and psychological readiness among the participants in our study. Our conclusion is supported by other studies ,34 that Factors that positively influenced the PA readiness included lower age, being male, being married, having higher education, lower NYHA classification, less time since diagnosis, lower BMI, and not suffering from COPD. Other studies confirm our outcomes. One study showed that women experienced more physical, social, and psychological motivations toward physical activity compared with men. Women often express being proud of themselves when they are regularly physically active and attribute their success to being in good physical shape. The HF-ACTION study  showed tObesity is a risk factor for inactivity and our study found that obesity is also associated with low PA readiness. A previous study  showed tThe findings of this study can assist nurses and other healthcare providers worldwide by highlighting the need for screening for PA readiness in HF patients to reduce the risk associated with engagement in PA and improving adherence to exercise guidelines. There are some limitations in this study. The cross-sectional design was a limitation in implying causal relationships between PA readiness. The generalizability of these findings may be limited to relatively healthy HF patients; therefore, the disease itself could be of little influence on the PA readiness. The population was also younger than the general HF population. This could be because the research included relatively healthy HF patients, as patients included were classified as NYHA I or II, with comparatively higher levels of functional ability as compared with NYHA Class III and IV patients with HF. Therefore, generalization of the results of this study to the entire HF population is cautioned. In addition, the focus of this study is predominantly on short-term exercise uptake, although the importance of long-term physical activity adherence should be highlighted in this regard. We use the PAR-Q for assessing the ability to safely engage in PA. We recommend the use of the PAR-Q+ to assess physical readiness in future studies as it may be more sensitive in detecting safety issues in engaging in PA . AnotherThis study shows that PA readiness has both a physical and a psychological component. More than half of the patients were not able to engage safely in PA. Motivation  was found to be important in PA, but most patients experienced low self-efficacy towards PA. Factors that positively influenced PA readiness included lower age, being male, being married, having higher education, lower NYHA classification, less time since diagnosis, lower BMI, and not suffering from COPD. When prescribing PA prescriptions to patients with HF, we should not only assess if it is safe for them to engage in PA but also assess if they are motivated and have self-efficacy to be able to become more physically active.