The use of biventricular impella support in patients with acute, reversible causes of biventricular cardiogenic shock may play a role in shortening the time to recovery and preventing significant negative outcomes such as renal or hepatic failure. The use of biventricular impella support in patients with acute, reversible causes of biventricular cardiogenic shock may play a role in shortening the time to recovery and preventing significant negative outcomes such as renal or hepatic failure. Following the initiation of an esmolol drip, the patient became lethargic, cool to touch, and hypotensive requiring norepinephrine.Laboratory data showed multi‐organ failure, and echocardiography revealed severe global hypokinesis with an EF of 5%. He was taken urgently for cardiac catheterization, which revealed a cardiac output of 2.8 L/min, a cardiac power output of 0.47, a pulmonary artery pulsatility index (PAPi) of 0.535, an RVSWI of 3.19, and an RA:PCWP ratio of 1.03 consistent with biventricular failure.An impella CP was placed with improvement in left ventricular function at 30 minutes, but with a persistently low PAPi, low RVSWI, and an elevated RA:PCWP ratio consistent with severe right ventricular dysfunction. An RP impella was placed with improvement in biventricular function and a significant improvement in mental status.His clinical status rapidly improved with mechanical support and treatment of his hyperthyroidism. He was weaned off of mechanical circulatory support within 3 days without any significant complications and was initiated on medical therapy for heart failure. On discharge, he had recovery of left ventricular ejection function to 35% and normal RV function. At his 6‐month follow‐up visit, he had normalization of biventricular function.A 31‐year‐old man with a history of Grave's disease presented with 5 days of lower extremity swelling and shortness of breath. He had been on methimazole as an outpatient for several years, but had not taken it for several weeks due to loss of his insurance. On admission, he had an irregular heart rhythm with rates up to 200 bpm and a blood pressure of 110/70. An EKG was done showing rapid atrial fibrillation.Laboratory data were consistent with thyroid storm. He was initiated on propranolol, PTU, and hydrocortisone with admission to the ICU. Heart rates continued to be elevated, and he was started on an esmolol drip. With rate control, he became confused, lethargic, cold, and hypotensive.A bedside echocardiogram was performed showing 4 chamber dilatation and biventricular failure with an ejection fraction of 5%. Laboratory data showed developing shock Table . He was 22.1A right heart catheterization was performed Figure , Table 2Repeat PAPi was 0.73 demonstrating minimal improvement in RV function with LV offloading. The RA:PCWP was 1.04 which was unchanged from the initial measurement prior to impella CP placement, and the RV stroke work index (RVSWI) improved modestly from 3.2 to 4.5, but was still significantly reduced, indicative of severe RV dysfunction. At that point, an RP impella was placed and repeat hemodynamics showed improved biventricular function  prompting removal of the RP impella. He was aggressively diuresed, and on hospital day 4, the impella CP was weaned off and removed.Diuresis and uptitration of guideline‐directed medical therapy for heart failure were continued over several days. On hospital day 8, he underwent successful TEE/DCCV. Prior to discharge, repeat echocardiogram showed marked improvement with an ejection fraction of 35% and normal right ventricular function by TAPSE. On discharge, he was taking metoprolol succinate, lisinopril, furosemide, apixaban, and methimazole.Clinical Follow‐up: 6 months later, he was asymptomatic and had an echocardiogram that showed normalized cardiac function.3In hyperthyroidism, the increased serum concentration of T3 up‐regulates several cardiac‐specific genes enhancing contractility, improving cardiac relaxation, lowering SVR, increasing blood volume, and elevating baseline heart rate.The above case illustrates how rapid recognition of the severity of illness accompanied by aggressive management with mechanical circulatory support can result in a good outcome and avoid serious comorbidities. While there are no prospective studies that determine treatment in thyroid storm, the current standard of care based on expert opinion consists of administering a beta blocker for control of adrenergic surge, use of a thionamide (in this case PTU) to block new synthesis, glucocorticoids to reduce T4‐T3 conversion, and an iodine agent to block release of thyroid hormone. Given the relative frequency of atrial fibrillation but relatively uncommon complication of cardiogenic shock in this population, it is not uncommon to initiate beta blockade without first assessing cardiac function. Furthermore, on presentation our patient appeared deceptively stable, which is likely due to his young age and ability to significantly increase his SVR despite a thyrotoxic state. This likely resulted in a false sense of security that beta blockade initiation would be well tolerated. When his heart rate dropped, his poor cardiac output led to rapid clinical decline and laboratory evidence of multi‐organ hypo‐perfusion. While it is not possible to delineate whether his ventricular dysfunction was due to prolonged tachyarrhythmia or thyrotoxicosis, this difference did not affect management as he required support while the underlying disorder was treated. The necessity of beta blockade to treat both his adrenergic surge and atrial fibrillation coupled with his severely reduced cardiac function illustrates the management dilemma in our patient and the importance of using mechanical support.Given his deteriorating clinical status and limited medical options, the invasive hemodynamics played an integral role in determining the step‐wise approach to mechanical support. In the laboratory, there was clear evidence of severely impaired left ventricular function by CPO. Several hemodynamic measurements including PAPi, RA:PCWP ratio, and RVSWI were indicative of severe right ventricular dysfunction Table . PreviouThe decision to place an impella CP was made based on what we identified as a reversible cause of cardiogenic shock. The use of impella over ECMO was based on the concept of ventricular unloading to allow the ventricle time to recover as the underlying cause of heart failure was treated. Following placement of the impella CP, the patient was monitored in the cath lab to see if the right ventricular function improved with offloading of the left ventricle. This resulted in a slight improvement of his PAPi and RVSWI; however, both were still severely reduced and his RA:PCWP ratio was unchanged and severely elevated. Prior studies have indicated that a reduced RVSWI is an independent predictor for biventricular support requirement in patient undergoing LVAD placementWhat followed was rapid improvement in his overall clinical status. Multi‐organ failure was reversed within 48 hours of mechanical support, and the need for other advanced supportive care was avoided. By 48 hours, there was significant improvement in biventricular function. With resolution of clinical cardiogenic shock and evidence of hemolysis Table , the RP This case illustrates that, despite contrasting evidence, the use of Bi‐Pella may have a significant impact on mortality in patients with acute, reversible causes of cardiogenic shock. In this setting, the use of the device both supported the patient through shock and allowed the continued use of beta blocker therapy possibly resulting in a quicker recovery. The short‐term use of the support device likely limited our device‐related complications to mild hemolysis and thrombocytopenia. This leads us to believe that Bi‐Pella has a “sweet spot” for duration of support where a mortality benefit can be gleaned. Further studies should be done to determine the balance between duration of support and degree of ventricular recovery that will have the greatest benefit in patient care.2 consumption. In a thyrotoxic state, this may underestimate true O2 consumption and lead to an underestimation of cardiac output and an overestimation of SVR. However, the patient had severe tricuspid regurgitation by echocardiogram, and in his clinically low‐flow state, thermodilution likely would yield similar limitations. Second, given his degree of illness, full hemodynamics were not performed at every stage, but only as necessary to direct management.One limitation in our case is that for our cardiac output we utilized the Fick equation with nomogram‐derived estimates of O4Our case demonstrates that rapid diagnosis and aggressive mechanical intervention in acute, reversible cardiogenic shock with Bi‐Pella can improve clinical outcomes without significant comorbidity. Further studies are needed to determine the ideal balance between ventricular offloading and duration of support so as to derive a mortality benefit with this device.The authors, Evan Caruso and Elias Iliadis, have no conflicts of interest to disclose with respect to the topics and management presented in this article.This study was performed with all appropriate ethical considerations with consent from all providers and patients included in the study.EC: collected background data, involved in analysis of hemodynamics, and is a primary author of manuscript development. EI: is a primary investigator, physician who managed patient and performed cardiac catheterization, and provided significant authorship in the development of manuscript.


Sodium is an essential mineral and nutrient used in dietary practices across the world and is important to maintain proper blood volume and blood pressure. A high sodium diet is associated with increased expression of β—myosin heavy chain, decreased expression of α/β—myosin heavy chain, increased myocyte enhancer factor 2/nuclear factor of activated T cell transcriptional activity, and increased salt-inducible kinase 1 expression, which leads to alteration in myocardial mechanical performance. A high sodium diet is also associated with alterations in various proteins responsible for calcium homeostasis and myocardial contractility. Excessive sodium intake is associated with the development of a variety of comorbidities including hypertension, chronic kidney disease, stroke, and cardiovascular diseases. While the American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines recommend limiting sodium intake to both prevent and manage heart failure, the evidence behind such recommendations is unclear. Our review article highlights evidence and underlying mechanisms favoring and contradicting limiting sodium intake in heart failure. Salt is an ionic compound made up of cation and anion. Edible salt consists of 40% sodium and 60% chloride by weight. Salt was historically used as a preservative since bacteria cannot flourish in the presence of high salt concentrations. Human cells require approximately 0.5 g/day of sodium to maintain vital functions. Most food preservatives have high sodium content and are major causes of increased dietary intake of sodium. The average sodium intake in most Americans is 3.4 g/day or 1.5 teaspoons of salt, which is greater than the physiological requirement for the human body. High sodium or salt intake can lead to chronic comorbidities including hypertension, heart failure (HF), chronic kidney disease, stroke, cardiovascular diseases, and increase mortality. Hence, current guidelines recommend restricting sodium consumption to 2–3 g/day [HF is a major burden of morbidity and mortality on the health care system and is classified into two major groups, heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Treatment of HFrEF involves both pharmacologic and non-pharmacologic strategies, while mainly heart rate and blood pressure control strategies are used in HFpEF since multiple clinical trials have not shown significant benefits of pharmacologic therapy . Sodium A low sodium diet is recommended in most national and international guidelines, as described in Systemic hypertension is one of the main risk factors for the development of HF. The lifetime risk of HF decreases with adequate treatment of blood pressure. Data from meta-analysis suggest a dose–response relationship between salt intake and increased blood pressure . In a po(TNF)-alpha, interleukin (IL)-1B and IL-6, chemokine (monocytes chemoattractant protein-1 and IL-8), as well as enhanced expression of adhesion molecules. Moderate sodium restriction (up to 2.8 g/d) was associated with reduced values of neurohormonal (B-type natriuretic peptide (BNP), aldosterone, plasma renin activity) and cytokine levels  and increased levels of anti-inflammatory cytokine (IL-10) over 12 months of follow up compared to low sodium restriction (up to 1.8 g/d) [1.8 g/d) . A recen1.8 g/d) . Similar1.8 g/d) . Adheren1.8 g/d) .p = 0.02) [In a randomized clinical trial, Aliti et al. studied the effect of the intervention of <2 g/d of salt intake in patients admitted with acute decompensated HFrEF with EF ≤ 45% on HF clinical congestion score compared to a control group with >2 g/d of salt intake . On 30 d = 0.02) . Similar = 0.02) . In a la = 0.02) . Subject = 0.02) .In animal models, sodium restriction in early stages of HF was seen to be associated with early aldosterone activation compared to normal or excess sodium intake . These fMHC) protein is formed of α and β filaments. Changes in the proportion of these protein filaments are associated with cardiac mechanical performance. A high sodium diet is associated with an increase in cardiac expression of β-MHC and a decrease in the α/β-MHC ratio [α/β-MHC ratio, which in turn improves myocardial mechanical performance [MEF) 2/nuclear factor of activated T cell (NFAT) transcriptional activity, and thereby increasing the expression of MHC genes [β-MHC gene with simultaneous downregulation of the α-MHC gene [MEF2/NFAT and genes associated with left ventricular hypertrophy [The myosin heavy chain , phospholamban (PLB), SERCA2a, Na+/Ca2+ exchanger (NCX), and ryanodine receptors (RYR). A high sodium diet is also associated with reduced expression of both PLB and NCX. Ca2+ handling is important to maintain myocardial performance. The LTCC plays an important role in action potential during systole. Once Ca2+ enters the myocardial cell, it activates RYR, which in turn triggers Ca2+ release from the sarcoplasmic reticulum. This increase in Ca2+ release is responsible for the activation of myocardial contraction during systole. During diastole, the opposite mechanism happens; Ca2+ is pumped back from the cytosol to the sarcoplasmic reticulum by SERCA2a and sarcolemmal NCX-1, which mediates regulation of Ca2+ and Na+ exchange and thereby maintains excitation–contraction coupling. Altered Ca2+ handing is an important pathophysiological mechanism by which preclinical HF develops. Salt restriction has been shown to be associated with decreased LTCC protein levels in the left ventricle, increased PLB expression, and reduced NCX levels. Combined, these mechanisms together decreases sarcoplasmic reticulum Ca2+ overload by having an inhibitory effect on SRCA2a activity, and thereby is associated with a decrease in the contractility index [There are five main proteins that are involved with calcium homeostasis and myocardial contractility—ty index ,54,55.Low-sodium diet recommendations not only apply to hospitalized patients but also to ambulatory patients to prevent acute worsening of symptoms. However, the evidence behind these recommendations is not conclusive. Alvelos et al. reported that in patients with chronic HFrEF with Ejection Fraction (EF) ≤40%, sodium restriction was not associated with improvement in NYHA functional class during 15-day follow-up . Colin-R2 [2. It also appears that sodium restriction is more beneficial for patients with advanced heart failure symptoms. Amongst 302 patients with HF, greater than 3 g/d dietary sodium intake was found to be associated with a hazard ratio of 2.54 (95% CI 1.10–5.84) for cardiac event-free survival in patients with NYHA III/IV HF symptoms compared to a hazard ratio of 0.44 (95% CI 0.20–0.97) in patients with NYHA I/II HF symptoms [Recent meta-analyses of randomized control trials of treatment of hypertension reveal that the older population, non-white population, and only study groups with blood pressure in the highest 25th percentile show a clinically significant drop in blood pressure with a low sodium diet ,63. The 2 . Such efsymptoms . These dsymptoms . Interessymptoms . They fosymptoms . The autResearch has shown that low serum sodium value (hyponatremia) is seen in about 20% of hospitalized patients with acute HF . Serum sThere are multiple clinical trials that aim to examine if sodium restriction in HF patients is associated with improved clinical outcomes. The Study of Dietary Intervention under 100 MMOL in Heart Failure (SODIUM-HF) is an open-label, multicenter, international, randomized controlled trial in ambulatory patients with chronic HF and aims to assess the effects of dietary sodium restriction on clinical outcomes . The GerThere are likely many potential reasons for conflicting evidence regarding the benefit/harm of sodium restriction. These include heterogeneity of HF patient population studied, lack of uniformity in limiting the amount of sodium restriction per day, unclear data on associated use of fluid restriction, and simultaneous usage of diuretics and neurohormonal blockade agents. Given there is clear evidence of the benefit of limiting sodium intake to prevent various comorbidities leading to HF, we recommend limiting sodium intake in those who are at risk to develop comorbidities to prevent the onset of heart failure. In patients with HF, we recommend to continue limiting sodium intake to prevent morbidity associated with HF. We also recommend avoiding too much limitation in sodium intake as this has been associated with worse outcomes in HF patients.The data supporting the restriction of dietary sodium intake in heart failure patients are unclear. While there appears to be a trend in reducing HF symptoms amongst patients using dietary sodium restriction, there appears to be no effect or slightly higher risk in mortality compared to no sodium restriction. A randomized control trial is hence needed to address this important clinical question.


Advanced chronic kidney disease often results in adverse cardiovascular outcomes and is the leading cause of mortality in patients with end stage renal diseases (ESRD). There is much information about the effect of chronic kidney diseases (CKD) on the left ventricle (LV) chamber, but the right ventricle (RV) as a neglected chamber had not been evaluated precisely, in spite of its importance.The aim of this study was to evaluate the impact of successful kidney transplants on the RV systolic and diastolic function using the advanced method of 2D speckle tracking echocardiography and comparison with the conventional methods.The study included 48 patients with CKD who were eligible for kidney transplantation and underwent successful kidney transplantations. Right ventricular indices were evaluated, while RV function was focused by conventional methods and 2D speckle tracking echocardiography before the successful kidney transplant and 1 week, 1 month, and 3 months after the successful kidney transplant.P = 0.024, P < 0.001 respectively). It also represented that kidney transplantation did not have significant effect on the RV mid cavity diameter, tissue velocity, Myocardial performance index, RV longitudinal diameter, and Tricuspid annular plane systolic excursion indices, but for other indices this effect was significant. On the differences between the mean slope of regression line of the GLS variable in hypertensive subjects (1.0 ± 0.2) and non-hypertensive subjects (0.36 ± 0.32), an independent t-test showed that between the two groups in terms of the improvement of RVGLS, there was a significant statistical difference (P = 0.0067).The results of the study showed that RV global longitudinal strain and RV free wall longitudinal strain improved over the time (Most of the ESRD patients had subtle RV dysfunction which could be better detected by recent echocardiography methods than conventional methods. Moreover, kidney transplantation led to considerable improvements in RV function in this population. Accounting for 40% of deaths in international registries, cardiac disease is the main cause of death in dialysis patients . It is dKidney transplant in comparison to dialysis lessens morbidity and mortality , applyinEchocardiography is a tool for the noninvasive assessment of hemodynamic parameters and the evaluation of cardiac chamber size and function of the heart. Recently, speckle tracking echocardiography (STE) has been considered as an advanced method that can evaluate subtle myocardium diseases.Data about the effect of CKD on the LV chamber are extensive, but the RV as a neglected chamber is not evaluated precisely, in spite of its importance. Two-dimensional STE has been validated as a promising tool for the evaluation of RV systolic function in several clinical settings .The aim of the present study was to evaluate the effect of kidney transplant on the heart using two-dimensional speckle tracking echocardiography and conventional methods, focusing on the RV size and function.Having an intricate anatomic structure, the RV is divided into two parts including the inflow and outflow tracts which are separated by crista supraventricularis.The form and motion pattern of the RV are intricate and there are problems with defining these endocardial surface of the thin RV free wall, so echocardiographic imaging of RV and measuring the ejection fraction have been tricky. The changeable loading conditions factor is regarded as the other important issue complicating the interpretation of RV function. Traditionally, RV function has been qualitatively assessed by 2D echocardiography.The systolic contraction of RV lateral wall leads to about 27% longitudinal shortening, while the base descends forward the peak which is pretty stationary , 7. Besi2 + RA pressure, where V is the peak velocity (in meters per seconds) of tricuspid valve regurgitant jet, and RA pressure is estimated from IVC diameter and respiratory changes  [The RV fractional area change usually applied as a measure of RV function can be considered as an area-based measure of RV function being calculated from a four-chamber view . A generressure)  (Table 1The Tissue Doppler imaging (TDI) measurement of displacement can give a similar measure. Global RV strain is the mean peak systolic strain from the three RV lateral wall segments , 12. BeiA condensed global RV strain expected worse prognosis in numerous diseases having an effect on the right ventricle such as CKD; therefore, the current study was an attempt to demonstrate that kidney transplant could cause reverse remolding of RV which may be insignificant and invaluable by conventional tools of measurement but may be more obvious and significant by 2D speckle tracking echocardiography.The current study was a longitudinal, prospective one being performed to evaluate echocardiography findings of 48 patients including 28 males (58.3%) and 20 females (41.7%) with ESRD undergoing living-donor kidney transplantation in four steps  at Shahid Modarres Hospital, Tehran, Iran, from January 2017 to January 2018. All the patients were in a stable condition and were carefully reviewed by a committee to be eligible for kidney transplantation after evaluating risks and benefits. Basic and demographic data of the participants according to their gender were summarized in Table All the recipients received a standard protocol with the post-transplant medical regimen including tacrolimus, mycophenolate mofetil, and prednisolone.Among these 48 ESRD cases, regard to type of replacement therapy before transplantation, some of them were pre-emptive kidney transplantation   and 2D echocardiographic imaging using an S4 transducer.We acquired the apical RV view to measure different indices of RV size and function, and then the off-line analysis of recorded images was done using CMQ Q-lab 9 . Images were obtained with the patient in the left lateral decubitus position.An experienced echocardiographer obtained all the images using the standard protocol. Then, one of the researchers, who were blind to the clinical data of the patients and study, analyzed the data and we requested another expert echocardiographer to analyze the strain imaging offline  intra-observer and inter-observer variability were assessed for strain analysis which were 0.92(0.90–0.94) and 0.90(0.87–0.93) respectively.The goal of the current study was to evaluate the RV function using different indices and especially by 2D STE. We measured the LV size, LVEDV,LV CO, and LVEF and also LA volume and indexed them base on Body Surface Area in 2D and assessed the LV diastolic function by TDI according to Lang et al.  and summtricuspid annular systolic velocity (s′) was measured in the apical 4-chamber view though tissue Doppler imaging. The isovolumic acceleration of the RV was computed as the peak isovolumic myocardial velocity divided by the time to peak velocity, evaluated by tissue Doppler imaging at the lateral tricuspid annulus. The RV Fractional Area Change was calculated by this formula RVFAC = (RV diastolic area–RV systolic area)/RV diastolic area  ×  100%. The RV diastolic and systolic areas were acquired from the apical 4-chamber view.  The right ventricular index of myocardial performance (RIMP) was the isovolumic time divided by the ejecting time, which was evaluated in the same pulsed. The isovolumic time was computed by subtracting the ejecting time from the tricuspid closure time. All findings were summarized in Table We evaluated the RV function by TAPSE, FAC, S velocity, MPI all according to Rudski et al. as explain here: M-mode was employed to assess the TAPSE. The M-mode cursor was placed through the lateral side of the tricuspid annulus in such a way that the position of annulus, changed along with the cursor. The systolic displacement of annular was assessed from end-diastole to end-systole. The The strain analysis was done on an offline basis Fig. . GeneralThe echocardiographic findings were gathered and analyzed in a blind fashion.Myocardial strain imaging is a sensitive echocardiographic technique for identifying ventricular dysfunctions .The measurement of myocardial strain by two-dimensional (2D) speckle tracking echocardiography (STE) has been demonstrated to be a feasible and sensitive quantitative technique for assessing left ventricular (LV) function for a variety of different cardiac diseases .Several studies have revealed that RV longitudinal systolic strain measurements by STE may be a valuable method for assessing the RV function because it can provide prognostic data and is more reliable than conventional parameters –21.Currently, a wide agreement regarding normal values is lacking and it seemed that it depends on the kind of machine and vendors as we can see in different articles .According to Fine et al., the mean RV strain was − 26 ± 4% and the estimate of RV free wall strain measured using tissue Doppler imaging was − 27 ± 1% and with STE was − 27 ± 2% in subjects with normal echocardiograms and without cardiopulmonary disease or risk factors .Continuous demographic and clinical data was demonstrated as mean and SD, and classified data was demonstrated as frequency and percentage. Chi-square test or Fisher’s exact test were used to investigate the independency of the two categorical variables. To check the normality of the data, the Kolmogorov-Smirnov test was performed. The change shape in RV global longitudinal strain and RV free wall longitudinal strain versus time during the four measurements was tested using the fractional polynomial regression method. To estimate the regression line slope of main variables i.e. RV global longitudinal strain and RV free wall longitudinal strain, the data was reshaped from wide to long. After that, regression line slope was calculated by Stata, using 4 recorded measurements for each case. The Fracpoly model was also used to determine the type of relationship between the main variable and outcome. This model was used due to the continuous nature of mentioned variables, as well as the disadvantages of converting continuous to categorical data. Also, a General Linear Model (GLM), repeated measurement-Analysis of Variance (ANOVA) procedure was used to compare the changes occurring in structural and functional RV indices before and 1 week, 1 month and 3 months after successful kidney transplant. The assumption of sphericity of this analysis was performed using Mauchly’s Test of Sphericity. Since the assumption of sphericity had been violated for any of the above three variables, in this analysis, the comparisons were performed using the Greenhouse-Geisser test. The significance level in all tests was considered 0.05. Data analysis was performed using stata MP13.This study was performed on 48 kidney transplant recipients including 28 men (58.3%) and 20 women (41.7%) with mean age of 43.3 ± 13.9 years. Of the whole participants in the study, 11 patients (22.9%) had diabetes, 31 patients (64.6%) had hypertension, and 4 patients (8.3%) were smokers. In terms of types of dialysis, 6 patients (12.5%) were categorized in pre-emptive kidney transplantation, 37 patients (77.1%) were treated with hemodialysis, and 5 patients had peritoneal dialysis. Moreover, in this study, kidney transplant rejection occurred in none of the participants under study. Other demographic and clinical data are reported in the following table.Table P = 0.024, P < 0.001 respectively). This relationship is shown in Fig. The results of the above table showed there was no statistically significant difference between the women and men participating in the study regarding all the basic demographic and clinical variables except for the status of smoking and serum calcium levels. The results of the study on the shape of RV global longitudinal strain and RV free wall longitudinal strain changes, using the fractional polynomial models, showed that the form of the relationship was linear and they improved significantly over the time (Table P > 0.05). The results also depicted that a weak and non-significant negative correlation was observed between the age of the subjects in the study and RV global longitudinal strain (P = 0.24). On the differences between the mean slope of regression line of the GLS variable in hypertensive subjects (1.0 ± 0.2) and non-hypertensive subjects (0.36 ± 0.32), an independent t-test showed that between the two groups in terms of the improvement of RVGLS, there was a significant statistical difference (P = 0.0067) . Figure The results demonstrated that there was no statistically significant difference between the dialyzed and the non-dialyzed participants before the transplant in terms of the slope of the estimated regression line of RV global longitudinal strain (P = 0.35) P < 0.001) and RV global strain  and in PAP  from baseline to 1 and 3 months following the kidney transplant. Also, it was found out RV diameter at the base  and major and minor RA diameter and RA volume index decreased significantly (p < 0.001) after the successful kidney transplant.In this study, we sought to investigate whether kidney transplant could improve the RV function to be evaluated by the noninvasive method of 2D speckle tracking echocardiography and conventional methods such as TAPSE and RV FAC. In this prospective study, the results showed that there was a significant improvement in RV free wall ; it could be due to low volume cases and short follow-ups.We also evaluated RV diastolic function by diastolic indices. There was no significant improvement in E/e’ and RV deceleration time after transplantation .Third, although there were multiple ultrasound platforms available, we only evaluated all data by only one vendor and platform (Philips IE33). According to Il’Giovine et al. , differeFourth, the normal range can be subjective because there are no established cutoffs for such studies.Sometimes, the impaired RV myocardial function in ESDR patients cannot be detected by conventional methods but can be detected by more sensitive newer methods such as 2D speckle tracking echocardiography. Additionally, it was depicted that successful kidney transplantation could improve RV function regardless of other risk factors except for hypertension and immunosuppressive regime.Consequently, it is reemphasized that kidney transplantation is the treatment choice for ESRD patients who are eligible for that.


Furthermore, E/e’ nor E/A changed significantly between baseline and follow-up, respectively 8 (7–9) and 8 (7–9) p = 0.17 and 1.1 (±0.4) and 1.1 (±0.4) p = 0.94. Follow-up NT-proBNP decreased with 23%, from 89 ng/L (47–142) to 69 ng/L (42–155), p = 0.10. Regression analysis revealed no association between change in inflammatory variables and cardiac function. Echocardiography showed no effect of anti-TNF treatment on the cardiac function in RA patients with low prevalence of cardiac dysfunction. Moreover, NT-proBNP decreased, possibly indicating (subtle) improvement of the cardiac function.Congestive heart failure (CHF) is the second most prevalent cause of death in rheumatoid arthritis (RA). The systemic inflammatory state in RA patients is deemed responsible for this finding. Anti-inflammatory treatment with anti-tumor necrosis factor (anti-TNF) therapy decreases CV risk and subsequently might improve the cardiac function by lowering the overall inflammatory state. This study investigated the effect of anti-TNF on the cardiac function in RA patients. Fifty one RA patients were included, of which thirty three completed follow-up. Included patients were >18 years, had moderate–high disease activity and no history of cardiac disease. Patients were assessed at baseline and after six months of anti-TNF treatment. Patients underwent conventional Speckle tracking and tissue Doppler echocardiography in combination with clinical and laboratory assessments at baseline and follow-up. The left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) showed no changes during follow-up, LVEF 63% (±9) to 62% (±8)  Patients with rheumatoid arthritis (RA) have a 1.5-fold increased risk of cardiovascular (CV) mortality . The sysSeveral studies have shown that anti-inflammatory treatment with anti-TNF therapy decreases the CV risk in RA ,14,15. IHowever, previous studies assessing the effect of anti-TNF on the cardiac function have shown conflicting results ,18. FirsThis study aimed to elucidate the effect of anti-inflammatory therapy, i.e., anti-TNF, on the systolic and diastolic cardiac function in RA patients assessed with comprehensive echocardiography  and cardiac biomarkers.Study population—a prospective study in fifty one RA patients was performed. Subjects were recruited randomly from a large rheumatology outpatient clinic (Reade) in Amsterdam, the Netherlands and Amsterdam UMC, Vrije Universiteit Amsterdam, department of Rheumatology, the Netherlands from December 2014 and June 2018. All participants gave written informed consent and the protocol (NL49652.048.14) was approved by the medical ethics committee of the Slotervaart hospital and Reade, Amsterdam, the Netherlands. Echocardiography and clinical and laboratory assessments were done at baseline and after 6 months of anti-TNF therapy. Inclusion criteria consisted of patients fulfilling the 1987 ACR criteria for RA , being aClinical assessment—disease activity was assessed by the disease activity score DAS28 . PhysicaEchocardiography—transthoracic echocardiography (TTE)—was performed by certified echo technicians at the European Society of Cardiology (ESC)-certified department of echocardiography of the Amsterdam University medical center, location VUmc, using a Philips ultrasound system . All echocardiographic recordings were stored digitally and were afterwards analyzed by an experienced cardiologist specialized in echocardiography (T.C.K.). TTE was performed according to the following protocol based on the guidelines provided by European Association of Echocardiography . AssessmIn addition, the modified H2FPEF score was used to calculate the a priori chance of the diastolic dysfunction in this cohort . The peaElectrocardiography (ECG)—ECGs performed were standard 12-lead ECGs, recorded at 25 mm/s paper speed. ECGs were analyzed by a single investigator (T.C.K.) whom was blinded to the clinical status of all the patients.Definitions—systolic LV dysfunction was defined as an LVEF <50%. Abnormal GLS was defined as >−17%. Diastolic function assessment was based on the ASE/EACVI 2016 guidelines  categorit-test was used. In case of non-normal distribution, the Wilcoxon signed-ranks test or log transformation was used. For comparisons of dichotomous variables between baseline and follow-up, the Pearson’s chi-square test was performed. Regression analysis was used to assess the possible effect of change in systemic inflammation on the cardiac function with the follow-up cardiac function parameter as a dependent variable adjusted for the baseline cardiac function parameter, the baseline inflammatory parameter and delta inflammatory parameter (absolute change of the inflammatory variable at follow-up). As inflammatory parameters, the DAS28, CRP and ESR were used. LVEF, GLS, E/e’, E/A and NT-proBNP were used as values for cardiac function.Statistical analysis—characteristics of the population are expressed as ±standard deviation (SD), median (interquartile range) (IQR) or percentages. For comparisons of paired continuous variables between baseline and follow-up with normal distribution, paired student’s p-values less than 0.05 were considered statistically significant.All analyses were done with SPSS version 23  and two-sided The sample size was based on the primary outcome, i.e., diastolic LV function as assessed with Doppler echocardiography and was calculated using the McNemar’s test for sample size estimation. With an expected improvement of 25% in diastolic LV function during anti-TNF therapy ,30 and aThe baseline characteristics are described in At baseline, three (7%) patients had diastolic LV dysfunction, of which two (4%) had diastolic dysfunction grade I, and one (2%) had diastolic LV dysfunction grade II. Importantly, two cases of diastolic dysfunction (grade I) was due to the presence of systolic dysfunction. None of the patients with diastolic dysfunction had hypertension nor diabetes mellitus (DM). In comparison, three of the thirty eight (8%) patients with normal diastolic function had hypertension and one (3%) had DM. Systolic LV dysfunction based on the ejection fraction was seen in two patients (4%). The GLS showed impaired systolic LV function in six patients (14%).A total of thirty seven ECGs were assessed of which three ECGs showed abnormalities. These were a left bundle branch block, a pathologic Q-wave  and a first degree atrioventricular block.p < 0.001. Furthermore, on average the patients mobility as scored with the HAQ improved from 1.3 (0.8–1.5) to 0.5 (0.0–1.3), p = 0.001. LVEF and GLS showed no change after 6 months of anti-TNF therapy, respectively 63.0% (±8.7) to 62.0% (±7.9), p = 0.097 and −19.8 (±3.5) to -19.9 (±2.6), p = 0.79. See A total of thirty three patients completed follow-up. Fourteen patients dropped out of which eight due to treatment failure (lack of efficacy), three participants withdrew out of the study and of two patients fell out of the follow-up date. DAS28 decreased significantly after six months anti-TNF therapy, from 4.44 (±1.23) to 2.72 (±1.23), p = 0.17 and 1.1 (±0.4) to 1.1 (±0.4), p = 0.94.From thirty of the thirty three patients with successful follow-up, it was possible to grade the diastolic function. Of these patients, twenty eight had normal diastolic function, one had diastolic dysfunction grade I and one diastolic dysfunction grade II. No patients had diastolic dysfunction grade III. Compared to the baseline, only in one case was the diastolic function changed from normal to grade I. Additionally, neither the E/e’ nor the E/A showed a significant change after six months of anti-TNF therapy, respectively 7.9 (6.6–9.0) to 7.7 (7.1–9.1), p = 0.10). Troponin-T did not show any change at follow-up, 6 (3–8) µg/mL to 7 (4–9) µg/mL, p = 0.43.NT-proBNP values decreased, although this did not reach statistical significance, with a reduction of 23% at follow-up compared to baseline, respectively 89 ng/L (47–142) to 69 ng/L  was compared with the other three quartiles, respectively E/e’>9 vs E/e’<9. Seven patients had an E/e’>9 at baseline who completed follow-up. In these patients, no echocardiographic parameters improved nor worsened after anti-TNF therapy .Regression analyses showed no association between changes in inflammatory parameters, i.e., DAS28 and ESR, and changes in cardiac parameters, i.e., E/e’, E/A, GLS and NT-proBNP, between baseline and follow-up.To our knowledge, this is the first and largest study investigating the effect of first line anti-TNF therapy on the cardiac function in a Western RA cohort assessed with comprehensive echocardiography  in combination with cardiac biomarkers. In contrast to what was expected, the echocardiographic results did not show improvement but importantly also showed no worsening of the cardiac function. Moreover, this study found a 23% decrease of NT-proBNP after six months of anti-TNF therapy, although this did not reach statistical significance.Overall, diastolic function categorized in grades changed in only one case. The E/e’-ratio, a robust marker for predicting LV filling pressures and indirectly diastolic (dys)function , also diSecond, this population had a relatively short disease duration and a relatively low disease activity compared to other studies, demonstrating an increased prevalence of cardiac dysfunction in RA patients compared to healthy subjects ,38. In aInterestingly, studies assessing the effect of biologic agents with modes of action other than TNF-blockade show more evident ameliorating effects on the cardiac function. Several studies conducted by Ikonimidos et al. investigating the effect of anti-interleukin (IL)-1 therapy (anakinra) showed a significant improvement in cardiac function assessed with echocardiography ,42,43. SA major strength of this study is the comprehensive and prospective approach in the assessment of cardiac function with the use of conventional Doppler and Speckle tracking echocardiography in combination with cardiac biomarkers. Therefore, this study was able to determine the different outcomes assessing the cardiac function. The main limitation of this study was, as the prevalence of cardiac dysfunction was unexpectedly low, the rather limited sample size.In conclusion, echocardiography showed no improvement nor deterioration of anti-TNF treatment on the cardiac function in RA patients with a low prevalence of cardiac dysfunction. However, NT-proBNP decreased 23% after anti-TNF treatment, which might suggest subtle improvement of the cardiac function.


Quantification of extracellular volume (ECV) fraction by cardiovascular magnetic resonance (CMR) has emerged as a noninvasive diagnostic tool to assess myocardial fibrosis. Secreted frizzled-related protein 2 (SFRP2) appears to play an important role in cardiac fibrosis. We aimed to evaluate the association between SFRP2 and myocardial fibrosis and the prognostic value of ECV fraction in patients with heart failure (HF).  In this prospective cohort study, 72 hospitalized adult patients (age ≥ 18 years) with severe decompensated HF were included. CMR measurements and T1 mapping were performed to calculate ECV fraction. Serum SFRP2 level was detected by an enzyme-linked immunosorbent assay kit. All patients were followed up, and the primary outcomes were composite events including all-cause mortality and HF hospitalization. r = 0.33), high-sensitivity C-reactive protein (r = 0.31), and hemoglobin A1c (r = 0.29) were associated with ECV fraction ; however, in multivariate linear regression analysis, SFRP2 was the only significant factor determined for ECV fraction . In multivariate Cox regression analysis, age  1.13, 95% confidence interval (CI) 1.04–1.22), ECV fraction , and NT-proBNP  were independent risk factors for primary outcomes.  During the median follow-up of 12 months, 27 (37.5%) patients experienced primary outcome events and had higher levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), SFRP2, and ECV fraction compared with those without events. In Pearson correlation analysis, levels of SFRP2 ( Higher ECV fraction is associated with worsened prognosis in HF. SFRP2 is an independent biomarker for myocardial fibrosis. Further studies are needed to explore the potential therapeutic value of SFRP2 in myocardial fibrosis. Heart failure (HF) is a growing global public health burden . It is eThe wingless (Wnt) signaling pathway plays an important role in cardiac fibrosis . A classIn this study, we investigated the association between SFRP2 and myocardial fibrosis, as measured with CMR, among patients with advanced HF. We also explored the possibility that ECV fraction and SFRP2 could serve as new biomarkers for prognosis in HF.In this prospective cohort study, hospitalized adult patients age ≥ 18 years) with severe decompensated HF and New York Heart Association (NYHA) functional class III–IV were screened from January 2019 to January 2020. Decompensated HF was defined as new-onset HF or decompensation of chronic HF resulting in hospitalization and requiring treatment with intravenous diuretics, inotropic agents, or vasodilators [ years wi2 or under renal replacement therapy), active bleeding or severe anemia (Hb < 60 g/L), autoimmune disease, or severe hepatic disease  were excluded.Patients with contraindications to CMR (pacemaker or claustrophobia), acute myocardial infarction (MI), sepsis, history of malignancy, severe renal failure (estimated glomerular filtration rate (eGFR) < 30 mL/min/ 1.73 mAll patients were treated in accordance with the principles recommended by the Chinese guidelines on HF . The stuC) ≥ 6.5% [Baseline characteristics including age, sex, smoking status, history of hypertension, diabetes mellitus (DM), cardiovascular disease, admission blood pressure (BP), heart rate, electrocardiogram, biochemistry tests, medicine, cardiac functional class, and echocardiographic parameters were collected from the hospital medical records. Hypertension was defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, according to the current Chinese guidelines for the management of hypertension . DM was ) ≥ 6.5% . The eGF) ≥ 6.5% . Based o) ≥ 6.5% . Body mag and 4°C for 15 min; serum was obtained and stored at −80°C until analysis. We used an enzyme-linked immunosorbent assay kit  to detect the levels of SFRP2, in accordance with the manufacturer's protocol. The intra-assay and interassay variations were 7.5% and 9.4%, respectively.Fasting venous blood was collected and subjected to centrifugation at 1500 × 2, matrix size 256 × 144, and flip angle 35°).All the patients were scheduled for CMR examination when stabilized (without significant congestive symptom and sign) after treatment. CMR measurements and T1 mapping were performed by two experienced CMR radiologists. All patients were examined in the supine position using a 3.0 T scanner . Briefly, after localization of the heart, to assess left ventricular (LV) and right ventricular (RV) myocardial function and mass, 10–12 consecutive short-axis images and 2-, 3-, and 4-chamber long-axis images of the LV were acquired using a steady-state free precession (SSFP) sequence. Then, midventricular short-axis modified Look-Locker inversion recovery (MOLLI) images were acquired for T1 determination using an 11-image, 18-heartbeat 3-(3)-3-(3)-5 SSFP sequence. A total dose of 0.1 mmol/kg gadobutrol  was injected at a rate of 2.0–3.0 mL/s; 10–15 min after contrast injection, short- and long-axis 2D inversion recovery late gadolinium enhancement images were acquired to evaluate focal myocardial fibrosis. Finally, 15 min postcontrast, MOLLI T1 mapping was repeated in a protocol identical to that used for precontrast T1 mapping  in the myocardium  and in the LV blood pool. We took special care to avoid partial-volume effects from neighboring tissues or blood pool when delineating the ROI. The following formula was used to calculate ECV fraction , in whicPatients were followed by review of the electronic medical record and/or telephone interview with the participants (or their family members if deceased). The primary outcomes were defined as composite endpoints of all-cause death or HF rehospitalization, which was defined as rehospitalization with HF as the primary cause and requirement for treatment with intravenous inotropes, vasodilators, or diuretics .t-test for normally distributed continuous variables, and Wilcoxon rank-sum test for nonnormally distributed continuous variables.All HF patients were categorized as with or without primary events during follow-up. Continuous variables are presented as mean and standard deviation (SD) or median and interquartile range. Categorical variables are presented as number and percentage. Baseline characteristics of patients with or without primary events were compared using the chi-squared test for categorical variables, two-tailed 2-transformed. The Pearson product-moment correlation coefficient (r) was calculated as a measure of linear association between covariates and ECV fraction. Multivariate linear regression analysis was performed to identify factors associated with levels of ECV fraction. Multicollinearity was evaluated by calculating the variance inflation factor (VIF), with a VIF > 2.5 suggesting the presence of multicollinearity [Non-Gaussian data, including N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, LVEF, eGFR, high-sensitivity C-reactive protein (hs-CRP) level, ECV fraction, and SFRP2 level were loginearity .P value < 0.10 in univariable associations were included in the multivariable model. Proportionality assumptions for the Cox regression models were evaluated by log-log survival curves with the use of Schoenfeld residuals.Receiver operating characteristic (ROC) curves were used to identify the potential relationships among ECV fraction, SFRP2 and NT-proBNP levels, and the primary outcomes. Patients were divided into the higher ECV fraction group, higher SFRP2 level group, higher NT-proBNP level group, and control group, according to their median levels, respectively. Kaplan–Meier curves were employed to evaluate the study endpoints over time, and the log-rank test was used to assess differences in outcomes between different marker groups. Predictors of outcome were analyzed through univariate and multivariate Cox regression analyses. Those risk factors with a P values were two-tailed, and values of P < 0.05 were considered statistically significant.Statistical analyses were performed using SAS Enterprise Guide version 7.1 . All Of the 93 patients who were screened, 21 were excluded due to predefined exclusion criteria. Among the remaining 72 patients who were included in the analysis , 49 werer = 0.33, P = 0.02), hs-CRP , and HbA1c  . The R2 value of SFRP2 for ECV fraction was 0.093, which indicated that 9.3% of the total ECV fraction variation can be attributed to the SFRP2 level. Multicollinearity was excluded because the VIF was 1.00.Pearson product-moment correlation analysis showed that the clinical variables associated with ECV fraction, in decreasing order of strength of association, were as follows: SFRP2 (= 0.047) . HoweverP < 0.001), NT-proBNP , and SFRP2  had predictive effects on the primary outcomes. Comparisons between AUCs showed that there were no significant differences among the three markers in ROC (P > 0.05).During a mean follow-up period of 12.2 months (interquartile 9.6–13.8 months), 27 (37.5%) patients in the cohort experienced the composite primary outcome, comprising 4 (5.6%) all-cause deaths and 23 (31.9%) HF hospitalizations. ROC analysis showed that levels of ECV fraction (area under the curve (AUC) 0.72, 95% confidence interval (CI) 0.60–0.82; P = 0.046) and NT-proBNP (log-rank test: P = 0.009) were significant predictors of primary outcomes. However, the association was not significant in the higher SFRP2 group (log-rank test: P = 0.19)  . In mult = 0.19) .This is the first study to report that serum SFRP2, an important Wnt signaling pathway modulator, is an independent marker of myocardial fibrosis. We also found that a higher ECV fraction was associated with worse prognosis in patients with severe HF, after adjusting for other risk factors.The ECV fraction of T1 mapping is a noninvasive indicator of myocardial fibrosis that is highly coincident with myocardial biopsy results , 27. TheSfrp2-null mice compared with wild-type mice [β-dependent Wnt secretion [We found it interesting that SFRP2 was significantly positively associated with the level of ECV fraction. Animal studies that focused on the effect of SFRP2 on myocardial fibrosis produced highly inconsistent results. Kobayashi et al. reported that collagen deposition was inhibited after MI in genetically modified ype mice . An antiype mice . In contype mice , 12. Furecretion . Similarecretion . In our ecretion . Therefoecretion  and inhiecretion –34. FurtIt is well documented that diabetes is an important risk factor associated with myocardial fibrosis. In linear correlation analysis, we also found that HbA1c was positively associated with ECV fraction, consistent with previous studies , 28, 35.ECV fraction was significantly associated with the prognosis in patients with advanced HF. SFRP2 is a novel biomarker of myocardial fibrosis in HF, as measured by ECV fraction. Further studies are needed to explore the potential therapeutic value of SFRP2 in the prevention or treatment of myocardial fibrosis.


This study aimed to compare the engagement in moderate- and vigorous-intensity PA in axSpA patients with and without current physical therapy (PT).In this cross-sectional study, a survey, including current PT treatment (yes/no) and PA, using the ‘Short QUestionnaire to ASsess Health-enhancing PA’ (SQUASH), was sent to 458 axSpA patients from three Dutch hospitals. From the SQUASH, the proportions meeting aerobic PA recommendations  were calculated. To investigate the association between PT treatment and meeting the PA recommendations, odds ratios (OR) with 95% confidence intervals (95% CI) were estimated using logistic regression models, adjusting for sex, age, health status and hospital.The questionnaire was completed by 200 patients, of whom 68%, 50% and 82% met the moderate-, vigorous- or combined-intensity PA recommendations, respectively. Ninety-nine patients (50%) had PT treatment, and those patients were more likely to meet the moderate- (OR 2.09 [95% CI 1.09–3.99]) or combined-intensity (OR 3.35 [95% CI 1.38–8.13]) PA recommendations, but not the vigorous-intensity PA recommendation (OR 1.53 [95% CI 0.80–2.93]). Aerobic exercise was executed in 19% of individual PT programs.AxSpA patients with PT were more likely to meet the moderate- and combined-intensity PA recommendations, whereas there was no difference in meeting the vigorous-intensity PA recommendation. Irrespective of having PT treatment, recommendations for vigorous-intensity PA are met by only half of the patients. Implementation should thus focus on aerobic PA in patients without PT and on vigorous-intensity PA in PT programs. Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease, with back pain and stiffness as main symptoms and encompassing both non-radiographic and radiographic axSpA (ankylosing spondylitis) , 2. The This raises the question to what extent people with axSpA are actually engaged in aerobic PA, either or not with vigorous intensity. A previous study reported that evidence on PA engagement of people with axSpA is limited and heterogeneous in nature . NeverthAnother limitation of previous studies on aerobic PA among people with axSpA, besides not distinguishing between moderate- and vigorous-intensity PA and between leisure time and work-related aerobic PA, is that none of the studies so far took the role of physical therapy (PT) into account. This is striking as relatively many axSpA patients have PT treatment  and it iTo implement aerobic PA recommendations in people with axSpA, it is important to know what the focus of implementation activities should be, both in patients with and without PT treatment. Due to the physical limitations for which axSpA patients seek PT treatment, it is not necessarily expected that patients with PT are more inclined to meet the aerobic PA recommendations. Moreover, PT programs may not include (advice on) aerobic PA . Given tThis cross-sectional, multicenter study consisted of a once-only survey among people with axSpA living in the southwestern region of the Netherlands. In this survey, participants were asked whether they had either individual or group PT treatment, to compare PA of patients with and without any guidance from a physical therapist. In the Netherlands, PT for people with axSpA can both be offered on an individual basis or by means of axSpA-specific supervised group exercise. This group exercise usually consists of weekly land- and water based exercises supervised by a physical therapist and is organized by local patient associations for people with a rheumatic disease . The stuIn 2015, registers of three hospitals in the southwestern region of the Netherlands  were screened for patients with a confirmed diagnosis of axSpA who had ever visited the rheumatology outpatient clinic. The survey was sent by postal mail to eligible patients, including an invitation letter on behalf of their treating rheumatologist, an information leaflet, an informed consent form and a pre-stamped envelope. No reminders were sent.Demographic and clinical characteristics: sex, age, year of diagnosis and use of medication related to axSpA (painkillers (acetaminophen or opioid painkillers); Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), biological Disease-Modifying Antirheumatic Drugs (DMARDs); synthetic DMARDs; no medication related to axSpA).Health status, using the Assessment of Spondyloarthritis International Society Health Index (ASASHI), which is a valid, reliable and responsive questionnaire measuring functioning, health and disease impact in people with axSpA , 37. Thecurrent PT; yes/no) or ever in the past (yes/no). Moreover, it was asked whether they were or had been treated individually in a practice (yes/no) and/or in a group with axSpA-specific group exercise therapy (yes/no). Furthermore, for individual PT, the duration , frequency  and contents (15 treatment options) of PT treatment were recorded. These 15 treatment options were clustered according to the four groups of treatment modalities as described in the national physical therapists’ professional profile developed by the Royal Dutch Society of Physical Therapy [PT treatment, by asking whether they had PT treatment, either at the time the study was conducted  , 40. TheThe survey was self-developed and first pilot-tested by patient representatives affiliated with the Dutch Arthritis Society. It measured the following variables:The returned questionnaires were scanned and analyzed by Cardiff® Software  and manually checked and corrected afterwards. Descriptive statistics were used to describe patient characteristics, the proportions meeting the aerobic PA recommendations and the engaged types of leisure time and non-leisure time aerobic PA. This was done for the total group of participants and for patients with and without PT guidance separately. Results were reported as percentages or medians with minimum (Min) and maximum (Max) values, where appropriate.To investigate the differences in characteristics between patients with and without PT, the median test for independent samples was used for continuous data and Pearson’s chi-square test for categorical data. In addition, six logistic regression models were estimated with meeting the moderate, vigorous or combined-intensity PA recommendations, both during all daily activities and during leisure time, as the dependent variables and current PT treatment  as independent variable. To control for confounding, sex, age, health status and hospitals were included in the models as independent variables. All statistical analyzes were performed with IBM SPSS Statistics for Windows, version 23.0 .n = 3) or invalid (n = 3).The questionnaire was sent to 458 axSpA patients of whom 206 returned it (response rate 45%). Six of them were excluded because the SQUASH data were either missing  had ever had PT. The differences between patients with and without current PT regarding the meeting of aerobic PA recommendations are shown in Fig. Figure This study found that people with axSpA who were having PT treatment were more likely to meet the moderate- and combined-intensity aerobic PA recommendations than those without PT, whereas there were no differences in meeting the vigorous-intensity PA recommendation. Irrespective of current PT treatment, the proportion of participants meeting the vigorous-intensity PA recommendation was relatively low and often not attained with leisure time activities.The finding that having PT treatment was associated with meeting aerobic PA recommendations was not necessarily expected, because PT programs may not include aerobic PA and those who need PT treatment are expected to have more physical limitations and may thus be less physically active. In our study, PT treatment was related to more aerobic PA, but this did not pertain to vigorous-intensity PA. Given the cross-sectional design of the study, it remains unclear whether the association between PT and aerobic PA is a result of PT treatment or that axSpA patients who are already relatively active are more inclined to seek PT treatment. Either way, the findings show that specifically axSpA patients without PT should be better educated on the benefits of aerobic PA. It is recently recommended that all health professionals in rheumatology should promote aerobic PA , but espThe finding that particularly vigorous-intensity PA was performed insufficiently by relatively many axSpA patients is consistent with previous findings –24. SimiAn important note when implementing vigorous-intensity PA is that caution is needed with sedentary individuals and people with an increased risk of cardiovascular complications during exercise , 43, 44.Regarding the types of actual activities, about half of the participants did not engage in any vigorous-intensity PA during leisure time at all. Studies reporting on the superiority of leisure time PA suggest that possible explanations for the greater benefits of leisure time PA are the difference in nature of activities and the presence of more opportunities to rest and recover when needed , 29. TheOverall, the proportion of patients meeting the WHO PA recommendation in the current study was much higher than in previous studies, namely 82% as opposed to around 50% in previous studies , 23, 25.This study has a number of limitations. First, because of the cross-sectional study design, no conclusions can be drawn about any causal relationships between having PT and aerobic PA. Second, and as already addressed, using a self-report questionnaire the amount of PA might have been overestimated . AnotherIn conclusion, axSpA patients with PT were more likely to meet the moderate- and combined-intensity but not the vigorous-intensity aerobic PA recommendations than those without PT. These findings imply first of all that in axSpA patients without PT, aerobic PA must be promoted. Second, as vigorous-intensity PA appears insufficiently implemented among those with PT, additional education of physical therapists regarding the importance of and requirements for vigorous-intensity exercise as an essential element of PT programs for axSpA patients seems warranted. With the education of physical therapists, it should be noted that only 19% of patients with PT reported executing aerobic exercise as part of their PT treatment. This may indicate that there is a window of opportunity for physical therapists to increase patients’ engagement with vigorous-intensity PA. Future research should thus focus on interventions to optimize aerobic PA in axSpA patients without PT and on the implementation of vigorous-intensity exercise in PT programs.


Acoustic cardiography can provide simultaneous electrocardiography and acoustic cardiac data to assess the electronic and mechanical heart functions. The aim of this study was to assess whether changes in acoustic cardiographic parameters (ACPs) before and after hemodialysis (HD) are associated with overall and cardiovascular (CV) mortality in HD patients. A total of 162 HD patients was enrolled and ACPs were measured before and after HD, including left ventricular systolic time (LVST), systolic dysfunction index (SDI), third (S3) and fourth (S4) heart sounds, and electromechanical activation time (EMAT). During a follow-up of 2.9 years, 25 deaths occurred with 16 from CV causes. Multivariate analysis showed that high △SDI , high △EMAT , and low △LVST  were independently associated with increased overall mortality. In addition, high △EMAT , and low △LVST  were associated with increased CV mortality. In conclusion, the changes in ACPs before and after HD may be a useful clinical marker and stronger prognostic marker of overall and CV mortality than ACPs before HD. Cardiac structural and functional abnormalities are also known to increase the risk of CV disease4, and therefore identifying these risk factors in these patients as early as possible is crucial. Patients with ESRD have a high prevalence of LV dysfunction, which has been associated with an increased risk of sudden death in ESRD patients7. Cardiac function is most commonly evaluated using echocardiography, however the accuracy of echocardiography is operator-dependent and time consuming.The incidence and prevalence of end-stage renal disease (ESRD) are increasing worldwide. Cardiovascular (CV) disease is common in patients with ESRD, including coronary artery disease, left ventricular (LV) hypertrophy, heart failure and arrhythmias8. Acoustic cardiographic parameters (ACPs) include the measurement of heart sounds and systolic time intervals. Previous studies have demonstrated the use of acoustic cardiography to non-invasively detect increased LV filling pressure and LV systolic dysfunction10. In addition, it has also been used to detect LV hypertrophy, ischemic heart disease, ventricular fibrillation, heart failure, constrictive pericarditis and sleep apnea8.Acoustic cardiography can provide simultaneous information on both electrocardiography and acoustic cardiac data to assess the electronic and mechanical functions of the heart11. However, whether changes in ACPs before and after HD (△ACPs) can be used as a prognosis marker remains to be determined. Therefore, the aim of this study was to assess whether △ACPs before and after HD are associated with overall and CV mortality in HD patients.Our recent study investigated ACPs in hemodialysis (HD) patients before and after HD, and found that the fourth heart sound (S4) and LV systolic time (LVST) were decreased and electromechanical activation time (EMAT) was increased after HDThe mean age of the included 162 HD patients was 60.4 ± 10.9 years. The clinical characteristics of the survivor and non-survivor groups are shown in Table Table p = 0.002), low △PR interval , high △SDI , high EMAT , high △EMAT , low LVST , and low △LVST  were independently associated with increased overall mortality.The median follow-up period was 2.9 (range 2.4–3.4) years for all patients, during which 25 patients died (15.4%), including CV death (n = 16), malignancy (n = 3), infectious disease (n = 3), and others (n = 3). Table p = 0.015).The adjusted Cox regression survival curves  for overall survival in the patients according to the 75th percentile of △EMAT 1%) are shown in Fig. % are shop = 0.015).The adjusted Cox regression survival curves for overall survival in the patients according to the 75th percentile of △LVST (9 ms) are shown in Fig. p = 0.012), high △EMAT , low LVST , and low △LVST  were significantly associated with increased CV mortality.There were 16 documented CV deaths during follow-up, including heart failure (n = 7), myocardial infarction (n = 3), ventricular fibrillation n = 4) and hemorrhagic stroke (n = 2). Table  and hemoTo the best of our knowledge, this is the first study to report associations between changes in ACP before and after HD with overall and CV mortality. Our results showed that high △heart rate, low △PR interval, high △SDI, high EMAT, high △EMAT, low △LVST, and low △LVST were significantly associated with increased overall mortality. In addition, low △PR interval, high △EMAT, low LVST and low △LVST were significantly associated with increased CV mortality.12. Previous studies have shown a strong association between EMAT and impaired LV contractility, and that EMAT increases steadily with age in patients with heart failure14. EMAT has also been shown to be a useful prognostic marker of CV outcomes. In a study of hospitalized patients with congestive heart failure, Zhang et al. found that elevated EMAT measured at admission was an independent risk factor for major adverse CV events15. In patients with acute heart failure syndrome, Chao et al. reported that EMAT could predict CV outcomes independently of LV ejection fraction, LV diastolic function, and serum N-terminal pro-brain natriuretic peptide16. In addition, Sung et al. reported that a high %EMAT or S3 strength may indicate an increased risk of de-compensation and mortality in patients with heart failure, and that intensifying diuretic and/or vasodilator therapy may alleviate potential adverse events17. But why did the EMAT increase after HD in our study? The potential mechanism may be insufficient coronary perfusion and cause resulting heart ischemia and impaired heart systolic function. Furthermore, there may be a stenosis lesion on coronary artery, so the coronary perfusion is susceptible to volume depletion (decrease in effective circulating volume) by ultrafiltration. In patients with elevated EMAT after HD, this may contribute to higher cardiovascular risk. In the present study, △EMAT was a stronger predictor of adverse outcomes than EMAT before HD. Therefore, dynamic changes in EMAT before and after HD may reflect impaired LV contractility more accurately than resting APCs before HD.The first important finding of this study is that high △EMAT before and after HD was associated with increased overall and CV mortality. EMAT is defined as the amount of time required for the left ventricle to generate sufficient force to close the mitral valve, and therefore reflects the velocity of force generation during systole18. Patients with LV systolic dysfunction often have a shorter LVST as more time is required to generate sufficient force to open the aortic valve and keep it open in situations with impaired ventricular contraction19. Zuber et al. also showed that patients with an LV ejection fraction < 50% had a higher prevalence of S3, lower mean LVST, and higher mean EMAT and EMAT/LVST. The authors concluded that these parameters can improve detection of LV systolic dysfunction20. In addition, in patients with intermediate brain natriuretic peptide levels (100 to 500 pg/mL), Shapiro et al. showed that EMAT/LVST could detect LV dysfunction with a high specificity (95%) and moderate sensitivity (55%) and improve the detection of LV dysfunction21. In the present study, we found that low △LVST was associated with increased overall and CV mortality, and that this was a stronger predictor of adverse outcomes than LVST before HD.The second important finding of this study is that low △LVST before and after HD was associated with increased overall and CV mortality. In 1970, Garrard et al. reported a significant correlation between LVST and angiographically determined LV ejection fraction and left ventricular end-diastolic volume22. Dillier et al. reported that both SDI (≥ 5) and S3 (4) score were strong independent predictors of mortality and could identify high-risk patients requiring more aggressive monitoring and therapy23. In the present study, we found that high △SDI was associated with higher overall mortality, and that it was a stronger predictor of adverse outcomes than SDI before HD.Another important finding of this study is that high △SDI before and after HD was correlated with increased overall mortality. In patients with heart failure, previous studies have shown that SDI can discriminate patients with severe LV systolic dysfunction (ejection fraction [EF] ≤ 35%) from those with moderate LV systolic dysfunction (35% < EF < 50%) with an SDI > 525. The autonomic system controls heart rate and rhythm via a balance between parasympathetic and sympathetic systems26. A previous study reported that HD patients are characterized by vagal withdrawal and sympathetic overactivity, and that this was linked to a poor CV prognosis27. In addition, Barnas et al. investigated hemodynamic patterns during dialysis hypotension, and demonstrated that tachycardia induced by ultrafiltration is part of the spectrum of normal CV autonomic activation. The authors concluded that tachycardia develops by increasing baroreflex-mediated sympathetic activity24. Rogovoy et al. investigated sudden cardiac death in ESRD patients using continuous electrocardiography monitoring, and found that sudden increases in heart rate during or after dialysis preceded non-sustained ventricular tachycardia events26. In addition, Severi et al. reported a significant increase (11%) in heart rate following changes in calcium, potassium and pH, without significant changes in autonomic activity indices25.In this study, the patients with an increased heart rate after HD had higher overall mortality. The reason for an increase in heart rate after HD is not fully understood, but it may be related to progressive volume depletion by ultrafiltration, sympatho-activation and changes in electrolyte levels28. Skampardoni et al. published a review of patients with chronic kidney disease or dialysis, and showed varying results of the association between PR interval prolongation and CV outcomes and overall mortality29. Moreover, Flueckiger et al. reported an association between prolonged PR interval and increased mortality30, while Kestenbaum et al. reported that a longer PR interval could not independently predict incident CV events or mortality31. In addition, Silva et al. reported that prolonged PR interval could predict bradyarrhythmias32. Regarding the difference between PR intervals before and after HD, Badarau et al. reported that an increased PR interval after HD was associated with lower rates of CV events and mortality33. During dialysis, changes in electrolyte levels, fluid shift and autonomic response may influence the PR interval29. In the present study, the patients who had low △PR interval before and after HD were associated with increased overall and CV mortality. Therefore, further studies are needed to investigate the significance and prognostic value of decreased PR interval after dialysis.Studies on the association between PR interval and mortality have reported inconsistent results. Magnani et al. conducted a prospective cohort study with 2722 older participants (age 70–79 years), and multivariable-adjusted analyses showed that every SD increase (29 ms) in baseline PR interval was associated with 13% increases in the 10-year risk of both incident atrial fibrillation and heart failure. However, they did not find an association between PR interval and all-cause mortalityThere are several limitations to this study. First, because relatively few patients died, the statistical power of the study was reduced. Further studies with a larger sample size should be performed to verify our findings. In addition, the quality of acoustic cardiography data is influenced by exogenous and endogenous noises. Finally, the ACPs were measured only before and after HD, and repeated measurements may be necessary.In conclusion, we demonstrated that high △SDI, high △EMAT and low △LVST were independently associated with increased overall mortality. In addition, high △EMAT and low △LVST were significantly associated with increased CV mortality. Changes in ACP before and after HD (△ACP) may be a useful clinical marker and stronger prognostic marker of overall and CV mortality than ACPs before HD. Acoustic cardiography is a non-invasive cost-effective technique to screen dialysis patients who are at high risk of adverse clinical outcomes.Written informed consent was obtained from each participant in accordance with institutional requirements and the principles of the Declaration of Helsinki. Moreover, the current study was approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20160071).This study was conducted at the dialysis unit of a regional hospital in southern Taiwan from October 2016 to April 2018, and enrolled 162 patients  receiving HD treatment three times a week. Each HD session lasted for 3.5 to 4 h. The dialyzer blood flow rates ranged from 250 to 300 mL/min with a dialysate flow rate of 500 mL/min. The study protocol was approved by the Institutional Review Board of Kaohsiung Medical University Hospital, and informed consent was obtained from all of the enrolled patients.vs. never) and comorbid conditions of the patients were obtained from medical records and interviews. After overnight fasting, blood samples were obtained and biomarkers including triglycerides, hemoglobin, albumin, fasting glucose, uric acid, and total cholesterol, calcium, phosphorus, and potassium were measured. The efficiency of dialysis was determined by Kt/V according to the Daugirdas method34. All blood samples were obtained within 1 month of enrollment into the study.Age, sex, smoking status . EMAT was defined as the time required for the left ventricle to generate sufficient force to close the mitral valve.LVST: the time from S1 to the second heart sound (S2).The third heart sound (S3): the probability that S3 existed. A single value between 0 and 10 was reported, and the presence of S3 was defined as a value ≥ 5.S4: as with S3, a single value between 0 and 10 was reported, and the presence of S4 was defined as a value ≥ 5.Systolic dysfunction index (SDI): SDI was derived from the nonlinear transformation of [(S3 score ÷ 10) × QRS duration × QR interval × %EMAT] and mapped onto a scale of 0 to 10.Acoustic cardiographic examinations were performed in the supine position 30 min before and 30 min after a mid-weekly HD session. Acoustic cardiographic data including heart sounds and related systolic time intervals were analyzed using an AUDICOR system . The following ACPs were measuredCases of CV and overall mortality were verified from medical records by two cardiologists, with disagreements being resolved by a third cardiologist. Patients were followed until death or September 2020. Patients who did not die were censored at the end of follow-up.p value < 0.05 was considered to be statistically significant. Statistical analyses were performed using SPSS 19.0 for Windows .Data are expressed as percentages, mean ± standard deviation for ACPs, mean ± standard error of mean for △ACP, or median (25th–75th percentile) for triglycerides. The patients were divided into two groups as survivors and non-survivors. Between-group differences in categorical variables were assessed using the chi-square test. Approximately normally distributed continuous variables were analyzed using the independent t-test, and continuous variables with skewed distribution were analyzed using the Mann–Whitney U test. △ACP was defined as the difference between the ACP measurement before and after HD. Multivariable linear regression analysis was used to identify the determinants for △ACP. Multivariable Cox proportional hazard analysis was used to identify associations between an ACP before HD and △ACP and overall and CV mortality. Survival curves for overall and CV mortality were derived using Cox-regression analysis. A


Pain to balloon time could have significant error due to often imprecise pain onset time. We hypothesize that TnI level measured on admission could be easy monitored, independent predictor of infarct size and left ventricle functionThe purpose of the study was to evaluate which of the two factors better correlates with LV function and delayed enhancement volume after successfully treated first ST segment elevation myocardial infarction (STEMI).34 patients with first anterior STEMI who underwent successful primary PCI (TIMI III) were included into the study. Cardiovascular MRI was performed on 1.5 T scanner at discharge, using 32-channel cardiac coil. Viability was evaluated on contrast-enhanced images acquired with the use of an inversion-recovery segmented gradient-echo sequence 20 minutes after contrast injection. Infarct size and LV function were analyzed quantitatively on AW workstation using MASS software.Mean pain to balloon time was 3.8 ± 2.6 h (ranged between 1 do 14 h). Median TnI level on admission was 0.6 ng/ml (ranged between 0.0 and 25.55 ng/ml). Mean LVEF was 40.7% ± 10.9, scar size was 48 ml ± 23 or 31% ± 13.7 as a percent of LV volume. Linear regression analyses revealed mild correlation between pain to balloon time and LV EF  and low but statistically significant with infarct size as a % of LV volume . No correlation was found between TnI level on admission and infarct size or LVEF.Patients with longer pain to balloon time have worse LV EF at discharge.TnI level on admission could not be a predictor of infarct size or early ejection fraction.


While necroptosis has been shown to contribute to the pathogenesis of post-infarction heart failure (HF), the role of autophagy remains unclear. Likewise, linkage between these two cell death modalities has not been sufficiently investigated. HF was induced by 60-min left coronary occlusion in adult Wistar rats and heart function was assessed 6 weeks later followed by immunoblotting analysis of necroptotic and autophagic proteins in both the left (LV) and right ventricle (RV). HF had no effect on RIP1 and RIP3 expression. PhosphoSer229-RIP3, acting as a pro-necroptotic signal, was increased in LV while deceased in RV of failing hearts. Total MLKL was elevated in RV only. Decrease in pSer555-ULK1, increase in pSer473-Akt and no significant elevation in beclin-1 and LC3-II/I ratio indicated rather a lowered rate of autophagy in LV. No beclin-1 upregulation and decreased LC3 processing also suggested the inhibition of both autophagosome formation and maturation in RV of failing hearts. In contrast, p89 PARP1 fragment, a marker of executed apoptosis, was increased in RV only. This is the first study showing a different signaling in ventricles of the late phase of post-infarction HF, highlighting necroptosis itself rather than its linkage with autophagy in LV, and apoptosis in RV. Understanding the mechanisms of cell death in heart failure (HF) after myocardial infarction (MI) is of great clinical importance, since the extent of cellular loss significantly determines the degree of cardiac injury, contractile dysfunction, adverse remodeling and finally patient prognosis ,2,3. TheNecroptosis has been recognized as a necrosis-like programmed cell death mode . Its molAutophagy has been known as an adaptive catabolic process activated under stressful conditions . In diseBoth necroptosis and autophagy have been studied in post-ischemic HF as stand-alone cell death modalities ,7,29,30.Data obtained from LV catheterization of post-MI rats showed impaired cardiac systolic and diastolic function indicating the development of HF: developed pressure and rates of pressure development and decline were significantly reduced, and end-diastolic pressure was increased compared to Sham group. Lungs weight and heart weight normalized to body weight were significantly increased in HF group .A complex profile of proteins involved in the canonical signaling of necroptosis is depicted in Levels of some important positive  and negative (Akt-mTOR axis) regulators of autophagy (including their activated forms and substrates) are depicted in Regarding another part of autophagy regulation, expression of Akt, upstream of mTOR , was uncTo assess cell death in the ventricles of failing hearts in a more complex view, we also analyzed some well-established markers of apoptosis. Interestingly, despite being unchanged in its zymogen form, significantly increased levels of cleaved caspase-8 were observed solely in the RV of failing hearts B,C. In sIn recent years, knowledge on necroptosis has advanced and a practically unknown process has become a well-established pathophysiological factor contributing to myocardial damage in various types of HF ,9,10,30.Regarding the relevance of other cell death modalities in late stage of HF, it is still unclear whether autophagy represents the salvage pathway  or ratheFrom aforementioned discussion it can be observed that there have been certain discrepancies in ULK1 regulation by AMPK and mTOR. The first irregularity is the lack of congruence between pSer2448-mTOR, an upstream inhibitor of autophagy through ULK1 Ser757 phosphorylation, and pSer757-ULK1 both in the RV and LV. Possibly, either pSer2448-mTOR does not always reflect mTOR activity ,46,47, oBoth necroptosis and autophagy could regulate each other in an upstream-downstream manner. In fact, in some cells, including H9c2 cardiomyocytes, necroptosis has been shown to act as an inhibitor of autophagic flux by “throwing a wrench” into the interaction of autophagosomes with lysosomes  or by inRecent studies reported a reduced ,7 or unaAdult male Hannover Sprague-Dawley rats  were housed in groups of 3–4 animals under standard conditions in a room with a constant 12 h:12 h light/dark cycle (lights on 6:00) and a temperature of 22 °C. Animals were fed with a standard pelleted diet and tap water ad libitum.Rats were randomly assigned into two groups: a group subjected to myocardial infarction with subsequent development of heart failure and a group which underwent a sham procedure (Sham).Protocol of the study  has been approved by the Ethics Committee of the Faculty of Pharmacy, Comenius University . All desi.p.) myocardial infarction was induced by 60-min ligation of the left coronary artery 1–2 mm distal to the left atrial appendage. In our hands, this procedure inducing irreversible ischemia affects around 40% of LV myocardium in Sprague-Dawley rats [n = 6) underwent chest surgery without the occlusion. After the release of the suture and chest closure, all spontaneously breathing animals were allowed to recover from anesthesia in separate cages and were given analgesia  for 3 days. Mortality of rats with MI was 40%. At the end of a 6-week period, the animals were subjected to invasive cardiac function assessment and thereafter sacrificed by exsanguination under anesthesia (n = 9), it was first separated the fibrotic infarcted zone from the remote/non-infarcted zone of the LV which was taken for analyses. In our recent studies using similar protocols, the mean infarcted zone occupied between 30% and 40% of failing LV midwall circumference [In anesthetized open-chest animals  placed on a heating pad keeping the animal core temperature at 37 ± 0.5 °C were subjected to the LV catheterization through the right carotid artery using the SPR-407 microtip pressure transducer. Data were acquired using MPVS 300 system  connected to PowerLab 8/30 . End-diastolic pressure, developed pressure, peak rates of pressure development and decline and heart rate were averaged from 3 measurements each comprising 5 consecutive cardiac cycles.Necroptosis and autophagy were analyzed in both LV and RV separately according to the Guidelines for evaluating myocardial cell death  and a qun) of animals in the group. Two-way ANOVA (2WA) coupled with a post-hoc test (Sidak’s multiple comparisons test) were applied for the comparison of differences in variables with normal distribution among 4 groups with the two 2WA factors being “ventricle” (LV-RV) and “heart failure” (Sham-HF). Differences between two groups were compared with an unpaired t-test. All analyses were performed with GraphPad Prism  and differences between groups were considered significant when p < 0.05.The data and statistical analysis comply with the recommendations on experimental design and analysis . Data anIn conclusion, the LV of failing hearts, where myocardium suffered a significant damage by MI, displayed increased pro-necroptotic environment as represented by upregulation of pSer229-RIP3  and suppDespite novel information about three major signaling pathways associated with death of cardiac cells in both ventricles of failing hearts, we are aware of some limitations of our study. Firstly, the study is mainly of a descriptive character, lacking some pharmacological interventions and/or genetic modulations specifically targeting key signaling events of the investigated pathways. Secondly, the presented statements rely mostly on the results of extensive protein analysis of signaling molecules. A more detailed insight into key events such as RIP3-MLKL interaction and translocation within cellular membranes and/or autophagosome formation would be supportive for these findings. Likewise, additional analyses—e.g., (immune)histological assessment of the extent of the heart injury as well as a participation of certain infiltrating cells—could provide further insights into the proposed relationship between necroptosis and autophagy and pathomechanisms of a late phase of post-infarction of heart failure. Lastly, our data are attached only to one timepoint of HF, while it develops through various stages over the long time course. Therefore, another set of experiments, with the investigation of hearts from different HF stages  would be desirable in order to fully understand relevance of the investigated mechanisms and their interconnection in disease progression.