Aim: The effect of sacubitril-valsartan (ARNI) in heart failure (HF) patients with mid-range ejection fractions (HFmrEF) remains unclear. This study aimed to investigate the effects of ARNI in HFmrEF patients.Methods: From inception to 15 February 2022, articles were searched via PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Whip, and Wanfang databases. Left ventricular functions, indicators related to HF, quality of life score, 6-Minute Walk Test, total effective rate, mortality, readmission rate, and adverse events were the outcomes. Relative risk (RR), weighted mean difference (WMD), and 95% confidence interval (CI) were used to evaluate the outcomes. The heterogeneity test was conducted for each indicator and measured by I2 statistics. Subgroup analysis was performed regarding the type of study and duration of treatment.Results: Sixteen studies involving 1,937 patients were included in this study. Our results showed ARNI was likely to improve left ventricular function by increasing the left ventricular ejection fraction (LVEF) , stroke volume , and left ventricular short-axis shortening rate , decreasing left ventricular end-diastolic dimension , left atrial diameter , C-reactive protein level , and N-terminal-pro B-type natriuretic peptide level . ARNI has a higher total effective rate , Kansas City cardiomyopathy questionnaire , and 6-Minute Walk Test  compared with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). In addition, ARNI decreased the readmission rate  . Nevertheless, there were no significant differences in the adverse outcomes.Conclusion: This meta-analysis suggests ARNI may be an effective strategy with which to improve the left ventricular function, and quality of life, and reduce the readmission rate in HFmrEF patients. However, long-term clinical studies with large samples are still needed to further explore the efficacy and safety of ARNI compared with ACEI or ARB in the HFmrEF population. Heart failure (HF) is a clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood . HF withSubstantial evidence has indicated that angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) could improve the partially attenuate left ventricular (LV) dilation and remodeling in HF, however, the morbidity and mortality of HF patients remain unacceptably high . In receHerein, we performed a meta-analysis to evaluate the potential clinical benefits and safety of ARNI in HFmrEF patients in which ARNI was compared with ACEI/ARB drugs.This meta-analysis was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines without registry.Databases including PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Whip, and Wanfang were searched without any restrictions from inception to 15 February 2022. The search strategy from the PubMed consisted of the following keywords: “Sacubitril Valsartan’’ OR “sacubitril and valsartan sodium hydrate drug combination’’ OR “sacubitril valsartan sodium hydrate’’ OR “sacubitril-valsartan sodium hydrate drug combination’’ OR “trisodium (3-(1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-3′-methyl-2′-(pentanoyl(2′-(tetrazol-5-ylate)biphenyl-4′-ylmethyl)amino)butyrate) hemipentahydrate’’ OR “sacubitril and valsartan drug combination’’ OR “sacubitril valsartan drug combination’’ OR “sacubitril-valsartan OR 3-(1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate-3′-methyl-2′-(pentanoyl(2′-(tetrazol-5-ylate)biphenyl-4′-ylmethyl)amino) butyrate’’ OR “sacubitril and valsartan sodium anhydrous drug combination’’ OR “sacubitril valsartan sodium anhydrous’’ OR “sacubitril-valsartan sodium anhydrous drug combination’’ OR “LCZ 696’’ OR “LCZ696’’ OR “LCZ-696’’ OR “Entresto’’ AND “Heart failure’’ OR Cardiac Failure’’ OR “Heart Decompensation’’ OR “Decompensation, Heart’’ OR “Heart Failure, Right-Sided’’ OR “Heart Failure, Right Sided’’ OR “Right-Sided Heart Failure’’ OR “Right Sided Heart Failure’’ OR “Myocardial Failure’’ OR “Congestive Heart Failure’’ OR “Heart Failure’’, Congestive OR “Heart Failure, Left-Sided’’ OR “Heart Failure, Left Sided’’ OR “Left-Sided Heart Failure’’ OR “Left Sided Heart Failure’’ OR “Heart failure with mid-range ejection fraction’’ OR “HFmrEF’’ OR “HFmEF’’.Inclusion criteria based on the PICOS principles were: 1) Populations: Patients diagnosed with HFmrEF; 2) intervention: ARNI as the observation group; 3) comparators: ACEI or ARB as the control group; 4) outcomes: left ventricular function, indicators related to HF, quality of life score, 6-Minute Walk Test (6-MWT), total effective rate, mortality, readmission rate, and adverse events; 5) study design: Randomized controlled trials (RCTs) or cohort studies 6) studies published in English and Chinese.The exclusion criteria were as follows: 1) animal experiments; 2) case reports, meta-analyses, reviews, and letters.Two investigators (Jianbin Qin and Weijian Wang) initially screened studies based on abstracts and reviewed the full text according to eligibility criteria. The final qualification for inclusion depended on the agreement between the two reviewers. Any differences should be resolved through consultation with the third reviewer (Ping Wei). The following data were extracted from each included study: basic characteristics of studies , characteristics of patients , ARNI and ACEI/ARB treatments (dosage and duration of treatment), outcomes, and quality score of include studies.For cohort studies, the quality of the literature was evaluated using the modified Newcastle-Ottawa criteria scale (NOS) . The totAccording to ESC guidelines, the diagnostic criteria for HFmrEF in this study was a LVEF of 40–49% .The primary outcomes were left ventricular functions including left ventricular ejection fraction (LVEF), left ventricular end diastolic dimension (LVEDD), left ventricular end-systolic diameter (LVESD), diastolic ventricular septal thickness (DVST), left atrial diameter (LAD), stroke volume (SV), left ventricular short axis shortening rate (FS), C-reactive protein (CRP) level. The second outcomes were 1) indicators related to HF including N-terminal-pro brain natriuretic peptide (NT-proBNP), soluble suppression of tumorigenesis-2 (sST2), growth differentiation factor-15 (GDF-15); 2) quality of life score including Minnesota heart failure scale score (MHFQL), and The Kansas city cardiomyopathy Questionnaire (KCCQ); 3) 6-MWT; 4) total effective rate; 5) mortality including 1-year mortality, and cardiac death; 6) readmission rate; 7) adverse events including HF worsen, malignant arrhythmia, renal function deterioration, hyperkalemia, hypotension, angioedema, serum creatinine (SCr) level. LVEF was calculated as end-diastolic minus end-systolic volume divided by end-diastolic volume . The nor2 tests for heterogeneity. When the heterogeneity statistic I2 ≥ 50%, random-effects model analysis was performed, otherwise, fixed-effects model analysis was applied. p < 0.05 was considered statistically significant. When the difference was statistically significant and I2 ≥ 50%, subgroup analysis was performed regarding the type of study and duration of treatment. Sensitivity analysis was performed for all outcomes. Begg’s test was examined to evaluate the potential for publication bias. When publication bias occurred, the “cut-and-fill method” was adopted to adjust publication bias. Software Stata 15.1  was used for statistical analysis.Relative risk (RR) was used as an effect indicator for categorical data. Continuous data were analyzed by calculating weighted mean difference (WMD), and the effect size was expressed by 95% confidence intervals (CIs). Heterogeneity of effects across trials was evaluated by IA total of 5,408 studies were identified in the initial literature search. By removing duplicates, 3,287 articles were retrieved. After screening for titles and abstracts, 34 articles were left. Finally, 16 studies  were inc2 = 95.6%, therefore, the random effect model was used. The result demonstrated that LVEF levels were significantly improved in patients with HFmrEF in the ARNI group   (p = 0.91). According to the duration of treatment subgroup analysis, there was no difference in LVEF between the two groups at 1 and 3 months of treatment (p > 0.05). At 6 and 12 months of treatment, the LVEF level of the ARNI group was higher than that of the control group, with the WMD being 4.53  in 6 months, and being 5.31  in 12 months, respectively  . Subgrou< 0.001) . Howeverectively .p < 0.001)  (p > 0.05). At 3 , 6  and 12 months of treatment , LVEDD in the ARNI group was lower than that in the control group  . Subgrou< 0.001) . In termol group .p = 0.85)  .2 = 99%, WMD: −2.03, 95%CI: −4.39 to 0.33, p = 0.091). However, according to the study type analysis, DVST was lower in the ARNI group than ACEI or ARB group.   .2 = 21.8%, WMD: −2.23, 95%CI: −2.83 to −1.63, p < 0.001) (Five studies investigate LAD between ARNI and ACEI or ARB treatment. ARNI showed a greater decrease in LAD (I< 0.001) .p < 0.001).2 = 95.9%, so the random effect model was used for analysis. The result demonstrated that FS after ARNI treatment was higher than ACEI or ARB treatment   .p = 0.024).A study p < 0.001)  or cohort study , patients treated by ARNI had lower NT-proBNP (p > 0.05) after 1 month of treatment. At 3 , 6  and 12 months  of treatment, nT-proBNP in the ARNI group was lower than that in the control group  . Based oT-proBNP . Accordiol group .p = 0.037)  .p = 0.879).p = 0.058)  .p < 0.001)  .2 = 5.1%, WMD: 51.35, 95%CI: 26.99 to 75.71, p < 0.001) (Three articles were included to assess 6-MWT. The fixed-effect model results showed that the treatment of ARNI significantly increased 6-MWT in HF patients with HFmrEF (I< 0.001) .2 = 0.0%, so fixed-effect model was used. The total effective rate of ARNI was higher than that of ACEI or ARB   .p = 0.230), with the 1-year mortality rate being 0.09 in the ARNI group and 0.18 in the ACEI or ARB group . The incidence of cardiac death was 0.04 after the ARNI treatment and 0.06 in the ACEI or ARB treatment   .A study by A clinical study  evaluatip = 0.151)  .p = 0.31)  .2 = 92.4%, WMD: −0.62, 95%CI: −21.05 to 19.81, p = 0.953)  .p = 0.460), LVEDD , NT-proBNP , readmission rate  did not have publication bias.Sensitivity analysis was performed through sequentially excluded individual studies to assess the stability of the results. The sensitivity analysis result demonstrated that our findings are trustworthy. Begg’s test was used to evaluate the publication bias for outcomes with ≥9 articles. According to the results, LVEF  and the ARB valsartan , is the From our study, there was no statistical difference in the incidence of adverse outcomes between the ARNI group and the ACEI/ARB group. Fröb et al. focused on the efficacy and safety of ARNI in an outpatient setting and found that ARNI improved LVEF, NT-probNP levels, and hospitalization rates, mostly without associated side effects . AlthougQuality of life is another key criterion to assess the treatment effect on HF patients. A previous study suggested that the proportion of patients with an improvement of 5 points in the KCCQ score was higher in the ARNI group , which iThe use of ARNI in cardiac devices treated patients has also been investigated. The study by Financial status may be particularly important given the high cost of the newer therapy ARNI approach; the high prevalence of geriatric diseases in elderly patients with HF, caregiver support may be particularly important in an era of the increasing complexity of pharmacologic regimens . In addiThere are several limitations to this meta-analysis. First, the results should be interpreted with caution given the limited number of included RCTs, and the small sample size. Second, due to the limitation of the included literature, we could not analyze the patients with a history of chronic diseases and drug history, which might have produced confounding bias for the evaluation. Third, in order to have a better understanding of the long-term benefit and potential side effects of ARNI on HFmrEF patients, longer duration studies are needed. Future RCTs with larger sample sizes and longer-duration are needed to confirm our findings.This study evaluated the effects of ARNI on HFmrEF patients compared with ACEI/ARB drugs, and found that ARNI may be an effective and safe strategy with which to improve the left ventricular function and quality of life, reduce readmission rate in HFmEF. In the future, more well-designed trials are needed to confirm these findings and investigate whether ARNI has a clear benefit in patients with HFmrEF.


In contrast, native T1-  and T2-values  were higher in AL. Considering particularities in myocardial density, “total extracellular mass” (TECM) was substantially higher in ATTRwt whereas “total intracellular mass” (TICM) was rather similar between ATTRwt and AL. Consequently, the “ratio TICM/TECM” was lower in ATTRwt compared to AL . Our data confirm the presence of a “native T1 vs. ECV paradox” with lower native T1 values in spite of higher myocardial mass and ECV in ATTRwt compared to AL. Importantly, this observation can be explained by particularities regarding myocardial density that result in a lower TICM/TECM “ratio” in case of ATTRwt compared to AL—since native T1 is determined by this ratio.Cardiovascular magnetic resonance (CMR) plays an important clinical role for diagnosis and therapy monitoring of cardiac amyloidosis (CA). Previous data suggested a lower native T1 value in spite of a higher LV mass and higher extracellular volume fraction (ECV) value in wild-type transthyretin amyloidosis (ATTRwt) compared to light-chain amyloidosis (AL)—resulting in the still unsolved “native T1 vs. ECV paradox” in CA. The purpose of this study was to address this paradox. The present study comprised N = 90 patients with ATTRwt and N = 30 patients with AL who underwent multi-parametric CMR studies prior to any specific treatment. The CMR protocol comprised cine- and late-gadolinium-enhancement (LGE)-imaging as well as T2-mapping and pre-/post-contrast T1-mapping allowing to measure myocardial ECV. Left ventricular ejection fraction (LV-EF), left ventricular mass index (LVMi) and left ventricular wall thickness (LVWT) were significantly higher in ATTRwt in comparison to AL. Indexed ECV (ECVi) was also higher in ATTRwt ( Deposition of amyloid fibrils in the myocardium leads to an infiltrative/restrictive cardiomyopathy. The most common forms of amyloidosis infiltrating the human heart  are (a) immunoglobulin light chain (AL)5. Moreover, the severity of cardiac involvement in amyloidosis can be assessed by measurement of LV wall thickness, LV mass and the degree of late gadolinium enhancement (LGE) in CMR8. In addition, CMR techniques such as LGE-imaging9, pre-/post-contrast T1-mapping with subsequent ECV calculation11 and feature tracking (FT) for strain analysis 12 allow to depict both the pattern and the extent of CA15.Cardiovascular magnetic resonance (CMR) is a robust diagnostic tool enabling detailed work-up of different cardiac diseases including LV hypertrophy of unknown origin. CMR was recently shown to offer a very high diagnostic yield regarding the diagnosis of cardiac ATTR and AL amyloidosis19. In the present study, we analysed multi-parametric CMR data of ATTRwt and AL patients in order to independently test and verify the presence of the “native T1 vs. ECV paradox” in cardiac amyloidosis. Moreover, we tried to find out an explanation for this “native T1 vs. ECV paradox” based on our comprehensive, multi-parametric CMR data and by considering particularities in myocardial tissue composition and density.Previous CMR studies addressing both ATTRwt and AL patients suggested a lower native T1 value in spite of a relatively higher LV mass and higher ECV value in ATTRwt compared to AL—resulting in the “native T1 vs. ECV paradox” in cardiac amyloidosis that is still unsolvedTo better understand our novel approach, we need to make us aware of LV mass calculations by CMR: they are based on a pre-specified “myocardial density” factor  and allow to calculate LV “mass” based on a contoured 3D volume of the LV. Importantly, this approach does not consider any potential differences in “myocardial density” or “gravity”, caused by e.g. the presence of specific cardiomyopathies (such as cardiac amyloidosis) … nor does it account for any differences in myocardial density between the intracellular vs. extracellular space of the myocardium. Considering the fact that amyloid fibrils accumulate in the “extracellular” space of the myocardium only, the undifferentiated use of the aforementioned myocardial density factor of “1.055 g/ml” for volume-based calculations of myocardial mass are neither appropriate nor acceptable. Therefore, we tried to address this issue by a different approach.In the present single-centre study, we carefully analysed the clinical, laboratory and CMR imaging data of 120 amyloidosis patients who were not treated with any disease specific therapy prior to our CMR study. All patients underwent comprehensive cardiac work-up including a multi-parametric CMR study and only patients with biopsy and/or bone scintigraphy-based proof of cardiac involvement were included. Cardiac biomarkers  as well as renal parameters  were obtained on the day of CMR at our specialised “cardiac amyloidosis unit” at the University Hospital Muenster, Germany.14. All patients with AL amyloidosis showed presence of elevated monoclonal proteins with elevated free light chains either in blood, urine or both. The other group of patients enrolled had either histologically proven ATTR and/or positive bone scintigraphy (in addition to positive CMR) in the absence of monoclonal gammopathy. A hereditary form of ATTR (ATTRv) was ruled out by genetic analysis and only patients with wild-type ATTR (ATTRwt) were included.All patients enrolled were assigned into two groups: (a) ATTRwt amyloidosis  and (b) AL amyloidosis  on the basis of established diagnostic algorithms Written informed consent was obtained from all the patients for the publication of any images or data included in this article. The study protocol is in accordance with the ethical guidelines of the 1975 Declaration of Helsinki and with the laws and regulations of Germany. The protocol was approved by the local ethics committee  of the University Hospital Muenster, Germany (ID 2019-437-f-S).The study protocol complies with the Declaration of Helsinki. Ethics approval was obtained from local authorities and written informed consent was obtained from the participants.20. Our CMR protocol comprised a cine steady-state free precession pulse sequence for ventricular function and a two-dimensional (2D) inversion recovery fast spoiled gradient-echo sequence 10-15 min after administration of a gadolinium-based contrast agent (Gadobutrol 0.15 mmol/kg) for detection of myocardial pathology as described earlier21. Image analysis and interpretation was performed using commercially available software . Analysis of ventricular volumes and function as well as LV mass was made by contouring short-axis cine images.CMR studies were performed on a 1.5-T system . CMR data acquisition was performed according to the standardized protocols21. Motion corrected native and post-contrast T1-maps were generated from the pre- and post-contrast T1-sequences. Motion corrected and segmented ECV maps were generated from the native and post-contrast segmented T1-maps, using the patient’s haematocrit level, measured on the same day as described by us elsewhere21. For T2-mapping, similar to T1 mapping, motion corrected but only native pre-contrast sequences were used. “Global” T1, T2 and ECV values were calculated by averaging all 16 segments from three short-axis slices.In addition, a modified Look-Locker inversion recovery (MOLLI) T1-mapping sequence was applied in basal, mid and apical short-axes prior to contrast agent administration and ~ 20 min thereafter to determine native T1 and ECV values as described previously22. Noteworthy, when calculating TICM, we used the well-known myocardial density value for humans of 1.055 g/ml. However, when calculating TECM, we used a different myocardial density value of 1.38 g/ml, since this value is expected to be more appropriate in case of extracellular “protein” accumulation—as is the case in an extracellular infiltrative disease such as cardiac amyloidosis23.In addition, (a) relative intracellular volume (ICV) was calculated with the formula ICV = [1–ECV]; (b) “total intracellular mass” (TICM) was calculated with the formula TICM = [ICV × total LV myocardial volume × myocardial density] and (c) “total extracellular mass” (TECM) with the formula TECM = [ECV × total LV myocardial volume × myocardial density] as described in previous works24. Landmarks for LV base  and apex were defined at end-diastole in all long-axis slices. Endocardial and epicardial borders were manually contoured in the end-diastolic frame in the three long-axis slices and in three short-axis slices, the most basal slice without through-plane distortion from the LV outflow tract, a mid-ventricular and an apical slice. Both the landmarks and the contours were automatically propagated throughout the cardiac cycle and manually corrected in case of inaccuracies. Subsequently, relative apical longitudinal strain (LS) was calculated based on the following equation: average apical LS / , as defined by Phelan et al.25.For the assessment of global LV deformation, three-dimensional (3D) LV global longitudinal strain (LV-GLS) derived from feature tracking (FT) was obtained using a validated algorithm integrated in the analysis softwareU test. Statistical analysis was performed with SPSS . A p-value < 0.05 was considered statistically significant. All figures were drawn by Prism Version 8 .As all data were non-normally distributed and therefore, non-parametric tests were used. Most variables are presented as medians and interquartile ranges (median ± interquartile range), few other parameters like ejection fraction (EF) and strain are expressed as change (%) from baseline (BL)—also mentioned in Tables p < 0.001) and gender distribution (p < 0.001) between the two groups. Body mass index (BMI) showed a marginal difference (p = 0.044) whereas other parameters like eGFR (p = 0.59) and clinical assessment of NYHA classification (p = 0.34) showed no significant differences between the two groups. Similarly, NT-proBNP serum values were elevated in both groups showing no substantial difference (p = 0.33).Details of clinical parameters as well as multi-parametric CMR findings are shown in Table p = 0.012; Fig. 2 vs. 75 ml/m2, p = 0.003] and LV-ESVi . Similarly, left ventricular mass (LVMi)  as illustrated in Fig. p = 0.64].3D-LV-GLS was reduced in both groups [− 8.0% in ATTRwt vs. − 7.2% in AL] without a statistically relevant difference . However, when LV mass was taken into consideration, indexed ECV values turned out to be substantially higher in ATTRwt compared to AL , with borderline significance . Consequently, the ratio [TICM/TECM] was significantly lower in case of ATTRwt when compared to AL  as well as TECM were substantially higher in ATTRwt compared to AL  The present data confirm the presence of the “native T1 vs. ECV paradox” in cardiac ATTR compared to AL, since a lower myocardial native T1-value was observed in ATTRwt patients—in spite of higher myocardial mass and higher global ECV-values—compared to AL patients. (2) A more detailed analysis of “intracellular” and “extracellular” myocardial mass revealed that total myocardial mass as well as “total extracellular mass” (TECM) were substantially higher in ATTRwt compared to AL, whereas “total intracellular mass” (TICM) was not significantly different between ATTRwt and AL. Consequently, the ratio [TICM/TECM]—which decisively determines the extent in change of native T1—was significantly lower in case of ATTRwt when compared to AL Fig. .Figure 417, the London group published several studies addressing the use of T1-mapping and ECV measurement  in patients with cardiac amyloidosis in the last years13. Based on this groups data regarding native T1 and LV mass in ATTR vs. AL, a "native T1 vs. ECV paradox" emerged in CA patients. Noteworthy, our present data are in line with the aforementioned CMR data from the London group and confirm the presence of the “native T1 vs. ECV paradox” in cardiac ATTR compared to AL: lower myocardial native T1 values were observed in ATTRwt—in spite of higher myocardial mass and higher global ECV values—compared to AL.As discussed in detail previouslyIn order to address this important question, we need to recapitulate some methodological aspects of CMR-based volume/mass quantification. “Volumetric” analyses in CMR are usually performed based on cine-CMR images by contouring of endocardial as well as epicardial LV myocardial borders. After receiving a 3D myocardial “volume” of the LV, the respective software uses a pre-specified “myocardial density” factor  in order to calculate LV “mass” based on the aforementioned 3D volume. Importantly, this approach does not consider any potential differences in “myocardial density”, caused by e.g. the presence of specific cardiomyopathies (such as cardiac amyloidosis) … nor does it account for any differences in myocardial density between the intracellular vs. extracellular space of the myocardium. Since amyloid fibrils accumulate in the “extracellular” space of the myocardium only, the undifferentiated use of the aforementioned myocardial density factor of “1.055 g/ml” for volume-based calculation of myocardial mass is not appropriate. Therefore, we tried to address this issue by a different approach …26. However, a detailed and convincing estimate of myocardial tissue composition based on pre-established laws for density, volume and compartment composition does already exist23. According to this model, the major three constituents that affect individual compartment/tissue density are a) proteins (+ solutes), b) water and c) fat—and of course their distribution and relationship. In case of a “normal” myocardial composition, the respective tissue density is around 1.053 g/ml according to this model—which is convincingly close to the aforementioned value of 1.055 g/ml that is known for human myocardium. However, if the percentage (concentration) of proteins (+ solutes) increases in this model (due to e.g. dehydration or due to e.g. amyloid deposition), then the respective compartment density also increases and approaches values of up to 1.40 g/ml. This substantial change in tissue density needs to be considered when we are approaching an “infiltrative” cardiac disease such as cardiac amyloidosis.First, we need to address the important issue of myocardial structure and the relationship between “composition” and “density”. Unfortunately, detailed data regarding the relationship between myocardial composition—with a specific focus on extracellular vs. intracellular compartments—and compartment-specific myocardial density are still missing (not only in case of cardiac amyloidosis)23.T1-mapping based measurement of global myocardial ECV allows to calculate the extent of myocardial ICV by the simple formula ICV = [1–ECV]. Importantly, the aforementioned calculation of the myocardial ECV proportion (and subsequent ICV proportion) is based on pre- and post-contrast T1-maps and therefore not dependent on volume- or mass-based analyses. Thereafter, we defined “total intracellular mass” (TICM) of the myocardium by the formula TICM = [ICV × total LV myocardial volume × myocardial density]. In this context, the parameter “total LV myocardial volume” was correctly derived from our volumetric short-axis cine-stack analysis. Similarly, “total extracellular mass” (TECM) was defined by the formula TECM = [ECV × total LV myocardial volume × myocardial density]. Such a detailed approach for analyzing TICM and TECM allowed us to further consider structural differences between the intra- vs. extracellular space based on the individual “myocardial density factor”. Taking into account some minor hypothetical inaccuracy, we supposed that structural changes in case of cardiac amyloidosis primarily take place in the extracellular space—but not in the intracellular space—since amyloid fibrils only accumulate in the extracellular compartment. Therefore, we used the well-known myocardial density value for humans of 1.055 g/ml when calculating TICM. In contrast, when calculating TECM, we used a different myocardial density value of 1.38 g/ml as a best estimate, since this value is expected to be more appropriate in case of extracellular “protein” accumulationUsing such a detached approach for quantification of TICM and TECM allowed us to subsequently calculate the ratio between TICM and TECM for ATTRwt and AL that turned out to be “lower” in case of ATTRwt compared to AL in spite of higher myocardial mass and higher global ECV values in ATTRwt. And since this ratio [TICM/TECM] is expected to decisively determine the extent in change of native T1, we may explain the “native T1 vs. ECV paradox” in cardiac amyloidosis  by the aforementioned lower ratio [TICM/TECM] in ATTRwt compared to AL. In other words, since amyloid deposits are particularly dense (and presumably denser than collagen-based fibrosis), a greater deposition in the extracellular compartment (supposed in case of ATTRwt due to higher TECM) is associated with a relatively lower increase in T1, since T1 is driven by the relative extent of TICM in comparison to TECM—if the extracellular free water content is relatively reduced by dense and insoluble amyloid deposits (whereas the intracellular free water content should rather stay untouched).27, but contradict recent data from Cuddy et al.27. Obviously, more extensive multi-center data are strongly required to better assess this important issue.From a simplified pathophysiological point-of-view, cardiac AL is different from cardiac ATTR and not only characterized by “extracellular” accumulation of (light-chain) amyloid fibrils, but also by toxic effects that are caused by those light-chains, subsequently leading to myocardial inflammation as well as intra- and extracellular edema (including myocyte swelling). Hence, in case of “active” cardiac AL, we expect a predominance of the aforementioned toxic effects in addition to extracellular light-chain accumulation. Consequently, these effects should also result in “increased” native T2 values in case of AL when compared to ATTRwt. Noteworthy, our present findings of increased myocardial T2 values in case of AL (compared to ATTRwt) are in line with previous data from the London groupToday, CMR does not only play an important clinical role for diagnosis of CA, but also for therapy monitoring since specific therapeutic options (being mostly highly expensive) are available today. Obviously, we need to (a) better understand the complex interplay between amyloid deposits in the extracellular myocardial space and subsequent changes in myocardial function … and (b) to better monitor such structural and functional changes—if possible at the cellular level. In this context, our present data illustrate that multi-parametric CMR does not only allow to accurately assess cardiac function in patients with CA, but also allows to accurately assess and monitor structural changes in the extracellular as well as intracellular compartment of these patients by considering disease-specific particularities regarding compartment-based “composition” and “density”. Such detailed information may play a decisive role when assessing the individual cardiac disease course and monitoring therapy response when approaching an “infiltrative” cardiac disease such as CA. Obviously, future studies addressing compartment-specific myocardial tissue densities are strongly required in order to better assess and understand this important issue.Obviously, the myocardial density factor of 1.38 g/ml that we used for calculation of TECM was not validated by any histopathological analyses within this study, since this was—unfortunately—technically not possible. This definitely needs to be done—if possible—within the scope of future studies. We discussed this issue in detail with our collaborating pathologists; unfortunately, an easy approach to determine extracellular vs. intracellular myocardial density based on biopsy samples does not exist so far. However, even if the respective myocardial density factor for the extracellular space in case of CA will be somewhat lower than 1.38 g/ml, we are convinced that the respective value (in advanced CA) will be much higher than 1.055 g/ml which is the well-known and mostly used myocardial density value for humans. Moreover, our AL group was rather small (N = 30 patients) since we only included those AL patients who were not treated with any disease specific therapy prior to our CMR study. Finally, future studies need to carefully assess possible gender differences regarding the findings of the present study.Our data confirm the presence of a “native T1 vs. ECV paradox” with lower native T1 values in spite of higher myocardial mass and ECV values in ATTRwt compared to AL. Importantly, this observation may be explained by a lower TICM/TECM “ratio” in case of ATTRwt compared to AL—since native T1 is determined by this ratio. Since non-invasive imaging methods such as CMR-based mapping are not only used for the diagnosis of cardiac amyloidosis, but also enable non-invasive monitoring of cardiac amyloidosis progression (or regression), a better understanding of mapping-based CMR results and of myocardial structure (with a particular focus on compartment-based “composition” and “density”) is crucial.


Myocardial recovery in patients supported by durable MCS devices is well recognized. However, predicting which patients will recover and improving the rates of recovery remains challenging.6 and 8.See Commentaries on pages 2 agonist) resulted in device explant in more than two-thirds of patients, these results have not been widely reproducible.,Durable left ventricular assist device (LVAD) support as a bridge to recovery leading to LVAD explantation remains the holy grail of advanced therapies for heart failure. Although pharmacologic therapy using the Harefield Protocol with Clenbuterol  LVAD. Our group initially reported that the patient presented with low-flow alarms and eventually displayed no meaningful pump output (B).In contrast, myocardial recovery can sometimes be forced. The most common indication for forced recovery is a refractory infection of the LVAD housing and/or driveline. Complete explant of the device is often the only option in nontransplant-eligible patients and the ability of the native heart to maintain adequate hemodynamic parameters—even with a poor LV ejection fraction—is commonly seen. Similarly, acute or subacute pump malfunction has led to the inadvertent recovery of the native heart because the pump ceases to provide any circulatory support. p output , B.3 AltFor the purposes of this review, we have intentionally excluded the prior examples of recovery. Rather, we focus on the potential ability of durable LVAD support to enhance reverse remodeling to the extent that functional recovery permits device explant. The concept of enhancing myocardial recovery to facilitate LVAD explant is largely credited to the Harefield group, which published their initial experience with 15 patients in 2006.All patients received guideline-directed medical therapy until regression of LV size was observed. They were then started on the β-agonist clenbuterol in an attempt to stimulate myocardial metabolism and cellular hypertrophy. Of these 15 patients, 11 displayed sufficient recovery to permit LVAD explant. There was 1 early death within 24 hours of explant and 1 late death at 27 months due to carcinoma. At 60 months of follow-up, the mean LVEF was sustained at 64%.There are a few important observations from the Harefield experience. Firstly, they excluded patients with ischemic cardiomyopathy who were unlikely to recover. Only 15 of the 24 patients with nonischemic cardiomyopathy completed the pharmacologic protocol yielding an explant rate of 11 out of 24 (46%). The explant rate in those that completed the full protocol was 11 out of 15 and if we exclude the early death, the successful explant rate was 67%. This level of recovery has yet to be duplicated.In the most recent Interagency Registry for Mechanically Assisted Circulatory Support report, the explant rate in more than 14,600 patients was only 5%. Again, many of these explants were forced due to infection or pump malfunction.P = .02).The Cardiothoracic Surgical Trials Network supported a prospective, randomized trial evaluating the efficacy of concomitant mesenchymal stem cell injection at the time of LVAD implant.The recently reported Remission from Stage D Heart Failure trial results suggest that >50% of patients with nonischemic cardiomyopathy can undergo successful LVAD explantation after optimization with a standardized pharmacologic regimen using a cocktail of widely available heart failure drugs.It appears that in carefully selected patients with chronic, nonischemic cardiomyopathy, myocardial recovery can be enhanced with targeted pharmacologic therapy. In those patients who display sufficient recovery to permit VAD explant, the recovery in myocardial function appears durable. However, when placed in context of all patients who receive durable mechanical circulatory support for either acute or chronic heart failure (many of whom have ischemic heart disease), the prevalence of true myocardial recovery remains small.Despite the low overall prevalence of myocardial recovery following LVAD support, we continue to assess all patients in a standardized fashion. Many protocols have been published to assess for myocardial recovery and to predict successful explant.Clearly, the need to address significant aortic or mitral insufficiency at the time of LVAD explant increases the perioperative risk of surgery and likely impairs the durability of recovery. Some authors have advocated for routine, repeated invasive hemodynamic studies to optimize LVAD function, and promote recovery.In our group, we assess LV size and function and perform invasive evaluations only in the case that LVAD explant is contemplated. In that event, the patient is heparinized and LVAD support is minimized, whereas invasive monitoring of arterial blood pressure, central venous pressure, and pulmonary pressures are performed.,16Heart failure is characterized by cardiomyocyte hypertrophy, expression of the fetal gene program, uncoupling of the G protein coupled receptors driving sympathetic hyperactivity, dysregulation of calcium handling,Transcriptional profiling has been used to provide insights into mechanisms of LVAD-induced reverse remodeling and to identify novel biomarkers of myocardial recovery. In a comprehensive study, only 238 out of 3088 (7.7%) transcripts that were dysregulated in heart failure, were altered with LVAD support.In another study, sequence-based transcriptional profiling of LVAD-induced changes in messenger RNA, micro RNA, and long noncoding RNA were examined.Surgical explant of a durable LVAD can be challenging, particularly in the case that the patient has been supported for >90 days. Forced explant due to pump infection usually necessitates complete excision of all foreign material mandating redo sternotomy. However, explant due to recovery can be accomplished with less-invasive techniques, tailored to the specific device.The HeartMate 2 (Abbott Cardiovascular) device has a unique polyethylene terephthalate inflow graft surrounded by a flexible silicone housing. Incising the housing can expose the graft facilitating ligation. Mobilization of the proximal outflow graft allows for ligation and the pump housing can be removed in its entirety, leaving the apical inflow conduit in situ and the distal outflow graft in the mediastinum. The latter thromboses rapidly and has not been associated with embolic events. We and others have even opted to leave the pump housing intact in the case that the inflow elbow is densely adherent to native tissues. Again, ligation of the inflow graft and outflow graft removes the LVAD from the circulation. In both instances, the driveline is cut as close to the pump housing as possible and pulled through the percutaneous driveline site. In situations where recovery is forced due to pump thrombosis, some authors have simply transected the driveline below the skin and left the entire pump in situ. Explantation of intrapericardial devices is usually easiest via lateral thoracotomy. The apical cannulation site is directly visualized and the proximal aspect of the outflow graft can be mobilized for ligation. Again, the entire pump housing can be left in situ and the driveline transected at the skin. Authors have also described removing the pump housing and filling the resultant apical defect with custom made plugs. An alternative approach is to perform a right anterior thoracotomy and access the distal end of the outflow graft for ligation. The driveline is transected at the skin and the entire pump housing left in situ without entering the pericardium.The ability to enhance myocardial recovery while on mechanical circulatory support remains an elusive goal. Whereas recent evidence from the Remission from Stage D Heart Failure trial does support the concept that targeted pharmacologic therapy can lead to a higher-than-average rate of LVAD explant. Most reports have confirmed that patients with dilated cardiomyopathy can display sustained recovery of myocardial function after LVAD explant.Surgical techniques to facilitate LVAD explant have evolved to pose little perioperative risk, particularly when a device is not infected. Given these data, it is incumbent upon LVAD caregivers to enhance native myocardial recovery with appropriate medical therapy and to continually assess their supported patients for evidence of recovery.Dr Rao is a consultant to Medtronic and Abbott and receives speakers fees from both companies and serves on the North American Surgical Advisory Board to Medtronic. The other author reported no conflicts of interest.Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.The


Non‐crocodylian reptiles have hearts with a single ventricle, which is partially separated by a muscular ridge that provides some separation of blood flows. An exceptional situation exists in monitor lizards and pythons, where the ventricular left side generates a much higher systolic blood pressure than the right side, thus resembling mammals and birds. This functional division of the ventricle depends on a large muscular ridge and may relate to high metabolic demand. The large leatherback turtle (<1000 kg), with its extensive migrations and elevated body temperatures, may have similar adaptations. We report on the anatomy of the hearts of two leatherback turtles. One stranded in Ballum, Denmark in 2020, and was examined in detail, supplemented by observations and photos of an additional stranding specimen from Canada. The external morphology of the leatherback heart resembles that of other turtles, but it is large. We made morphometric measurements of the Ballum heart and created an interactive 3D model using high‐resolution MRI. The volume of the ventricle was 950 ml, from a turtle of 300 kg, which is proportionally almost twice as large as in other reptiles. The Ballum heart was compared to MRI scans of the hearts of a tortoise, a python, and a monitor lizard. Internally, the leatherback heart is typical of non‐crocodylian reptiles and did not contain the well‐developed septation found in pythons and monitor lizards. We conclude that if leatherback turtles have exceptional circulation needs, they are sustained with a relatively large but otherwise typical non‐crocodylian reptile heart. Modelling of the leatherback turtle heart based on magnetic resonance imaging showing that the atrioventricular valve  is entirely to the left of all three major arteries, as is typical of most reptile hearts. Its global population meets the IUCN Red List criteria for being considered “vulnerable,” with some regional populations increasing and others decreasing  on 3 November 2020. It had a curved carapace length of 148 cm and was estimated to weigh 300 kg. It was brought to The Fisheries and Maritime Museum in Esbjerg, Denmark, given the specimen ID “R2117”, and kept frozen until its dissection on 6 August 2021. The other heart examined came from a stranded leatherback in Canada (2009), which was examined in Australia, mainly to confirm the foramen between the arterial and pulmonary arteries described by Adams . Photos 2.2The Ballum heart was dissected free and all major structures were more or less intact. Accordingly, the dissected tissue included parts of the major arteries, oesophagus, and the left lung, together with coagulated blood, and weighed in total of 11.2 kg. This specimen was kept in a 25 L bucket filled with 4% formaldehyde buffered to pH 7.4. The formaldehyde was renewed after 3 days and the total immersion fixation time was 1 week. After this, the heart was transferred to a phosphate‐buffered saline and washed twice for 3 days to remove residual formaldehyde in preparation for magnetic resonance and x‐ray computed tomography imaging (MRI and CT).2.33, spatial resolution 0.5 mm isotropic, number of averages = 4, acquisition time = 3.7 h.Magnetic resonance imaging (MRI) was performed on an Siemens Magnetom Skyra system equipped with a Flex Large 4 surface coil using a T2‐weighted 3D sequence with the following parameters: field strength = 3 T, repetition time = 1000 ms, echo time = 132 ms, flip angle = 120°, field‐of‐view = 288 × 288 × 160 mm3, spatial resolution = 0.8 mm isotropic, convolution kernel = FC18, acquisition time = 90 s.X‐ray computed tomography (CT) was performed using a Toshiba Aquillon Prime SP system with the following parameters: x‐ray tube voltage = 120 kVp, x‐ray tube current = 250 mA, integration time = 1000 ms, field‐of‐view = 410.1 × 410.1 × 404.0 mmThe MRI and CT generated image stacks were imported to the 3D software Amira . Labelling of structures were done in the Segmentation Editor module. The volumes of labelled structures were retrieved using the Materials Statistics module. Distances were measured in Orthographic view using the Measure Line tool on either images of the image stack or a volume rendering of the label file. The Amira model was converted to an interactive 3D pdf as previously described  (Jensen et al., A particularly well‐developed trait in monitors and pythons is a bi‐layered configuration of the muscular ridge and the bulbuslamelle (Jensen et al., Our description of a typical chelonian heart in the leatherbacks strongly indicates a considerable capacity for cardiac shunting and a lack of ventricular pressure separation. Other chelonians have large cardiac right‐to‐left shunts during diving (i.e., where oxygen‐poor systemic venous blood entering the ventricle from the right atrium is delivered to the aortas (e.g., Hicks, Most chelonian hearts have a cartilage or bone deposit where the muscular ridge merges with the truncus arteriosus (López et al., In conclusion, despite leatherback turtles exhibiting adaptations to their unusual lifestyle, such as a high hematocrit (Lutcavage et al., Figure S1Click here for additional data file.


Computational modeling of the whole human heart has become a valuable tool to evaluate medical devices such as leadless pacemakers, annuloplasty rings and left ventricular assist devices, since it is often difficult to replicate the complex dynamic interactions between the device and human heart in bench-top and animal tests. The Dassault Systèmes Living Heart Human Model (LHHM) is a finite-element model of whole-human-heart electromechanics that has input parameters that were previously calibrated to generate physiological responses in a healthy heart beating at 60 beat/min (resting state). This study demonstrates that, by adjusting only six physiologically meaningful parameters, the LHHM can be recalibrated to generate physiological responses in a healthy heart beating at heart rates ranging from 90–160 beat/min. These parameters are as follows: the sinoatrial node firing period decreases from 0.67 s at 90 bpm to 0.38 s at 160 bpm, atrioventricular delay decreases from 0.122 s at 90 bpm to 0.057 s at 160 bpm, preload increases 3-fold from 90 bpm to 160 bpm, body resistance at 160 bpm is 80% of that at 90 bpm, arterial stiffness at 160 bpm is 3.9 times that at 90 bpm, and a parameter relating myofiber twitch force duration and sarcomere length decreases from 238 ms/mm at 90 bpm to 175 ms/mm at 160 bpm. In addition, this study demonstrates the feasibility of using the LHHM to conduct clinical investigations in AV delay optimization and hemodynamic differences between pacing and exercise. AV delays in the ranges of 40 ms to 250 ms were simulated and stroke volume and systolic blood pressure showed clear peaks at 120 ms for 90 bpm. For a heart during exercise, the increase in cardiac output continues to 160 bpm. However, for a heart during pacing, those physiological parameter adjustments are removed that are related to changes in body oxygen requirements . Consequently, cardiac output increases initially with heart rate; as the heart rate goes up (>100 bpm), the increasing rate of cardiac output slows down and approaches a plateau. Continued advances in computational power and methods have enabled whole human heart modeling ,2,3,4,5 As the heart beats faster, its dynamic interactions with a device are likely to intensify. Moreover, the changes in device–heart interaction ,2,3,5 maPatients with long term pacemaker implants often develop “pacemaker syndrome”, where patients feel symptomatically worse after pacemaker placement and present with progressively worsening symptoms of congestive heart failure. A multitude of factors could be contributing to this phenomenon, including improper programming of the pacemaker and differences in pacing and natural heart contractions. A computational model that can be used to study the effects of pacemaker settings on strains in the cardiac tissue and the difference between a natural vs. paced heart is a useful tool to help find solutions for pacemaker syndrome.An example is AV delay. AV delay is the delay in conduction between the atria and ventricles at the AV node . AV delaAdditionally, there are other important reasons to consider heart rate in predictive multiscale computational modeling. For example, heart failure with preserved ejection fraction (HFpEF) is considered the greatest unmet need in cardiovascular medicine today because of a general lack of effective treatments. In September 2017, the National Heart, Lung, and Blood Institute convened a two-day working group meeting of experts in HFpEF and novel research methodologies  to discuss research priorities for HFpEF. Their white paper pointed out the need for improved animal models, including large animal models, which incorporate the effects of exercise . CertainThe objectives of this study are to (1) calibrate the LHHM for different heart rates during exercise, (2) study the hemodynamic differences between a natural heart beat during exercise and an artificially paced heart at an elevated heart rate and (3) to evaluate the feasibility of using LHHM in AV delay optimization.Baillargeon et al.  created During exercise, sympathetic nerves of the autonomic nervous system increase heart rate, electrical propagation, myocardial contractility and blood flow ,15. ExerWe simulated six key effects of exercise from the literature. The corresponding changes we made to the LHHM mimicked neural/hormonal modulations and increased oxygen demand . First, After the baseline hemodynamic performance was first established to simulate hearts during exercise, we then studied the hemodynamic differences of hearts during exercise and pacing. For a heart during pacing, heart rate changes are often not associated with excise and changes in body oxygen requirements, and the hemodynamic behaviors would be different for a paced heart from that of a heart during exercise. For a paced heart without oxygen demand increases, the heart model was then simulated with pacing only and those physiological parameters that related to exercise were removed  at 90 bpm , after wHemodynamic outcomes such as blood pressure, pressure of left ventricle and left atrium, stroke volume, cardiac output, etc. were extracted and the trend curves were plotted.After adjustments to the LHHM model inputs , cardiacWhen LHHM is configured to simulate pacing without exercise, the model outputs show that the stroke volume reduces with an increasing heart rate . This reIn the LHHM, for a paced heart, cardiac output increases initially with heart rate; as the heart rate goes up (>100 bpm) the rate of CO increase slows down and approaches a plateau; for a heart during exercise, the CO increase continues to become a higher heart rate . These rAV delays in the range of 40 ms to 250 ms were simulated in the Living Heart Human Model. The results on stroke volume show a clear peak at 120 ms in the LHHM at 90 bpm , which aOur results demonstrate the feasibility of using the LHHM to simulate the consequences of an elevated heart rate, i.e., increase in cardiac output, increase in blood pressure and decrease in cardiac time intervals. We also demonstrated that the model can differentiate between a pacing- and exercise-induced elevated heart rate. Due to the lack of neural/hormonal modulations and lack of increased oxygen demand during pacing, when the heart rate goes up, the cardiac output increase slows down and approaches a plateau, whereas during exercise, the cardiac output continues to increase to a higher heart rate. This study also demonstrates the feasibility of using the LHHM to optimize AV delay to achieve maximal stroke volume and systolic blood pressure.This model provides a virtual environment to evaluate device–heart interaction at an elevated heart rate. Already, we have used the LHHM to simulate the effects of very different annuloplasty rings for correcting mitral regurgitation ,4,5 and Our study is among the very few published that couple the left and right heart, including atria and ventricles, to the rest of the systemic and pulmonary circulations ,27. Our To the best of our knowledge, ours is the first study to use a whole human heart model to simulate the effects of heart rate on ventricular mechanics. A recent example of a finite-element model used to simulate heart rate effects on cardiac mechanics is the study by Sturla et al.  on the eIt would not have been practical to optimize every parameter in the LHHM in order to best fit  measurements of hemodynamics and cardiac output at different elevated heart rates. The total number of variables in the LHHM is 196, with 57 parameters associated with the electrical model, 132 parameters associated with the excitation-contraction coupling model and 7 parameters associated with the systemic blood circulation model. In a recent machine learning study [Perhaps the greatest limitation of our modeling study of the whole human heart is that we used a time-varying elastance approach, rather than a cellular model approach, to simulate electromechanical coupling. There are great savings in computation time when a time-varying elastance approach, in which active stress is an analytic function of time since the onset of contraction, intracellular calcium concentration and sarcomere length, is used instead of a cellular model approach in which, for example, active stress is computed from a system of 30 or more ordinary differential equations , especiaThis study demonstrates that by calibrating only six physiologically meaningful parameters, a computational model of a whole human model can accurately capture physiological responses of a healthy heart at heart rates ranging from 90–160 bpm. The results demonstrate the feasibility of using the heart model (LHHM) to conduct clinical investigations in AV delay optimizations and in studying the hemodynamic differences between hearts during exercise and pacing. The outputs from the LHHM, in general, are in good agreement with in vivo measurements, although some parameters show the correct trends but with some quantitative differences. Our model is useful to evaluate medical devices that allow complex dynamic interactions between the device and human heart to be considered, which is difficult to replicate in bench-top and animal tests.Future development plans include continuing to improve the fidelity of the LHHM to include more complex heart physiologies that are critical for providing a realistic boundary condition for device testing and evaluation. The current living heart model includes some complex and nonlinear physiologies, such as active tissue material modeling intended to capture the Frank–Starling effect  . Advance


Endovascular revascularization has become the first-line treatment of chronic mesenteric ischemia (CMI). The qualitative visual analysis of digital subtraction angiography (DSA) is dependent on observer experience and prone to interpretation errors. We evaluate the feasibility of 2D-Perfusion Angiography (2D-PA) for objective, quantitative treatment response assessment in CMI.49 revascularizations in 39 patients with imaging based evidence of mesenteric vascular occlusive disease and clinical signs of CMI were included in this retrospective study. To assess perfusion changes by 2D-PA, DSA-series were post-processed using a dedicated, commercially available software. Regions of interest (ROI) were placed in the pre- and post-stenotic artery segment. In aorto-ostial disease, the inflow ROI was positioned at the mesenteric artery orifice. The ratios outflow to inflow ROI for peak density (PD), time to peak and area-under-the-curve (AUC) were computed and compared pre- and post-interventionally. We graded motion artifacts by means of a four-point scale. Feasibility of 2D-PA and changes of flow parameters were evaluated.outflow/PDinflow increased by 65% (p < 0.001) and AUCoutflow/AUCinflow increased by 85% (p < 0.001). The time to peak density values in the outflow ROI accelerated only minimally without reaching statistical significance. Age, BMI, target vessel , stenosis location , calcification severity, plaque composition or the presence of a complex stenosis did not reach statistical significance in their distribution among the feasible and non-feasible group (p > 0.05). Motion artifacts due to a mobile vessel location beneath the diaphragm or within the mesenteric root, branch vessel superimposition and inadequate contrast enhancement at the inflow ROI during manually conducted DSA-series via selective catheters owing to steep vessel angulation, necessitated exclusion of 26 measurements from quantitative flow evaluation. The feasibility rate was 47%. In 23 technically feasible assessments, PDCompared to other vascular territories and indications, the feasibility of 2D-PA in mesenteric revascularization for CMI was limited. Unfavorable anatomic conditions contributed to a high rate of inconclusive 2D-PA results.  In chronic mesenteric ischemia (CMI), occlusive disease affecting at least two of three mesenteric arteries causes inadequate blood supply to meet the metabolic demands of the intestine . The preMain goals of revascularization are symptom relief, improvement of the nutritional status and avoiding progression to acute-on-chronic mesenteric ischemia with bowel infarction , 3. PercDuring stenting of stenotic mesenteric arteries, the subjective, qualitative visual analysis of monochromatic digital subtraction angiography (DSA) images in the splanchnic territory is challenging. In general, evaluation of disease extent and treatment success in DSA depends on observer experience and is prone to perceptual bias and interpretation errors, leading to a high degree of inter-observer variability and poor reproducibility . EspeciaIn different vascular territories and indications, 2D-perfusion angiography (2D-PA) proved to be a useful tool providing on-table visualization of a complete DSA series in a color-coded contrast flow chart as well as objective, intra-procedural quantification of flow changes –17. Neve2 (range 14.9–34.5). Additionally, 38% of our patients presented with endoscopically proven ischemic gastritis or colitis with intestinal bleeding episodes. The other patients had normal or inconclusive endoscopic results with regard to gastric or colonic ischemic mucosal injury. We present the patients’ demographics and clinical symptoms in Table In total, 49 mesenteric endovascular revascularizations in 39 consecutive patients suffering from CMI were included in this retrospective, single-center observational case–control study. Our study group consisted of 21 men and 18 women with a median age of 69.7 (range 48–87 years), scheduled for endovascular revascularization at our tertiary care hospital from August 2013 to August 2021. At presentation, the leading clinical symptom consisted of recurrent abdominal pain immediately after a meal or, in one case, triggered by hemodialysis-associated hypotension. As a result, the majority of our study population complained unintended weight loss due to food fear and malabsorption. The patients’ weight loss ranged between 7 kg in 48 weeks to 10 kg in 4 weeks. The median BMI was 19.3 kg/mMoreover, prerequisite for inclusion was imaging based evidence of occlusive visceral artery disease of atherosclerotic origin in abdominal computed tomographic (CT) or magnetic resonance (MR) imaging. In symptomatic patients, we considered a more than 70% stenosis in single-vessel disease or a more than 50% stenosis in multi-vessel disease relevant . PreprocOur interdisciplinary conference of vascular surgeons and interventional radiologists approved the indication for endovascular visceral revascularization in each case. In addition, we reviewed clinical and imaging records of each case in our Clinical Information System and Picture Archive and Communication System to collect further information about the patients’ medical history and the post-procedure follow-up of median 21 months (range: 4 months to 7 years). One interventional radiologist with 25 years post-certification experience performed the visceral revascularizations via a trans-femoral access route, using a monoplane, ceiling-mounted angiographic system . In two cases, catheter instability due to iliac artery elongation and an acute angle between target vessel and aorta necessitated switching to a trans-brachial approach. At least, one stenotic or occluded mesenteric artery had to be recanalized.The mesenteric target vessels were examined by selective manual angiograms in laterally angled, parasagittal views using different 5 F catheter configurations and iodinated contrast media . In order to visualize the extent of aorto-ostial stenosis, a 0.018-inch guidewire was placed through the selective catheter distally to the stenotic segment and a angiogram was performed with the catheter tip being retracted into the aortic lumen next to the mesenteric artery orifice. Intra-arterial contrast was administered manually by a single operator before and after mesenteric revascularization via selective catheters or long guiding sheaths. For separate pre- and post-interventional hand injection, we used a flow rate of approximately 8 ml/s and a 1:1 normal saline dilution of contrast media (Imeron 300) for each patient regardless of patient size. Only in a few cases, pump-assisted selective angiograms were conducted with 20–30 ml of contrast (80–100% Imeron 300 dilution) and a flow rate of 6–7 ml/s . The parameters were chosen at the operator’s discretion according to the target vessel size and the patients’ renal function.Due to impaired renal function and previously performed diagnostic CT- or MR-angiographic images, we waived pump-assisted aortography in the majority of cases. DSA images were acquired at 2 frames per second with a range of approximately 5–6 s per DSA run.During the procedure, we did not administer spasmolytic agents.We assessed major complications according to the reporting standards of the Society of Interventional Radiology . Table 2To evaluate perfusion changes by 2D-PA, we performed post-processing of monochromatic DSA series before and after mesenteric stenting on a dedicated workstation using a commercially available clinical software application . In 2D-PA, a single computed, color-coded composite image provides clustered information about vessel morphology and contrast concentration changes per time during a complete DSA run. In addition, 2D-PA allows calculation of flow curves and blood flow parameters in user-defined regions of interest (ROI). Therefore, 2D-PA enables an objective assessment of flow changes and perfusion parameters.rd of the vessel diameter. In cases of aorto-ostial disease, we placed the inflow ROI in the aortic lumen next to the mesenteric artery ostium. We located the outflow ROI, intended for statistical analysis, at least 2 cm distally to the stenotic segment. The reported 2D-PA technique using a two ROI based evaluation  is independent of a standardized contrast-bolus protocol [Initially, we selected pre- and post-interventional DSA series taken in almost identically angled views to be evaluated by 2D-PA. The chosen DSA series were prepared for 2D-PA-analysis by automatic isocenter calibration ) according to the instructions for use. Next, in total four ROI were placed, at least one proximally and one distally to the stenotic mesenteric artery segment. ROIs were arranged in the same position pre- and post-interventionally, to ensure measurements at comparable locations. ROIs were adjusted to at least 2/3protocol .2, the ratio between outflow and inflow maximal contrast density per ROI after contrast media application (ROI Peak/Ref Peak or PDoutflow/PDinflow). Furthermore, the time to peak density per ROI in seconds from the first moment of increase of density to the maximum contrast density (ROI Peak time or TTP) and the ratio between outflow and inflow area-under-the-time-density-curve (ROI AUC/Ref AUC or AUCoutflow/AUCinflow).In 2D-PA, the computed time-versus-ROI-contrast-intensity result tables offer the following numeric parameters: ROI Area in mmIn addition, we calculated the ratio between outflow and inflow time to peak in order to overcome variations in the flow rates between consecutive manual angiograms.Additionally, we assessed the 2D-PA-images qualitatively for motion artifacts during a DSA run. To this end, we graded motion artifacts by means of a four-point scale . Furthermore, we evaluated the time versus contrast density curves with regard to conclusiveness of hemodynamics. We considered results hemodynamically conclusive, if an adequate contrast enhancement is present at the inflow ROI during the DSA run.outflow/TTPinflow) decreases, since the density peak in the outflow ROI will be reached earlier. The peak density-ratio (PDoutflow/PDinflow) increases, since the maximal contrast density in the outflow ROI rises following intervention. Correspondingly, the AUC-ratio (AUCoutflow/AUCinflow) increases as well, since the outflow AUC approximates the inflow AUC post-interventionally.In theory, following successful revascularization, the TTP-ratio  served as a data collection tool. For statistical analysis, we used a dedicated software . Descriptive data were presented as means ± standard deviation for normally distributed variables or medians with ranges for non-normally distributed variables. We reported categorical variables as frequencies and percentages with n (%). The Anderson Darling test was applied for assessment of normality, rejecting the hypothesis of normality when the p-value was less or equal to 0.05. Ratios of peak density, time-to-peak and area under the time-contrast curve pre- and post-interventionally were evaluated for statistical significance by using the pairwise Wilcoxon´s signed rank test for non-normally distributed variables. In addition, we assessed whether parameters, potentially influencing the feasibility, were more frequently represented in the feasible- or non-feasible group by using the fisher’s exact test for nominally scaled variables, the Wilcoxon´s signed rank test for ordinally scaled variables and the T-test for scaled, normally distributed variables. A p-value of less than 0.05 was designated as statistically significant.Completion of the post-processing process was achieved in each case. With regard to motion artifacts, we recorded mild to moderate artifact levels in 84% of evaluated arteries. In 16% severe motion artifacts rendered adequate flow evaluation impossible. Artifacts were due to a combination of the patients’ inability to hold their breath during a DSA run and bowel movement. In five cases, vessel branching and tortuosity precludes free projection of the intended inflow or outflow vessel segments for ROI placement Fig. .Fig. 1ImAs a result, hindered 2D-PA due to motion artifacts, vessel superimposition and inadequate pre-stenotic contrast enhancement necessitated exclusion of overall 26 2D-PA measurements from quantitative flow evaluation. Therefore, the technical feasibility rate of 2D-PA in mesenteric stenting was 47%. Further 2D-PA results are included in Table outflow/PDinflow (p < 0.001) and 85% for AUCoutflow/AUCinflow (p < 0.001). The time to peak density values in the outflow ROI following mesenteric stenting accelerated only minimally without reaching statistical significance (p = 0.553). The decrease in the TTPoutflow/TTPinflow ratio pre- and post-interventionally was -2%. The correlation between the increase of AUCoutflow/AUCinflow and the post-procedural weight gain yielded statistical significance (p = 0.016).Nevertheless, we recorded the following changes of flow parameters pre- and post-interventionally in 23 technically feasible, conclusive 2D-PA measurements: PD and AUC in the target outflow ROI were significantly higher following treatment, resulting in an increase of 65% for PDMoreover, a subgroup analysis of variables’ impact on the feasibility of 2D-PA yielded no statistical significance in the majority of cases. Age (p = 0.475), BMI p = 0.343), target vessel , stenosis location , calcification severity (p = 0.187), plaque composition (p = 0.639) or the presence of a complex stenosis (p = 0.086) did not reach statistical significance in their distribution among the feasible and non-feasible group. A higher artifact level (p = 0.006) and a hemodynamically inconclusive result (p < 0.001) were found more often in the non-feasible group by reaching high statistical significance. Changes in 2D-PA following mesenteric stenting are presented in Table 43, targeThis study adds further aspects to the growing experience in 2D-PA by showing that 2D-PA in the mesenteric territory for treatment evaluation in chronic mesenteric ischemia is challenging. Non-interpretable 2D-PA evaluations necessitated exclusion of 26 measurements from quantitative flow evaluation, resulting in a feasibility rate of 47%. Previously published studies indicated 2D-PA as highly susceptible to motion artifacts, since they cause inaccurate measurements of perfusion parameters. Indeed, in comparison with previously published studies, our feasibility rate was considerably lower. For instance, 2D-PA in peripheral artery disease proved to be technically feasible in all cases reported by Hinrichs et al. and Dewald et al. , 17. FurOur results may be triggered by additional challenges in occlusive mesenteric artery disease. First, the mobile vessel location beneath the diaphragm or within the mesenteric root, rendered 2D-PA vulnerable to motion artifacts. Since we did not apply spasmolytic agents during our interventions, their effect on artifact reduction remains unclear. Second, especially in the celiac territory, superimposition of vessel branches precluded free projection of the intended inflow or outflow vessel segments for ROI placement.However, the main drawback was steep angulation between the aorta and the target vessel. As a result, we recorded insufficient contrast enhancement at the inflow ROI in manually conducted angiograms via selective catheters or long guiding sheaths Fig. . In thesSince 49% of our patients had impaired renal function (CKD stages 3 to 5), and previously performed CT- or MR-angiographic images were available in each case, additional aortography solely for 2D-PA reasons was not justified in the majority of our cases. The fact that 2D-PA is independent of additional contrast media application and radiation exposure is one major strength of the reported 2D-PA technique.Another key feature of the reported 2D-PA technique is “on-table” visualization of color-coded and quantitative flow changes during the procedure. To date, other promising novel imaging techniques enabling flow evaluation and/or color-coding of flow velocities such as 4D flow MRI are time consuming and not available intra-procedurally. Further, contrary to 2D-PA, they are prone to artifacts caused by dense calcifications and stent material . In addiIn a subgroup analysis, none of the presumed factors influenced the feasibility significantly. Neither a higher patient age, nor a higher BMI were more frequently found in the non-feasible group. Moreover, ostial stenosis as well as the presence of complex stenosis or a higher calcification severity were not significantly differently distributed among the feasible and the non-feasible group. As expected, only a high motion artifact level and an insufficient inflow contrast enhancement proved to be highly significant limitations for 2D-PA.In accordance with previously published data, 2D-PA evaluation in our feasible group showed a significant increase in the AUC-ratio and the PD-ratio indicating improved perfusion of the treated artery following stenting. In contrast, the TTP-ratio decreased only minimally without reaching statistical significance.2-angiography of the limb [This result is in accordance with Dewald et al., who reported only a low trend towards decrease of the TTP-ratio in their assessment of 2D-PA in COthe limb . The autthe limb . With ththe limb .Furthermore, a combination of the complex vascular anatomy with varying disease distribution patterns, the high capacity of collateral blood circulation, post-prandial flow changes, vessel wall elasticity, the intestinal vascular suction effect as well as post-occlusive reactive vasodilatation complicates the analysis of flow parameters in the mesenteric territory . Previououtflow/AUCinflow and the post-procedural weight gain yielded statistical significance (p = 0.016). However, the clinical relevance of this result is questionable, since the patients’ body weight depends on many factors. Six patients in our feasible group presented with symptom recurrence. Due to the small sample size and a multitude of influencing factors, correlation between changes in flow parameters and symptom relapse seems not appropriate. This study has several limitations. Due to the retrospective nature of our study, we solely focused on the feasibility of 2D-PA for intra-procedural treatment response assessment during mesenteric stenting and did not perform other techniques such as duplex sonography or pressure wire measurements to compare our 2D-PA results. As previously mentioned, there are many factors influencing the perfusion between the proximal mesenteric artery stenosis and the bowl’s capillary system, which are not gathered by the reported 2D-PA technique. Hence, 2D-PA is not able to point to absolute measurements of mesenteric perfusion. Further studies should focus on the influence of the collateral flow and techniques to evaluate the real 3D perfusion of the capillary phase of the mesenteric territories.Contrary to the creatinine levels in renal artery stenting, we did not consider any clinical or laboratory parameter appropriate for statistical correlation with changes in perfusion parameters to predict the procedures’ outcome in our retrospective data set. Only the correlation between the increase of AUCThe small number of patients, the high number of non-interpretable 2D-PA evaluations and the moderate loss of patients available for follow up in our multi-morbid patient collective rendered a structured follow-up analysis and reliable correlation of 2D-flow parameters with clinical outcome parameters in order to define criteria for effective therapy inadequate.Compared to other vascular territories and indications, the feasibility of 2D-PA in endovascular mesenteric revascularization for CMI was limited. Unfavorable anatomic conditions contributed to a high rate of inconclusive 2D-PA results. With our data, we intended to contribute to the growing preliminary knowledge about objective treatment assessment with 2D-PA. Especially in the mesenteric territory, further prospective standardized evaluations comparing different flow measurement techniques with larger study populations and structured longitudinal follow up periods are needed to gain deeper insights in the complex mesenteric flow characteristics and to define objective standardized endpoints of successful mesenteric revascularization.


A woman that suffered burns previously presented with leg swelling and was diagnosed with venous thromboembolism. Heparin was given until she suddenly developed myocardial infarction. Ventricular septal rupture was detected and managed by transcatheter closure. She developed massive bleeding and extensive thrombosis that made treatment paradoxical and eventually died. Ventricular septal rupture was managed by transcatheter ventricular septal defect closure device in a patient with acute myocardial infarction subsequent to potential heparin‐induced thrombocytopenia. From deep venous thrombosis (DVT) to acute myocardial infarction (AMI) to ventricular septal rupture (VSR) and the paradox between massive bleeding and extensive thrombosis, there are many pathophysiologic processes involved in the course of her disease, of which heparin‐induced thrombocytopenia (HIT) probably played the most crucial role. Despite the active management administered, this patient eventually died of multiple organ failure (MOF). In this study, we wish to report the “butterfly effect” of a burn accident and the fatal effect that HIT has played in this chain reaction.29/L. Venous ultrasound showed extensive thrombosis of the left lower extremity. Computed tomography pulmonary angiography (CTPA) later demonstrated pulmonary embolism (PE).  was then given to bridge the patient to a possible transcatheter closure. After the placement of IABP, low dosage of heparin was used for flushing for a few days to prevent thrombosis, and then, the patient's platelet count witnessed a drop again, to 56*109/L. Three weeks later, transcatheter VSR closure was performed successfully , and thus was deemed at high risk of undergoing HIT. It is worth mentioning that tirofiban‐induced thrombocytopenia should be differentiated, but tirofiban‐induced thrombocytopenia usually occurs within a few hours after exposure and is associated with a higher risk of bleeding rather than thrombosis.The diagnosis of HIT involves both clinical and laboratory components. There are several proposed scores to predict the likelihood of HIT by clinical characteristics, and the most commonly used is the 4T score by Warkentin et al.,Although venous thromboses are more common in HIT, arterial thromboses may also occur. According to a 14‐year study that analyzed 127 HIT patients, venous and arterial thrombotic events occurred in 78 and 18 patients, respectively.With respect to the management of HIT, it is of paramount importance to terminate any source of heparin administration when a clinician has at least a moderate suspicion of HIT, including heparin, LMWH, heparin‐coated catheters, and heparin flushes.Although currently no studies have directly addressed the benefit over risk of platelet count monitoring in patients receiving heparin or LMWH, the catastrophic outcomes following HIT of this patient have clearly warranted its necessity. The 2018 ASH clinical guidelines recommend platelet count monitoring be performed every other day from Day 4 to Day 14 (or until heparin in stopped) for patients considered at high risk (>1%) of HIT, and every 2 to 3 days for patients considered at intermediate risk (0.1%–1%) of HIT, and no platelet count monitoring for patients at low risk (<0.1%).In summary, this patient experienced a series of devastating cardiovascular events following a minor burn accident, of which the most important trigger was HIT during heparin treatment. This case has provided painful lessons to be learnt for physicians. First, the prevention of DVT in trauma patients, including burned patients, is important; second, it is necessary to monitor platelet count in patients with at least moderate risk of HIT during heparin therapy; third, any type and any dosage of heparin exposure should be avoided when HIT has already been suspected.Yuansong Zhu: Data curation; writing – original draft. Suxin Luo: Writing – review and editing. Chun Zeng: Visualization. Bi Huang: Writing – review and editing.Not applicable.The authors declare that they have no competing interests.The study complied with the Declaration of Helsinki and was approved by the Human Ethics Committee of the First Affiliated Hospital of Chongqing Medical University.Written informed consent was obtained from the patient's next of kin for the publication of this article.


LVAD therapy is an effective rescue in acute and especially chronic cardiac failure. In several scenarios, it provides a platform for regeneration and sustained myocardial recovery. While unloading seems to be a key element, pharmacotherapy may provide powerful tools to enhance effective cardiac regeneration. The synergy between LVAD support and medical agents may ensure satisfying outcomes on cardiomyocyte recovery followed by improved quality and quantity of patient life. This review summarizes the previous and contemporary strategies for combining LVAD with pharmacotherapy and proposes new therapeutic targets. Regulation of metabolic pathways, enhancing mitochondrial biogenesis and function, immunomodulating treatment, and stem-cell therapies represent therapeutic areas that require further experimental and clinical studies on their effectiveness in combination with mechanical unloading. Heart failure (HF) remains one of the most significant public concerns, affecting almost 100 million people worldwide, and 1-year mortality is estimated at 15–30% despite improved diagnostics and expanding knowledge . TherefoVADs are mechanical pumps that reduce the workload of the heart, providing support for the left ventricle (LVAD), the right ventricle (RVAD), or both ventricles (BIVAD). They are attached to the heart through cannulae that allow blood to enter a pumping chamber from which it is ejected into the systemic and/or pulmonary circulation. Devices are classified as pulsatile or continuous-flow based on how blood is pumped into the devices. The main goal of VADs is to restore cardiac output and stress relief before a failing heart leads to irreversible end-organ dysfunction, including pulmonary hypertension, renal failure, liver dysfunction, and cardiac cachexia. Currently, VADs might provide 1–2 weeks of support with ECMO and IMPELLA devices (short-term), 30 days by external centrifugal pumps (medium-term), or longer than 30 days via HeartMate3 and EXCOR pumps (long-term). Short-term VADs are intended for a wide range of clinical conditions, such as high-risk invasive coronary artery procedures for the management of cardiogenic shock, acute decompensated heart failure, or cardiopulmonary arrest. Among mid- and long-term VADs, LVAD is the most common type that has revolutionized the treatment of end-stage heart failure .The first implantation of a mechanical assist device was performed in 1963 by bypassing the LV from the LA to the descending aorta at Baylor University in Huston. After 4 days, mechanical support was discontinued due to the patient’s coma and death ,11. ThisOver the past decade in the United States, 25,551 patients with heart failure underwent continuous-flow LVADs placement . AccordiThe annual report from Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) has shown that DT is currently the most common form of therapy . The impAs previously mentioned, short-term mechanical unloading is recommended to prevent cardiogenic shock (CS) in acute conditions . It has 2+ cycling, and proinflammatory proteins [+/Ca2+ exchanger (NCX) during LVAD therapy [2+ handling through significant tubule remodelling [2+ channels and transverse tubules (t-tubule) have been normalized in the rodent model of mechanical unloading compared to unfavourable outcomes from only HF rats. T-system defects and related-Ca2+ handling aberration are features of heart failure progression and, hence, are thought to be the key to the proper functioning of cardiomyocytes and novel predictors for functional cardiac recovery after mechanical unloading [A growing body of evidence has shown that, in respondent patients, LVAD induces structural and functional changes at the cellular, molecular, and whole-heart levels, known as reverse remodelling ,37,38. Tproteins ,43,44. Rproteins . Interesproteins ,46. The  therapy . It resu therapy . Furtherodelling . It has nloading ,50. Mechnloading ,52; howenloading ,54. Howenloading . Metabolnloading . To provnloading . This spnloading . It has nloading . Howevernloading ,61. Overnloading  and in vnloading . TherefoLimitations regarding myocardial recovery might be divided into two categories: adverse events and unfavourable changes in cardiomyocytes, both associated with prolonged mechanical unloading. In the first case, LVAD patients struggle with many post-implantation complications, as shown in The effectiveness of LVAD therapy is evidenced by a sufficient myocardial recovery that allows device explantation and life without mechanical support . To incrp = 0.024) and reduced hazard of death and HF-related hospitalization (p = 0.013) in response to combination therapy. These changes are in line with previous [p < 0.001), LV internal diastolic diameter (p = 0.003), and increased LV ejection fraction (p < 0.001) compared to pre-implantation status (p < 0.001) and better quality of life defined by the Kansas City Cardiomyopathy Questionnaire  and 6-minute walk test . Moreover, recovery permitting device explantation was also more favourable in the NHB group (p = 0.04). LVAD patients receiving triple NHB therapy performed best, analogical to data from HFrEF guidelines . The consistency in results from small clinical studies and cohort analysis gives credence to the notion that intensive NHB treatment is beneficial for LVAD patients and may set the trajectory for future medical regimens.The promotion of reversed remodelling has also been described in another pharmacologic regimen. In the study of Grupper et al., patients who had ischemic cardiomyopathy were randomly assigned to the neurohormonal blockade (NHB) therapy  or the control group without any NHB drug after LVAD implantation . Achieviprevious  and receprevious  studies.n status . Interesn status . Analysip = 0.043). It has been previously reported that angiotensin–neprilysin inhibition reduces NT-proBNP levels in patients with acute HF, with no greater incidence of renal dysfunction, hyperkalaemia, and symptomatic hypotension [A different strategy might be the pre-operative use of sacubitril–valsartan (ARNI: angiotensin receptor antagonist and neprilysin inhibitor) to reduce post-operative mortality in patients undergoing LVAD implantation. Heder et al. reported an association with better survival outcomes after cardiac surgery (LVAD or HTx) . Accordiotension . Interes2+ cycling, increase fibrosis, and induce myocardial atrophy [2+ transients, and normalized collagen area fraction compared to only unloaded hearts. Thus, the combination treatment promoted to a greater extent reverse remodelling. Metoprolol has also been investigated but only reduced myocardial atrophy. A similar study was performed to examine the effects of clenbuterol and metoprolol in the same HF model during mechanical unloading [A combined approach was also examined in a rodent model of HF using the established and reproducible procedure of LV unloading . Since c atrophy ,89, Nava atrophy . It has nloading . UnfortuIn summary, The Harefield protocol was one of the first studies to successfully combine pharmacological agents with LVAD. Particularly interesting are higher rates of recovery when adjuvant medical therapy is included in the LVAD strategy . TherefoMechanical unloading is associated with cardiomyocyte atrophy, resulting in a decline in myocyte densities and LV mass continuously ,93. The Regenerative therapy is based on embryonal or adult stem cells as an effective therapeutic target for cardiogenesis and angiogenesis. The main goal of this strategy is to boost cell production directly and then indirectly to improve cardiac function by injecting stem cells into a wounded region of the heart . In prioClinicalTrials.gov, accessed on 10 June 2022). Expanding knowledge in this field is aimed to find potential therapeutic targets and limit negative changes caused by prolonged circulatory support. Since microRNAs (miRNAs) were reported as key regulators of cardiomyocyte proliferation, a few studies investigated the possibility to promote cardiomyocyte division and lead heart regeneration by injecting specific RNAs. It has been discovered that the administration of hsa-miR-590 and hsa-miR-199a and, further, miR-19a/19b have enhanced cardiomyocyte proliferation and normalized cardiac function parameters in animal models ,111. MorCardiac metabolism plays a central role in the pathophysiology of HF . Its altp = 0.036) and quality of life after 1 month of treatment compared to the non-treated group [ClinicalTrials.gov, accessed on 10 June 2022) Perhexiline, a drug developed for angina, was proven to be simultaneously favourable for hemodynamic and metabolic cardiac function in cardiovascular disease ,123,124.ed group . Recentln = 19 and n = 55, respectively) and well-designed clinical trials on a bigger scale have not been performed yet. Given insufficient clinical evidence, trimetazidine is not included in the latest ESC Guidelines (2021) for chronic HF treatment [Another mitotrope, trimetazidine, is also thought to have potential cytoprotective effects in HF treatment . It mighreatment .Sodium/glucose cotransporter 2 (SGLT2) inhibitors are thought to be promising cardioprotective agents in cardiovascular diseases. Empagliflozin, the very first tested, was revealed to reduce the risk of HF hospitalization in patients with and without diabetes type 2 ,135. FurThe selective agonists of peroxisome-proliferator-activated receptors (PPARs) regulate the expression of specific genes in lipid or glucose metabolism ,146. TheIn summary, the regulation of cardiac substrate metabolism is an important approach with still few translational trials compared to any other pharmacological agents. It targets cellular and molecular pathways with a proven global effect on the heart, such as FA oxidation, glucose metabolism, ATP production, and even gene transcription. It is underlined that heart recovery is inseparable from specific metabolic changes that not only increase energy production but also activate cardioprotective pathways. Hence, this new therapeutic strategy should be enlarged for LVAD patients, where specific metabolic changes have been recently reported . In thisp = 0.026) and HF hospitalization (p = 0.033) in comparison to the placebo group. These results are in line with a more recent meta-analysis, where reduced mortality and improved exercise capacity were noted in HF patients with CoQ supplementation [Mitochondrial biogenesis, structure, and function have been of special interest with wide clinical testing since their improvement is thought to ameliorate cardiac function directly . The redentation . Moreoveentation . Anotherentation  and its entation . In turnentation . SS-31 sentation  but, in entation . Decreasentation . In addientation . Howeverentation .ClinicalTrials.gov, accessed on 10 June 2022) will evaluate whether boosting NAD+ levels through NR administration may improve cardiac function in heart failure. Despite the lack of studies evaluating the NAD+ pool after mechanical support, it should be emphasized that compounds known to ameliorate mitochondrial structure and function might induce reverse remodelling and thus warrant further investigation.To prevent pathological heart remodelling, it is proposed to maintain the nicotinamide adenine dinucleotide (NAD+) pool and NADH (reduced form of NAD+)/NAD+ ratio . An elevThe anti-inflammatory approach originated from the strong need to counteract high mortality and morbidity, along with a better understanding of protective or harmful immune mechanisms in heart failure progression . It has Patients with LVAD might be at particular risk of a higher level of serum TNF-α levels compared to only HF or HTx subjects . Tabit eAnakinra is a recombinant human receptor for IL-1 and blockades successfully both isoforms (α/β) from proinflammatory signalling. Concordant with prior studies, IL-1 inhibition has effectively dealt with an inflammatory response in acute myocardial infarction  and LV d2+ homeostasis and impaired myocardial contractility through increased intracellular calcium concentrations [Restoration of SERCA2a expression is thought to prevent severe systolic and diastolic dysfunction equally to mechanical assist devices in advanced HF treatment . Down-retrations . Therefotrations . Howevertrations . In turntrations . Therefotrations . The 24 trations . Interestrations . TherefoMany studies highlighted the cardioprotective effect of oestrogen receptors (ER) agonists and suggested therapeutic opportunities in HF treatment ,196. ER A strategy of combining LVAD with intensive pharmacotherapy has demonstrated more favour in cardiac, clinical, and survival outcomes, with a higher likelihood of myocardial recovery than any other form of HF treatment. In this context, progressively more clinical trials provide credibility to combining the benefits of LVAD therapy with novel pharmacotherapies. Considerable potential exists in stem cell therapy, regulators of substrate oxidation, treatment targeted to mitochondrial biogenesis, structure, and function, as well as inhibitors of a harmful immune response. Despite sustained progress in the engineering, experimental, and clinical fields, further investigation is needed to discover mechanisms of reverse remodelling and increase the effectiveness of the bridge to recovery strategy.