To find simple imaging-based features on cardiac magnetic resonance (CMR) that are associated with major adverse cardiovascular events (MACE) in takotsubo syndrome (TTS).2RT score . Clinical follow-up data was reviewed up to three years after discharge. The relationship between PE2RT features and the occurrence of MACE  was examined using Cox regression analysis and Kaplan–Meier estimator.Patients with TTS referred for CMR between 2007 and 2021 were retrospectively evaluated. Besides standard CMR analysis, commonly known complications of TTS based on expert knowledge were assessed and summarised via a newly developed PE2RT score . PE2RT score was associated with MACE on Cox regression analysis . Two or more PE2RT complications were strongly associated with the occurrence of MACE (log-rank p < 0.001).Seventy-nine patients  with TTS were included. CMR was performed in a median of 4 days  after symptom onset. Over a median follow-up of 13.3 months , MACE occurred in 14/79 (18%) patients: re-hospitalisation due to acute symptoms  or chronic heart failure symptoms , and cardiac death . Patients with MACE had a higher PE2RT complication score might enable an easy-to-assess outcome evaluation of TTS patients by CMR.The introduced PE• Complications like pericardial effusion, pleural effusion, right ventricular involvement, and ventricular thrombus (summarised as PE2RT features) are relatively common in takotsubo syndrome.• The proposed PE2RT score (one point per complication) was associated with the occurrence of major adverse cardiac events on follow-up.• Complications easily detected by cardiac magnetic resonance imaging can help clinicians derive long-term prognostic information on patients with takotsubo syndrome. Takotsubo syndrome (TTS), also known as broken heart syndrome or stress-induced cardiomyopathy, is an acute transient cardiomyopathy characterised by left ventricular (LV) systolic dysfunction with reversible regional wall motion abnormalities (RWMA) . The apiWhile the clinical spectrum and epidemiological features of TTS have become increasingly well characterized in recent decades, the data on its long-term prognosis is conflicting: TTS was widely believed to be a benign disease with favourable prognosis and complete recovery of LV systolic function . HoweverCardiac magnetic resonance (CMR) is an important tool in the diagnostic work-up of suspected TTS as it can confirm its diagnosis and differentiate it from other causes of acute cardiac symptoms, such as acute myocarditis , 11. CMRIn this study, we explored the association between pathological CMR findings and the occurrence of long-term major adverse cardiovascular events (MACE) in TTS patients. In particular, easy-to-assess complications like the presence of pericardial and pleural effusions, RV involvement, or intraventricular thrombus, were analysed. The aim of the study was to find simple CMR imaging features associated with TTS outcomes that could be incorporated into an imaging-based score in the daily clinical routine of any cardiovascular imaging centre.This retrospective, observational single-centre study was conducted at a tertiary care centre. From November 2007 to January 2021, patients with clinical suspicion of TTS referred for CMR were identified. TTS was defined based on the International Takotsubo Diagnostic Criteria including CMR results and standard clinical work-up . AccordiCMR was performed using 1.5-Tesla systems . For signal reception, a 16-channel body array coil with a digital interface was used. The CMR protocol consisted of electrocardiogram-gated steady-state free-precession cine imaging  for functional analyses, T2-weighted short-tau inversion-recovery imaging  for the assessment of myocardial oedema, and LGE imaging using segmented inversion-recovery gradient-echo sequence  for the detection of myocardial scarring, necrosis or fibrosis. In a subgroup of patients, additional parametric mapping sequences were available (T1 mapping based on a standard 3(3)3(3)5 modified Look-Locker inversion recovery (MOLLI) acquisition scheme and T2 mapping based on a 6-echo gradient spin echo (GraSE) sequence). Mapping sequences were performed as previously described , 19, 20.pleural effusion (> 20 mm) and pericardial effusion (> 5 mm), right ventricular involvement with visual RWMA [thrombus was assessed and classified as “present” or “not present”. Based on expert knowledge, the PE2RT score was built by calculating the sum of these typical TTS complications (one point for each). The calculated PE2RT score ranged from 0 (no complication) to 4 .Images were analysed in consensus by two radiologists  using certified software . Readers were blinded to clinical outcomes. Functional analysis , assessment of myocardial oedema by visual and semi-quantitative approach , presence of myocardial scars by LGE imaging, and quantitative assessment of global myocardial T1 and T2 relaxation times, and haematocrit corrected extracellular volume fraction (ECV) values were performed standardised according to current recommendations including centre-specific reference values as previously described –22. RWMAFollow-up data were collected by reviewing in-house and outpatient medical records. MACE was defined as a composite of cardiovascular death, re-hospitalisation due to acute myocardial injury , new onset of arrhythmia, or re-hospitalisation due to chronic heart failure symptoms. Cardiovascular death was defined as death directly related to heart failure, myocardial infarction, arrhythmia, or cardiovascular disease. Other causes of death were classified as non-cardiovascular or unknown. The primary endpoint was the occurrence of MACE up to 3 years after discharge.t-test or Mann-Whitney’s U-test for continuous variables, and chi-squared test or Fisher’s exact test for dichotomous variables. Univariable Cox regression analysis was applied to test the association of different clinical and imaging parameters regarding MACE. After a forward selection of relevant covariates with p < 0.05 in univariable analysis, covariates were added in a multivariable model to further fit the impact of variables. Kaplan-Meier analysis stratified by PE2RT score (< 2 vs.  ≥ 2) was performed, and a log-rank test was used to compare survival curves. The level of statistical significance was set to p < 0.05.Statistical analysis was performed using Prism  and SPSS Statistics . Normality assumptions were assessed by visual inspection of the data distribution supplemented by the Shapiro-Wilk test. For continuous variables, data are presented as means ± standard deviation or median with interquartile range (IQR) as appropriate. Categorical variables were presented as absolute frequencies with percentages in parentheses. Group comparisons between patients with and without MACE were performed using Student’s n = 81). Patients with a diagnosis of TTS (n = 79) were included  for analysis. A study flow diagram is presented in Fig. One-hundred-sixty patients referred for CMR with clinical suspicion of TTS were identified. Patients with unconfirmed TTS diagnosis were excluded n = 8. PatientThe demographic and clinical data of the study population at the time of CMR are shown in Table 2RT score was 0 points in 30/79 patients (38%), 1 point in 28/79 patients (35%), 2 points in 12/79 patients (15%), 3 points in 6/79 patients (8%), and 4 points in 3/79 patients (4%). Representative examples of imaging-based complications are shown in Fig. The CMR characteristics of the study population are given in Table The median duration of follow-up was 13.3 months . During follow-up, MACE occurred in 14/79 patients (18%). All events are summarised in Table p = 0.001). On CMR, patients with MACE had lower LV ejection fractions , higher heart rates , and lower T2 signal intensity ratios . No significant differences were found in T1 and T2 relaxation times or ECV values (Table p < 0.001), pleural effusion , ventricular thrombus , and RV involvement . A representative clinical example is shown in Fig. 2RT score was higher in patients with MACE . MACE did not occur in patients who did not have any of the PE2RT features .There were no significant differences in clinical and laboratory parameters between patients with and without MACE, except that of diabetes mellitus Table . In pati2RT score . In multivariable Cox regression analysis, the presence of 2 or more PE2RT features was an independent predictor for MACE   are frequently observed in TTS and are associated with MACE. At least one of these complications was observed in 62% of patients, and at least two of these complications were present in 27% of patients. A PE2RT score of  ≥ 2 was associated with MACE and was identified as an independent predictor in multivariable analysis. Our results demonstrate that a simple CMR assessment of concomitant complications may allow risk stratification of TTS.In this study, we demonstrated that easy-to-identify imaging markers on CMR summarised as PEIn the past, TTS was believed to be a primarily benign syndrome due to recovery of LV function over the short to medium term in the majority of patients. However, in the last decade, several large multicentre studies have shown that the short- and long-term prognosis among patients with TTS is less favourable than previously thought , 2. In aSeveral studies also demonstrated that different clinical  and imaging characteristics  were factors related to worse long-term prognosis , 10, 25.2RT) revealed an HR of 2.38 per score point for the occurrence of MACE during follow-up. A PE2RT score of  ≥ 2 was associated with MACE and was identified as an independent predictor in multivariable analysis. These results are also in partial agreement with an echocardiographic study by Kagiyama et al that revealed a prognostic impact of RV involvement [2DS2-VASc score and GRACE score , also allowed the prediction of mortality and MACE in patients with TTS [Although CMR is becoming more and more important for the diagnostic work-up of patients with suspected TTS , 12, itsolvement . In a reolvement . Applicawith TTS , 29. HowLGE is an established marker of worse outcomes in non-ischemic cardiomyopathies; however, no associations were found between the presence of LGE and the occurrence of MACE in our study. This can be explained by the fact that TTS is predominately characterised by the absence of LGE , 18, altFocal myocardial oedema correlating with typical RWMA is a major diagnostic criterion for TTS, which was present in 94% of patients in our study. Only 6% of patients had a primarily diffuse pattern of myocardial oedema, which could not be detected visually, but with the T2 signal intensity ratio or with T2 mapping. Patients with MACE, however, had less pronounced signs of diffuse myocardial oedema with lower T2 signal intensity ratio values, indicating limited reversibility of myocardial injury. The absence or a lesser degree of myocardial oedema has been reported to be associated with prolonged recovery time or worse outcomes in non-ischemic cardiomyopathies , 32.Our study has limitations. Due to its retrospective design, some clinical and imaging data  was not available for analysis in every patient. Due to the relatively low number of events, the multivariable analysis might be prone to overfitting. Therefore, information on the incremental diagnostic value of the score is limited. Furthermore, our sample size was too small to generate a score that is based on a training and validation cohort. Therefore, the regression models are limited in their generalizability, and this study should be considered hypothesis generating. The proposed complication score needs to be validated in larger TTS cohorts and compared with other clinical and imaging parameters, preferably in prospective studies.2RT score can be visually assessed using standard diagnostic CMR images and does not require any additional advanced quantitative analysis like strain analysis or mapping analysis and can therefore be applied in any clinical centre.In conclusion, our CMR study shows that scoring four easy-to-assess complications  might be useful for long-term risk stratification among patients with TTS. All complications are relatively common in TTS and should generally be included in any CMR report, as their presence may also influence patient management . The proposed PE


In recent years, development of mechanical circulatory support devices has proved to be a new treatment modality, in addition to standard pharmacological therapy, for patients with heart failure or acutely depressed cardiac function. These include left ventricular assist devices, which mechanically unload the heart when implanted. As a result, they profoundly affect the acute cardiac mechanics, which in turn, carry long-term consequences on myocardial function and structural function. Multiple studies have shown that, when implanted, mechanical circulatory assist devices lead to reverse remodelling, a process whereby the diseased myocardium reverts to a healthier-like state. Here, we start by first providing the reader with an overview of cardiac mechanics and important hemodynamic parameters. We then introduce left ventricular assist devices and describe their mode of operation as well as their impact on the hemodynamics. Changes in cardiac mechanics caused by device implantation are then extrapolated in time, and the long-term consequences on myocardial phenotype, as well as the physiological basis for these, is investigated. Chronic pathological hemodynamic stress following an index event  alters myocardial molecular, cellular, and interstitial factors, manifesting clinically as changes in size, shape, and function of the heart. Each stressor can affect the operation and mechanics of the heart distinctly across time and with often different underlying mechanisms , 2. HoweMechanical support devices can provide univentricular or biventricular support, can be implanted percutaneously or surgically, provide varying amounts of cardiac output (CO) support and for different durations . An impoIn this review we focus exclusively on LV assist devices (LVADs)—that is, those that mechanically unload the LV. These include both durable LVADs (d-LVADs), such as the HeartMate 3, which are surgically implanted and can be used for prolonged periods of time, as well as transvalvular micro-axial flow pump devices (tma-LVAD), such as the Impella, which can be percutaneously implanted and are typically used for acute mechanical support and for shorter durations . We begiTo understand the effects of mechanical support devices on cardiac mechanics an understanding of pressure-volume (PV) loops is required. A brief description of the main determinants of cardiac mechanics is shown here—for a more detailed review see .Ea) shown as a line that connects the end-diastolic (EDV) and end-systolic (ESV) volume points  via the Frank-Starling relationship. Preload refers to the mechanical load the heart is exposed to prior to the beginning of systole—it is appreciated by the end-diastolic pressure or volume point in the PV loop . Afterloe points . The Fra2) (see below). Cardiac function is dependent upon preload and afterload and so within the in vivo state where these are constantly varying it is challenging to assess unless they are well controlled for (E(t), that has enabled determination of cardiac function irrespective of mechanical load. E(t) is a load-independent measure of contractile state and is defined using E(t) is the instantaneous elastance, P(t) and V(t) instantaneous pressure and volume respectively and DV is dead volume—that is, the volume below which no pressure generation occurs in the heart (Ees), can be approximated by the instantaneous end-systolic pressure-volume relationship (ESPVR), which is a load-independent measure of intrinsic contractility (Ees), while decreased contractility, known as decreased inotropy, has opposite effect (The PV loop is demarcated by the 4 phases of the cardiac cycle : (1) iso2)  9) (see (see2)  pumped from the LV to the aorta irrespective of cardiac cycle phase. The continuous antegrade flow leads to a loss of the isovolumic contraction phase of the cardiac cycle, resulting in a “triangular” shaped PV loop that shifts down and to the left  42)..42).The degree to which the loop will shift to the left, and thus the LV will be unloaded, depends on the extent of support provided by the device , which is adjustable . Increas2, is determined by the area under the PV loop curve and corresponds to stroke work plus potential energy   , 48   9). dem. dem2, i2 in accordance with Laplace's law of the heart, protecting the heart from ischemic injury  diastolic stress on the heart, and (b) stroke volume (given Frank-Starling) decrease. In hemodynamically unstable patients this is critical, as decreased myocardial stress correlates to decreased MVOc injury . Decreas control . The Pro control , compare control . Of note control , 54. Oth control . Part of control , 56.PAo, and left ventricular diastolic pressure, PLV, according to the In addition to lowering oxygen demand, LVAD devices can also increase myocardial oxygen supply by increasing coronary perfusion pressures. Coronary blood flow occurs in diastole and is a function of the pressure gradient between aortic pressure, Despite known improvements in CO and left diastolic pressures after LVAD implantation , reporteEes) is unable to match the pulmonary vasculature afterload (Ea), RV dysfunction occurs. As aforementioned, the increased preload with increased pump speeds can further contribute to this. Alternative treatment strategies, such as blood pressure control with or without increased pump speed and stratified by patient specific hemodynamic parameters, such as decreased coupling ratio (RV Ees/aE) (Aortic insufficiency (AI) is another common complication of LVAD, affecting up to 20% of patients within 1 year of implantation , and can Ees/Ea)  or incre Ees/Ea) .Mechanical unloading is associated with recovery of cardiac function, in a process known as reverse remodelling , 69. We Long-term LVAD use leads to reduced LV and left atrial (LA) volumes , 71. VenRecently, such changes in ventricular structure have been shown to be maintained with more prolonged device implantation . In pati2+ content  composition, structure and its cellular interactions are vital in adaptation to hemodynamic and neurohormonal stressors . LVAD-inNumerous clinical studies demonstrate that neurohormonal blockers reverse pathological cardiac remodelling by restoring normal heart geometry, reducing LV volume and mass, and improving LVEF . During An understanding of the effects on mechanical support devices on hemodynamics is essential to appreciate their mechanism of action and therapeutic potential. In this review, we have discussed the use of LVADs as mechanical support devices. We have covered their immediate hemodynamic consequences, the long-term effects of these on the mechanical and neurohormonal axis, as well as the key mechanisms of reverse remodelling as well as the phenotypic alterations.


Autonomic imbalance between the sympathetic and parasympathetic nervous systems contributes to the progression of chronic heart failure (HF). Preclinical studies have demonstrated that various neuromodulation strategies may exert beneficial cardioprotective effects in preclinical models of HF. Based on these encouraging experimental data, vagus nerve stimulation (VNS) has been assessed in patients with HF with a reduced ejection fraction. Nevertheless, the main trials conducted thus far have yielded conflicting findings, questioning the clinical efficacy of VNS in this context. This review will therefore focus on the role of the autonomic nervous system in HF pathophysiology and VNS therapy, highlighting the potential reasons behind the discrepancy between preclinical and clinical studies. It has It is widely accepted that HF is characterized by an autonomic imbalance with a sustained increase in sympathetic drive and by withdrawal of parasympathetic activity . Decreas2.It has been considered for decades that HF is characterized by autonomic imbalance and hormonal hyperactivity. Autonomic dysfunction has been regarded as a manifestation of the clinical syndrome of HF, presumably as a consequence of hemodynamic changes associated with alterations in cardiac function , 10. AutAt the cardiac level, cardiac ganglionated plexi (GPs) exist in the fat pads around the heart and constitute the so called “intrinsic cardiac nervous system”. GPs connect with the intrathoracic extracardiac ganglia . The nodose ganglia (the inferior ganglia of the vagus nerve) are extrathoracic and extracardiac while the dorsal root ganglia are intrathoracic and extracardiac. At each level, the system has the ability to modulate cardiac activity with efferent feedback loops. GPs coordinate the sympathetic and parasympathetic inputs received from the rest of the cardiac ANS .Sympathetic hyperactivity produces cardiac toxicity, which induces interstitial fibrosis, cardiac apoptosis, and inflammation . On the Vagal withdrawal is also a critical element in the pathophysiology of chronic HF. Lower vagal activity is associated with unfavorable long-term prognostic implications for patients with HF , 23. Ove3.Multiple mechanisms responsible for the protective effects of VNS on failing hearts have been observed . It has 3.1.VNS could improve autonomic imbalance in failing hearts. The stimulation electrode is implanted in the mid-cervical portion of the vagal nerve and delivers a biphasic current that continuously cycles between on and off periods. Vagal afferent activation generated by VNS projects to the medulla located in the brainstem . The medThe cervical vagal nerve contains both afferent and efferent fibers. Vagal fibers include A-, B- and C-fibers . Differe3.2.Nitric oxide (NO) plays a critical role in normal physiological functions and pathophysiological development in the heart. There are 3 distinct isoforms of nitric oxide synthase (NOS): neural NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS) , 37. NO 3.3.As cardiac output becomes less efficient, a reduction in renal reperfusion increases the secretion of renin and activates the renin-angiotensin system (RAAS). Renin is a circulating aspartic proteinase that converts angiotensinogen to angiotensinogen I. Subsequently, angiotensinogen I is rapidly cleaved by angiotensin-converting enzyme to generate angiotensinogen II (Ang II). The effects of Ang II include vasoconstriction, ventricular remodeling, fibrosis, endothelin generation and sympathetic nervous action. Ang II contributes to enhancing sympathetic outflow in HF via central and peripheral effects. Mounting evidence demonstrates that AngII contributes to the increased SNA in CHF by acting in different brain regions, including the PVN, RVLM and area postrema. Ang II facilitates sympathetic neurotransmission at adrenergic nerve endings , 43. VNS3.4.The vagal nerve facilitates the interactions of the neuroimmune system. It is now clear that VNS treats various inflammatory disorders of the organism. VNS contributes to controlling the inflammatory response by the cholinergic anti-inflammatory pathway through a vago-vagal reflex . Choline4.Preclinical studies suggested that chronic VNS could exert protective effects on the heart in animal models of heart failure see . In 2004Hamann et al. developed a canine model of HF induced by intracoronary microembolizations that has been used for chronic vagal nerve stimulation without causing heart rate reduction. They found that VNS treatment significantly increased LV ejection fraction, reduced left ventricular chamber dimension, and improved biomarkers of inflammatory cytokines and cellular apoptosis in heart failure . These p5.VNS was approved for the treatment of patients with drug-refractory epilepsy in 1997 and medically refractory depression in 2005. Based on the efficacy of preclinical studies and the safety of VNS management in patients, clinical studies of the treatment of VNS were started see .Schwartz et al. reported a single-center pilot study of 8 patients with severe HF who were implanted with the Cardiofit system. This first-in-man experience of chronic VNS in patients with HF demonstrated that VNS significantly reduced the NYHA classification, markedly improved the quality of life and decreased left ventricular end-systolic volume . This re6.Currently, most neurostimulation devices provide stimulation in an open-loop manner; however, closed-loop neurostimulation devices  may provide more effective and efficient therapy. Herein, we focused on clinical trials of implantable closed-loop vagus nerve stimulation for the treatment of chronic heart failure , 62. Thep < 0.05), but no significant decrease in LV end-systolic volume was noted. Improvements in NYHA classification (77% of patients) and the Minnesota Living with Heart failure score were observed. Interestingly, no statistical significance was noted between left-sided and right-sided vagal stimulation. Owing to insufficient dosing of autonomic regulation therapy (ART) such as VNS, larger clinical studies need further to be studied. Recently, the ANTHEM-HFrEF study was designed to explore whether VNS using appropriate ART could improve morbidity and mortality as well as symptoms and function for patients with advanced HF. The ANTHEM-HFrEF study, with adaptive sample size selection, is an adaptive, open-label, randomized, controlled study . No significant change in the LV end-systolic dimension of the primary endpoint was noted. No significant differences in LV end-systolic and diastolic volume, LVEF or plasma biomarkers were noted as secondary endpoints, whereas significant improvements in NYHA functional class and quality of life were observed .The INOVATE-HF study was a pivotal phase III multicenter study enrolling 707 patients with NYHA class III, LV ejection fraction <40% and LV end-diastolic diameter 50–80 mm. Patients were randomized 3:2 to either the VNS group or the sham implantation group. The primary endpoints of this study focused on complications at 90 days, all-cause mortality and HF hospitalizations at 12 months. This trial was stopped in the last year by the Steering Committee due to the results. There was no significant difference in primary efficacy between the VNS group and the control group. No significant difference in LV end-systolic volume index was observed between groups. However, significant improvements in NYHA classification, quality of life and 6 min walking distance were noted , n is the parasympathetic influence (<1), and HR0 is the intrinsic HR (p = <0.0005) after 12 months of VNS, while SDNN from HRV increased from 95 ms to 109 ms (p = <0.01). This information is not presented in the INOVATE-HF study, so it is not possible to determine the effectiveness of PNS stimulation that was applied in this study.Resting heart rate (HR) is a simple index reflecting the external autonomic regulation of the intrinsic heart rate at the sinus node level that is achieved with the combined activity of the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS). In fact, heart rate has two components -the intrinsic and the extrinsic component. Intrinsic HR is the HR measured in the absence of sympathetic and parasympathetic inputs (achieved by denervation or pharmacologic blockade). In healthy human subjects, this is approximately 100 bpm and is age- and gender-dependent . Intrinsinsic HR . Given tIt is currently unknown what the most appropriate stimulation protocol would be. Indeed, all studies applied protocols with variances in amplitude, frequency of stimulation, and afferent—efferent vagus activity targeting . The effectiveness of the applied protocol may be estimated according to the above comment 1 from ΔHR while ΔHR = HR baseline—HR post VNS. Additionally, measuring the differences in plasma concentrations of catecholamines pre- and post-VNS (Δ Nor-Epinephrine and Δ Epinephrine) may also serve well as a useful biomarker of a therapeutic efficient new SNS-VNS status, especially if these catecholamines are found to decrease after VNS application. Before any VNS study's results be interpreted, it is necessary to clarify whether the applied VNS protocol was optimal and therapeutic. One simple way to quantify the response of the ANS to the applied VNS is by comparing the achieved differences in heart rate and catecholamines.It is unclear whether the afferent or the efferent vagus nerve fibers targeting neurostimulation is cardio-protective. Afferent targeting VNS may be necessary for ANS central reset. Further research is required. Vagal function may include two distinct components: reflex vagal activity  and toni9.The auricular branch of the vagus nerve (ABVN) on the outer ear is the only peripheral branch of the vagus nerve distributed on the skin . TranscuThe different translation results of VNS treatment on HF, another reason was that the patients were not able to tolerate higher-intensity stimulation in clinical trials. As a result, VNS could not achieve the effective stimulation. In order to reduce the adverse effects and increase the tolerance of VNS, recently, selective VNS was also considered as a promising strategy –93. Sele10.Experimental and clinical pilot studies of VNS yielded encouraging results in the treatment of HF. However, the results of large randomized clinical trials have been disappointing. The discrepancy between experimental and large clinical trials may be associated with optimal dosing of stimulation, appropriate patient selection, and study design. The clinical translation of VNS in the treatment of HF is a challenge. The era of vagus nerve stimulation for the treatment of heart failure is approaching; however, significant experimental and clinical research is still needed .


Systemic lupus erythematosus (SLE) is a chronic inflammatory disease, and several studies have suggested possible early RV involvement. Aim of the study was to evaluate the 3D echo parameters of the right ventricle (RV) and the metabolomic profile to correlate both with SLE severity. Forty SLE patients, free of cardiovascular disease, were enrolled and the following 3D parameters were evaluated: the RV ejection fraction (RV-EF), longitudinal strain of the interventricular septum , longitudinal strain of the free wall (Free-LS) and the fractional area change (FAC). In addition, a metabolomic analysis was performed. Direct correlations were observed between TAPSE values and the RV 3D parameters. Then, when splitting the population according to the SDI value, it was found that patients with higher cumulative damage (≥3) had significantly lower FAC, RV-EF, Septal LS, and Free-LS values; the latter three parameters showed a significant correlation with the metabolic profile of the patients. Furthermore, the division based on SDI values identified different metabolic profiles related to the degree of RV dysfunction. The RV dysfunction induced by the chronic inflammatory state present in SLE can be identified early by 3D echocardiography. Its severity seems to be related to systemic organ damage and the results associated with a specific metabolic fingerprint constituted by 2,4-dihydroxybutyric acid, 3,4-dihydroxybutyric acid, citric acid, glucose, glutamine, glycine, linoleic acid, oleic acid, phosphate, urea, and valine. Systemic lupus erythematosus (SLE) is a systemic chronic disease characterized by the aberrant activity of the immune system that leads to a highly variable course and prognosis. SLE affects nearly 1.5 million people in the United States, and its prevalence is three- to four-folds higher in Black than in White females . We . We 4]. 3. Subsequently, to evaluate the possible presence of RV dysfunction due to the underlying disease, we split the population according to the SDI values in patients with the absence of cumulative systemic damage (score = 0) and patients with more significant impairment (score ≥ 3).4. Patients with higher cumulative damage showed statistically significantly lower RVEF, RVLS septal, RVLS Free, and FAC values than individuals with minimal impairment .1H-NMR: The metabolomic analysis highlighted a statistically significant correlation between the metabolism of the enrolled subjects and the RVLS septal, while the correlation with the RVLS Free did not reach significance (p = 0.09).2  and Q2 (0.635), which were confirmed by ANOVA cross-validation (p = 0.04).Subsequently, we verified whether the division into two groups carried out based on SDI values allowed us to identify different metabolic profiles related to the degree of RV dysfunction identified with 3D echocardiography; the built OPLS-DA model showed good values of RGC/MS: Analyses carried out using GC/MS allowed us to find significant correlations between the metabolism of LES patients and several 3D RV systolic parameters: RVEF, RVLS Free, and RVLS Septal .p-value, good values for the R2 and Q2 ; the metabolites that were significantly involved in the observed correlations and clustering both at the multi-variate and univariate analyses were: 2,4-dihydroxybutyric acid, 3,4-dihydroxybutyric acid, citric acid, glucose, glutamine, glycine, linoleic acid, oleic acid, phosphate, urea, and valine .Overall, these results allow us to hypothesize that SLE causes progressive RV dysfunction, which was correlated to the severity of the cumulative damage and associated with a specific metabolic fingerprint.RV failure represents the leading cause of morbidity and mortality in SLE patients and substantially impacts the quality of life and prognosis in these subjects.Buonauro et al. already demonstrated a reduction in the 3D FE, RVLS septal and RVLS free values in SLE patients compared with healthy controls . In our It is known how the TAPSE correlates with the RVFE measured with the scintigraphic method and with right cardiac catheterization ,15, and In line with these data, the evidence of a more significant RV function impairment in patients with higher SDI values was found, which, therefore, led to a higher burden of organ damage. In addition, the reduction in TAPSE measured with the M-Mode in the SDI ≥ 3 group was associated with the reduction in systolic function parameters, both of those based on the study of size (FAC and RVFE) and those derived from myocardial deformation  .Tektonidou et al. found diastolic dysfunction of the RV and antibodies syndrome in SLE patients, regardless of the presence of valvular disease and RV systolic dysfunction . In anotLeal et al., using 2D echocardiography and LS evaluation, identified a subclinical systolic dysfunction of the RV in children with childhood-onset SLE .Despite these exciting results, 3D ultrasound is superior to 2D; in fact, the 3D volumetric reconstruction of cardiac structures is not based on geometric assumptions, but on the direct measurement of volumes and, therefore, of the EF. Quantifying RV geometry and function using 3D ultrasound was reproducible and accurate, even when compared with cardiac MRI ,24.Vitarelli et al. demonstrated the prognostic value of 3D RVEF in patients with acute pulmonary embolism, which is a clinical condition in which increased pulmonary pressures are often present .Although few studies have evaluated the association between 3D LS and clinical outcomes, its feasibility has also been confirmed in clinical practice .Also, in our study, the 3D evaluation allowed for unmasking an early longitudinal dysfunction of the RV that was correlated with the severity of the patients’ global organ damage.Pieretti et al. had already shown that, in SLE patients without clinical or echocardiographic evidence of valvular or coronary artery disease, the SDI could predict an increase in LV mass . The SDIThe finding of early and subclinical impairment of the RV systolic function is not simple instrumental data; it represents a critical issue, since RV dysfunction is associated with poor prognosis and higher mortality risk in comparison with subjects with a preserved systolic capacity, as was already highlighted in patients affected by PH .Moreover, both left and right ventricular dimensions and function modifications correlate with prognosis ,30 and rOn these bases, the evaluation of the RV is of outstanding importance and could become a routine practice for cardiologists in the setting of both primary and secondary cardiovascular diseases. In the setting of SLE, the degree of longitudinal dysfunction of the RV is, on the whole, associated with the extent of organ damage measured with the SDI.Inflammation is a biological defense system, which is essential in response to pathogenic noxae, such as infections or tissue damage, and it is supported by the activity of the immune system in order to ensure survival. Inflammatory responses may be considered as part of a classic homeostatic system, which maintains the normal function of organs and systems .In the heart, the activation of “sterile” inflammatory processes is mainly similar to that observed during infections: this involves the release of vasoactive peptides; the expression in cardiac cells  of adhesion molecules (such as vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1), which promote the myocardial recruitment of inflammatory cells ; the release of inflammatory cytokines and chemokines; and the activation of adaptive immune responses mediated by T cells ,35,36,37The activation of inflammatory processes in the RV is associated with and contributes to its remodeling and progression to dysfunction ,38,39.In RV failure, a high expression of cytokines and chemokines modulates numerous intracellular pathways in cardiac cells, thus leading to hypertrophy and the death of cardiomyocytes, mitochondrial dysfunction, endoplasmic reticulum stress, and cardiac fibrosis, which is characterized by fibroblastic proliferation and differentiation, as well as collagen deposition ,37.Furthermore, these inflammatory mediators can also alter the myocardium’s metabolic processes and the cardiomyocytes’ contractile properties.This data seems to be confirmed by the results of the metabolomic analysis, which showed a direct correlation between RV systolic parameters, such as EF and LS, and the metabolism of SLE patients.Our group had already demonstrated a correlation between the LV longitudinal systolic function, assessed by the longitudinal strain rate, and the metabolic profile of healthy subjects and patients suffering from heart failure of increasing degrees .Few works in the literature evaluate metabolism in pulmonary hypertension and RV failure; our study is the first in humans to investigate the correlation between metabolism and RV systolic function in SLE patients who are PH-free, with traditional parameters of systolic function that are still within normal limits, but with echocardiographic evidence of subclinical RV dysfunction.The correlation between the RVEF and RVLS septal and the RVLS free and metabolism suggests that, even in the RV, the biogenesis of chemical energy is fundamental for maintaining contractile function. It is well known that myocardium metabolism is based, in physiological conditions, on the preferential use of free fatty acids, while, in the course of the disease, it switches to the consumption of glucose .In line with this hypothesis, various studies have shown impairment in the energy metabolism of the RV over the course of hypertrophy/failure.RV maladaptive alterations involve aerobic glycolysis  and glutaminolysis (which reflects the activation of cMyc induced by ischemia) .Accordingly, our findings show the importance of glucose, fructose, citric acid, glutamine, ketone bodies, oleic, and linoleic acids in determining the clustering of impairment degree and the correlations with the echocardiographic parameters of RV systolic function.Overall, these findings seem to point out a disarrangement of the energetic metabolism of the RV, and it has already been demonstrated that, in experimental RV hypertrophy, the glycolytic metabolic shift is associated with RV dysfunction . This me2+ stress under normoxia [More recently, Fowler’s group demonstrated that an altered functioning of the creatine kinase system is present in the decompensated RV and that an improvement in energy metabolism could be one of the causes of the better survival of rats with PH that were treated with beta-blockers . In linenormoxia ; furthernormoxia .Another metabolite that suggests an energetic metabolism alteration is the urea, whose cycle upregulation can increase the contribution of arginine to the Krebs cycle through the generation of fumarate, which acts as a Krebs cycle intermediate ; in addiIn this context, cytokines play a crucial role : among tIn conclusion, our study confirms the efficacy of 3D echocardiography in identifying RV function subclinical changes in SLE patients, especially in the absence of clinical evidence of cardiovascular disease. Furthermore, the alteration of RV systolic function, which underlies the existence of subclinical damage to the RV myocardium, correlates with SLE patients’ metabolisms, and the latter results are different based on the SDI values.The ability of the OPLS-DA to discriminate between the groups based on the SDI score, together with the correlation between metabolism and RV systolic function parameters, seem to suggest that the subclinical dysfunction identified in SLE patients results from myocardial damage that is induced through various mechanisms, including oxidative stress and by inflammatory cytokines; this damage would subsequently be superimposed on alterations in energy metabolism that would likely be similar to those observed in left ventricular decompensation, which would perpetuate and aggravate RV dysfunction.


The development of microvascular plugs (MVPs) has enabled novel transcatheter deliverable endoluminal pulmonary flow restrictors (PFRs) with the potential to treat newborns and infants with life-threatening congenital heart diseases (CHDs) in a minimally invasive manner. We present our experience to evaluate the efficacy of this concept in controlling pulmonary blood flow in various CHDs.Retrospective clinical data review of patients with CHD and pulmonary over-circulation who received bilateral PFRs percutaneously.Twenty-eight PFRs  were finally implanted in 14 patients with a median age of 1.6 months  and a median weight of 3.1 Kg . Nine patients had large intra-cardiac left-to-right shunts , 2 had borderline left ventricles, 2 had Taussig-Bing anomaly, and one had a hypoplastic left heart. Four patients had concomitant ductal stenting. Two MVP-5Qs were snare-removed and upsized to MVP-7Q. Patients experienced a significant drop in oxygen saturation and Qp/Qs. All patients were discharged from the ICU after a median of 3.5 days  postoperative. Five patients had routine inter-stage catheterization and no device embolization or pulmonary branch distortion was seen. Fourteen (50%) PFRs were surgically explanted uneventfully on a median of 4.3 months  post-implantation during biventricular repair in 6 patients and stage-2 palliation in one patient. The latter died 1 month post-operative from severe sepsis. Four patients are scheduled for surgical PFR removal and biventricular repair. Two patients with trisomy 18 died at 1 and 6.8 months post-procedure from non-cardiac causes. One patient with trisomy 13 is alive at 2.7 months post-procedure.It is feasible to bespoke MVPs and implant them as effective PFRs in various CHDs. This approach enables staged left ventricular recruitment, comprehensive stage-2 or biventricular repair with lower risk by postponing surgeries to later infancy. Device explantation is uneventful, and the outcomes afterward are promising. A novel, less invasive, and less aggressive potential alternative is to manually convert the thin polytetrafluoroethylene (PTFE)-covered, nitinol-framed, self-expandable microvascular plugs (MVPs)  from occlusion devices into endovascular pulmonary flow regulators (PFRs) –3. Follo2.2.1.We performed a retrospective clinical data review of all patients with CHDs who had transcatheter implantation of manually modified MVPs to PFRs at our institutions between September 2021 and September 2022. Standard safety and outcomes were assessed. All cases were discussed and approved during multi-disciplinary team meetings before the intervention. Approval from the institutional review board was obtained. Signed informed consent was obtained for the patient's legal guardians. This approach was applied as a part of total percutaneous stage 1 palliation in patients with a single ventricle. The PFRs were also used as short-term palliation in patients with two ventricles and significant left-to-right shunts such as atrioventricular septal defect (AVSD) or large ventricular septal defect (VSD) before complete repair. Patients with fatal trisomy 13 or 18 had palliative care programs. Some patients were deemed high-risk surgical candidates or needed time for staged left ventricular recruitment.2.2.The MVP is a US FDA-approved and CE-marked self-expanding mechanical occlusion device. It is designed as a single-cage hexagonal framework made of a flexible, laser-cut Nitinol wire . The mai2.3.Considering that MVPs are originally designed for occlusion of less dynamic peripheral vasculature, the sizes of the manually modified devices were oversized according to the branch PA diameter. We implanted MVP-5Q for vessels with a diameter up to 4 mm, MVP-7Q for up to 6 mm, and MVP-9Q for up to 8 mm.2.4.ex-vivo theoretical calculated area of the fenestrated triangle within each model and the equivalent inner diameter of a circle with the same area are outlined in The first operator stabilized the position of the MVP by holding the delivery cable with one hand and fixing the distal radiopaque marker with the other hand with toothless forceps. It is important not to hold the nitinol cage because it is flimsy. The second operator used a thin carbon steel surgical scalpel blade No. 11  to slice the PTFE membrane within the selected diamond at the most proximal inflow V-line of the nitinol wire. We speculated that this will keep the fenestration open even if there is compression on the device after implantation. The PTFE membrane was held under slight tension with toothless forceps. The distal base of the triangle was sliced with the scalpel to fenestrate half a diamond  . The PTF2.5.The intervention was performed under general anesthesia, antibiotics prophylaxis, systemic heparinization, and biplane fluoroscopy. Anemia was corrected before the procedure to avoid jeopardizing the hemodynamic assessment. Femoral venous access was obtained with a 4 or 5-Fr Prelude sheath introducer . 6-Fr venous access was obtained in case of concomitant ductal stenting or balloon atrial septostomy. Jugular access was used in case of compromised femoral access. A 4-Fr arterial line was obtained. The QP/QS measurement was performed under an inspired fraction of oxygen (FiO2) at 21%. The tricuspid valve was crossed with a standard 2.7-Fr Progreat  or a steerable SwiftNINJA®  microcatheters. A 4-Fr multipurpose Radiofocus GlideCath  was used for selective hand angiograms in the left pulmonary artery (LPA) in 30° left anterior oblique/lateral 90° projections and in the right pulmonary artery (RPA) in 30° right anterior oblique/lateral 90° projections . AngiogrWhen needed, balloon atrial septostomy was done before bilateral PFR placement and finally, the ductal stenting, as is routine in the Giessen hybrid approach . It is tAfter size selection, preparation, and modification of the MVP device, the system was then inserted in the same glide catheter through the Y-connector. It is important to go distally, place the distal radiopaque marker at the target area, and then rapidly uncover the MVP . The disThe RPA was then engaged using the microcatheter, but more carefully not to accidentally cross to LPA, even with wire, as this could change the geometry of the left PFR. The coronary wire was then placed distally over which the glide catheter was taken distally in the RPA. After the right PFR deployment, we did an exit angiogram  and anot2.6.Post-procedure, all patients were sent sedated and intubated to the intensive care unit, and were weaned progressively from ventilator overnight or the next day. Follow-up drug treatment consisted of continuous infusion of heparin (20 UI/kg/h) for 2 days, overlapped by daily oral clopidogrel (0.2 mg/kg) and acetylsalicylic acid (5 mg/kg). In all patients receiving diuretics (furosemide 1 mg/kg/dose every 8 or 12 h and spironolactone 1–2 mg/kg daily given in 1–2 divided doses) before the intervention, diuretic therapy was kept identical the next post-procedure day. Patients were slowly weaned off the diuretic therapy over 2–7 days according to the oxygen saturation and ultrasound assessment of the intravascular volume. No other cardiovascular drugs were used. Following discharge, routine outpatient follow-ups were scheduled. The assessment included clinical evaluation, physical examination, saturation measurements, and TTE. Before surgical explantation of PFRs, follow-up cardiac catheterization was performed in patients with borderline anatomy and physiology to decide on the repair project. Patients with large intra-cardiac left-to-right shunts (AVSD and VSD) were directly sent for surgical explantation of PFRs and biventricular repair.2.7.U test. A p-value <0.05 was considered statistically significant. All reported p values are two-sided.Statistical analyses were performed using SPSS, Version 22.0 for Macintosh . Categorical variables were reported as frequency and percentage and continuous variables were represented as median with IQR (interquartile range) as appropriate. Statistical analysis for continuous variables was conducted using Mann–Whitney 3.During the study period, 28 PFRs  were finally implanted in 14 patients with a median age of 1.6 months  and weight of 3.1 Kg . Nine patients had large intra-cardiac left-to-right shunts, 2 had borderline left ventricles, 2 had Taussig-Bing anomaly, and one had a hypoplastic left heart. Six patients with large intra-cardiac left-to-right shunts had trisomy disorders . The patients' clinical characteristics are outlined in 3.1.At the time of the intervention, 7 patients were intubated, 7 had non-invasive ventilation support and 6 had inotropic support. Three patients had balloon atrial septostomy. No branch PA stenosis was identified on baseline angiography. The median diameter of LPA was 4.8 mm  at the proximal segment and 4.5 mm  at the distal segment. The median diameter of RPA was 5.4 mm  at the proximal segment and 5.1 mm  at the distal segment. Two MVP-5Qs were wasted. In patient no. 5, MVP-5Q was pulled out, after release, with a 7 mm micro-snare from the LPA because it was loose and was upsized to MVP-7Q. In patient no. 8, we retrieved one MVP-7Q from the LPA before release because the patient became cyanotic. We tried the MVP-5Q but it was loose and was removed. We re-implanted the previously used MVP-7Q after adding another triangle. The Doppler pattern was not the reason to switch devices in both patients.p < 0.001). The baseline oxygen saturation significantly decreased from a median of 100%  to a median of 85%  (p < 0.001). Four patients had subsequent ductal stenting. The median overall fluoroscopy time was 27.5 min . In patient no. 5, short-run supraventricular tachycardia was treated with cold saline infusion. There was no device embolization or procedure-related death. The procedural data and clinical outcomes are outlined in We obtained a systolic-diastolic Doppler flow profile in all patients before device release. It is noteworthy that we haven't witnessed hemodynamic changes after first implanting the left PFR. At the end of the intervention, the baseline Qp/Qs significantly decreased from a median of 3  to a median of 1.4   postoperative. No inotropic support was needed after extubation. All patients were discharged from the intensive care unit after a median of 3.5 days  postoperative. At hospital discharge, the median non-invasive oxygen saturation was 90% , the median maximum velocity of the continuous-wave Doppler tracing was 3.9 m/s  on LPA and 3.9 m/s  on RPA.3.3.On a median follow-up of 5.3 months , there was limited variability in the oxygen saturation and the maximum velocity of the continuous-wave Doppler tracing on both PA branches . Five pa4.Conventional surgical PA banding has been practiced for almost 70 years, but it is a procedure that carries multiple potential risks and morbidities , 7. ThisWe observed that all patients with intra-cardiac shunts did well, especially when treated early. The vascular pulsatility is more apparent in QP/QS mismatch lesions and the PA cross-sectional shape is not completely circular both leading to higher odds of para-device leaks. For those reasons, early interventions when PA branches are not yet dilated and over-pulsatile should give better results when compared to later interventions beyond 6 weeks of age. Having a large ductal shunt on top of the intracardiac shunt will increase the oxygen saturation but the symptoms will improve. This is not surprising because the arterial duct will shunt in the systolic and diastolic phases while VSD will shunt only in the systolic phase.Post-natal biventricular repair is uncertain in patients with a small ventricle. The hypoplastic ventricle must be rehabilitated using a balanced procedure that allows adequate blood flow in the ventricular cavity for further post-natal growth of the borderline left heart structures. This new appealing transcatheter concept turned out also a safe and effective strategic choice for patients with borderline left heart structures to avoid sophisticated neonatal biventricular repair and to lay the basis for further post-natal growth of the sub-aortic chambers .4.1.Modified MVP is an attractive device to be used as an endovascular band due to its low profile, smooth delivery, easy positioning, and retrievability . Howeverex-vivo conditions, equivalent to the overall surface area of a circle PA band with an inner diameter of 2.8, 3.9, and 4.4 mm in luminal diameter, respectively (in-vivo.Customization of the MVP is a new highly appealing concept and the overall experience is limited to two reports , 4. Everectively . In retrWe used the multipurpose GlideCath and did not replace it with a slightly angled Judkins right or Cobra-shaped glide catheter for PFR placement as has been previously reported by other colleagues –4. This We acknowledge the risk of jailing the upper lobe branches. However, this risk is minimized with appropriate device size to ensure stable positioning, keeping in mind that MVP distal part is not covered. The soft Nitinol skeleton allows to retract and re-position the MVP until satisfactory implantation is obtained. Hence, care should be taken with repeated device re-sheathing as this may lead to small tears in the PTFE membrane . It has 4.2.ex-vivo luminal size of the PA band and control the degree of pulmonary flow restriction (By uncovering a specific number of triangles at the proximal end, one could accurately predict the theoretical triction . The MVPtriction . This isRetrieval of those plugs is technically easy and it has been previously described –4. Altho4.3.Most of our patients had a weight higher than 2.5 kg and probably would not have major contraindications for surgical PA banding. We adopted this promising novel transcatheter deliverable endoluminal PA bands to avoid one surgical step and sternotomy. There is a learning curve to achieve before taking this practice to a wider scale. Longer-term comparison studies are necessary to demonstrate the benefits over existing therapies. Treating PA branches with diameters beyond 8 mm will likely cause distal migration of the MVPs exposing the upper lobe branches or jailing them. More importantly, the para-device leak is more considerable when reaching those sizes.We adopted the usual practice of monitoring the efficacy of surgical PA bands, which is the peak Doppler gradient. Previous teams noticed that the diastolic gradient increases over time resulting in increases in the mean gradient. We, however, did not record the mean gradients to discuss that observation. It is also noteworthy that hemodynamics including PFR characteristics are different in anesthetized or deeply sedated patients and the PFR effects can be very different. Effectiveness of the endoluminal PA band determined by clinical signs and Doppler pattern should be also analyzed in terms of cardiovascular co-medications affecting residual or intermittent overflow conditions. Speculating about the definition of an “optimal” sized hole for a PFR is highly debatable. For those reasons, we used several parameters to evaluate the efficacy of the endoluminal band such as oxygen saturation, blood pressure, angiograms, cardiac index, and ultrasound peak systolic gradients.Our experience with the percutaneous stage-1 approach in patients with HLHS is limited to one. During surgical PFR removal in patient no.14, the left side was unproblematic, but there was a laceration on the right side. Patch expansion of the LPA or prophylactic stent placement can be needed during stage-2, but should not be necessary . HoweverWe had a small group of patients with fatal trisomy disorders who were stuck on the mechanical ventilator for multiple reasons, including the left-to-right shunt. Although we managed the QP/QS mismatch, as demonstrated by invasive measurements, these patients are not always going to benefit from the intervention. They have more complex respiratory, neurological, and muscular problems related to the syndrome itself that could prevent the child from benefiting from the procedure or lead to death.4.4.in-vivo size of the fenestration. In our opinion, the ideal diameters of the fenestrations could be 2.8, 3.2, and 3.6 mm.We applaud the pioneering efforts of Schranz and colleagues in promoting this novel technique in percutaneous stage 1 palliation. We expand upon their findings and report the safety and efficacy of this concept in various congenital heart lesions. As we described earlier in detail, the shape and dimensions of the MVP device are not ideal. The distal part of the MVP device is not covered, and this helps to avoid pinching or jailing the upper lobe PA branches. On the other hand, the surgical perspective could be that the uncovered part of the device is responsible to grow too much into the vessel wall. Based on your initial experiences, we think that there is room in the industry to develop ready-to-use PFRs with perfectly created fenestrations. A custom-made device for transcatheter endoluminal PA banding should be first deliverable through a 4-Fr catheter and has a distal marker for accurate positioning together with a proximal radiopaque micro pin for mechanical delivery and easy snare-recapture of the device, if necessary. In comparison with the MVP, the custom-made device should be shorter with 8 and 10 mm lengths which both are sufficient for a stable landing. It should also be designed in 5 diameters starting from 5 mm and incrementally moving in 1.5 mm up to 11 mm for a more tailored approach while respecting a reasonable 1.5 mm of additional oversizing. The proximal parachute covering should include 80%–100% of the device length as we think this is necessary to obtain a stable PTFE membrane while reducing the length of the bare-metal device part. A double-layer sandwich PTFE covering design could be beneficial to obtain a thicker PTFE membrane ready to impose enough resistance to blood flow when subjected to high-pressure, high-flow circulation. The fenestration should be either circular or oval-shaped, centrally created, shallow, and most importantly metal-reinforced to obtain an accurate 5.In our experience, we showed that MVP-based bespoke PFRs can be effectively used as short-term palliation in two ventricle patients with excessive pulmonary blood flow before complete repair. Patients with a single ventricle program or with borderline physiology are also good candidates for this appealing technique but are more challenging cases because perfectly balanced pulmonary and systemic circulation is critical to their future success. Surgical explantation during subsequent palliative or definitive surgeries is fairly straightforward with no residual vessel injury noted.


Reference values for right ventricular function and pulmonary circulation coupling were recently established for the general population. However, normative values for elite athletes are missing, even though exercise-related right ventricular enlargement is frequent in competitive athletes.We examined 497 healthy male elite athletes (age 26.1 ± 5.2 years) of mixed sports with a standardized transthoracic echocardiographic examination. Tricuspid annular plane excursion (TAPSE) and systolic pulmonary artery pressure (SPAP) were measured. Pulmonary circulation coupling was calculated as TAPSE/SPAP ratio. Two age groups were defined (18–29 years and 30–39 years) and associations of clinical parameters with the TAPSE/SPAP ratio were determined and compared for each group.n = 349, 23.8 ± 3.5 years) displayed a significantly lower TAPSE/SPAP ratio , TAPSE/SPAP to body surface area (BSA) ratio , diastolic blood pressure , septal wall thickness  and left atrial volume index , but a higher SPAP  compared to athletes aged 30–39 . TAPSE was not different between the age groups. The TAPSE/SPAP ratio was positively correlated with left ventricular stroke volume  and training amount per week  and negatively correlated with E/E′ lat. .Athletes aged 18–29 (The reference values for pulmonary circulation coupling determined in this study could be used to interpret and distinguish physiological from pathological cardiac remodeling in male elite athletes. Functional and structural changes of the right and left ventricle, known as the “athlete´s heart”, have been described in elite athletes performing mixed and endurance sports disciplines –3. TheseIn this context, the pivotal role that the RV and the pulmonary circulation coupling play in many different cardiopulmonary conditions has been emphasized –13. FurtRecently, new non-invasive echocardiographic methods have emerged as surrogates for pulmonary circulation coupling and were successfully validated against invasive measurements , 16. TheIn contrast to the age changes in LV-arterial coupling that are characterized by a proportionally stiffening of both LV and the arterial vascular tree , 19, a rE/A, LV stroke volume, E/E′, heart rate) on pulmonary circulation coupling in these athletes. We hence hypothesized that our examined male elite athletes would not show significant differences from the proposed reference values for healthy male individuals nor between the two examined age groups.However, these parameters have not been evaluated in elite athletes, until now, and reference values for athletes are missing. We, therefore, conducted this echocardiographic study in two different age groups of male elite athletes performing different mixed sports to deliver first reference values and to gain more insights into the functional and structural adaptations of the pulmonary circulation coupling in highly trained individuals. Since professional athletes typically display functional and morphological parameters at the high end of the healthy spectrum, we did not expect to discover significant differences when compared to healthy adults of comparable age. Accordingly, the present study aimed to describe the relationship between structural and functional adaptations to exercise and compare them to the published reference values for the general population . FurtherThis was a single-center, cross-sectional study conducted at the university hospital Giessen involving professional athletes during the routine pre-season medical monitoring program of the first German handball and basketball divisions and the second German handball and ice-hockey divisions. Data were collected in July and August of the years 2017–2021 after a 6-week competition-free interval. Only male athletes aged 18–39 were included in the study. Due to the overwhelming male athlete population service by our center, we did not have enough elite female athletes to investigate potential gender differences.All participants provided their written informed consent. Subjective health status, medication, nutrition supplementation, amount of training, and history of training were assessed by questionnaire. Only individuals free of underlying cardiovascular diseases and medication were included. All tests were conducted at least 3 h post-prandially, and subjects refrained from exercise for at least 36 h prior to the test.The local ethics committee of the university of Giessen approved the study protocol (AZ 15/17). The study was performed in accordance with the ethical standards laid down in the Declaration of Helsinki and its later amendments.The participants were 497 healthy, injury-free Caucasian male professional athletes of different nationalities performing different mixed sports . All participants included were non-smokers and none took medication or supplements on a regular basis. All individuals were subjected to a physical examination, 12-lead electrocardiogram (ECG), blood pressure measurements at rest and transthoracic echocardiography. Age, height, weight, and body mass index were determined. Body surface area was calculated using the formula of DuBois. Athletes then were divided into two age groups (18–29 years and 30–39 years) and statistical analyses were performed. The division in two age groups was made to compare the results with the reference population  and to gResting brachial blood pressure was measured using a validated automatic device based on a standard sphygmomanometer technique . The cuff used for measurements was adjusted to the individual´s arm circumference. Measurements were performed by a trained research associate on both arms in a sitting position after a resting period of 5 min and repeated after 2 min. The average blood pressure (BP) was used for statistical analyses. Athletes with a mean BP ≥ 140 mmHg systolic or ≥ 90 mmHg diastolic were excluded from the study.All athletes were examined by standard transthoracic echocardiography administered by an experienced cardiologist according to the current recommendations , 22 usinLeft ventricular (LV) wall thicknesses and diameters were evaluated in the parasternal long-axis view at the level of mitral valve coaptation. Furthermore, volumes and ejection fraction were determined using Simpson´s biplane-method. LV stroke volume was calculated as the product of LV outflow tract area and outflow tract time-velocity integral. RV stroke volume was accordingly calculated as the product of RV outflow tract area and outflow tract time-velocity integral.2. Left atrial volume index (LAVI) was obtained by the area-length method.LV mass was calculated using the Devereux formula and indexed to body surface area to obtain the LV mass index (LVMI). LV hypertrophy was defined as a LVMI > 115 g/mPeak tricuspid regurgitant velocity (TRV) was measured from the spectral profile of the tricuspid regurgitation jet in the right ventricular inflow projection of the parasternal short-axis view or the apical four-chamber view. Pulmonary artery systolic pressure (SPAP) was then calculated based on the simplified Bernoulli equation applied to TRV by adding a value of right atrial pressure as measured by inferior Vena Cava respiratory index to the systolic trans-tricuspid gradient. SPAP was assumed to equate the right ventricular systolic pressure in the absence of pulmonic stenosis and/or right ventricular outflow tract obstruction.Tricuspid annular plane systolic excursion (TAPSE) was measured from the four-chamber views by placing an M-mode cursor through the tricuspid annulus, measuring the excursion distance between end-diastole and end-systole in millimeter (mm).The TAPSE/SPAP ratio was calculated as TAPSE divided by SPAP for each participant. To avoid confounding effects of anthropometric differences, and to ensure comparison to the published reference values , we alsot tests. Bivariate relations were analyzed using the Spearman correlation coefficient. The Pearson partial correlation test was used to assess the relationship between clinically relevant variables such as age, body mass index (BMI), body surface area (BSA), training history, amount of training per week, LV stroke volume, heart rate, E/A and E/E′.Descriptive analyses were carried out on all study variables for the total sample and separated by age status (18–29 years and ≥ 30–39 years). All data are presented as mean ± standard deviation (SD). The Shapiro–Wilk test was used to determine normal distribution. If the data were determined to have a skewed distribution, all analyses were performed on normalized data. Between-group comparisons were made using independent sample Then, multiple regression analyses were performed to test the weight of these variables within and across two age classes. For this, we divided the cohort into two groups according to their age class (18–29 years and 30–39 years).A quantile regression analyses was used to describe quantiles  of SPAP, TAPSE, TAPSE/SPAP and TAPSE/SPAP/BSA as reference values for these parameters in professional male athletes.p < 0.05 for all measurements. All statistical analyses were performed using the IBM SPSS Statistics for Macintosh, Version 27.0 .Two-tailed significance level was set at 2. The probands were experienced athletes who had participated in professional training for 9.4 ± 4.1 years with a current mean training time of 18.7 ± 3.2 h per week.All 497 male elite athletes included in the study were participants in mixed team sports disciplines that are characterized by a high-intensity level  [p < 0.001). The clinical characteristics, anthropometric data, and specific training data are displayed in detail in Table There were no significant differences regarding height, weight, body mass index and body surface area or amount of training per week between athletes aged 18–29 and those aged 30–39 years. As expected, the older group had a longer professional training history than the younger group  lower diastolic BP (76.6 ± 7.9 mmHg) and mean BP (91.7 ± 7 mmHg) compared to their older (30–39 years) peers . None of the included athletes had a systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg.The mean systolic and diastolic BP values of the entire study cohort was 123.8 ± 16.4 mmHg and 76.4 ± 7.7 mmHg, respectively. There were no significant differences in systolic BP between athletes aged 18–29 (123.8. ± 10.7 mmHg) and those aged 30–39 (123.8 ± 10.3 mmHg). In contrast, younger athletes (18–29 years) displayed a significantly (p = 0.013), left atrial volume index (p < 0.001) and septal wall thickness (p < 0.001), with older athletes (30–39 years) displaying higher values for each parameter.Echocardiographic characteristics of the two age groups are summarized in Table p = 0.035) in older athletes compared to the younger group. As TAPSE was not different (p = 0.308) between the two groups, we observed a significant difference in the TAPSE/SPAP ratio (p = 0.039) and the TAPSE/SPAP/BSA (p = 0.017), with older athletes (30–39 years) having higher values.In addition, SPAP was lower , BMI  and the LV stroke volume  in the whole study cohort. There were positive correlations between SPAP and BMI , BSA  and E/E′ lat. , whereas a negative correlation with training per week  was apparent.TAPSE was positively correlated with age , LV stroke volume  and negatively correlated with E/E′ lat. . This negative correlation remained after adjustment for BSA  as displayed by the TAPSE/SPAP/BSA.The TAPSE/SPAP ratio as surrogate parameter of right ventricular-pulmonary coupling was positively correlated with training duration per week , SPAP  and negatively associated with TAPSE/SPAP/BSA . In the group of older athletes (30–39 years), LV stroke volume was positively associated with TAPSE/SPAP  and TAPSE/SPAP/BSA .The model was not able to predict TAPSE, SPAP, TAPSE/SPAP and TAPSE/SPAP/BSA in both groups. In younger athletes (18–29 years), BSA was positively associated with TAPSE (β = 0.387, Age-specific normative values for TAPSE, SPAP, TAPSE/SPAP and TAPSE/SPAP/BSA were calculated and displayed in Table The present study, to our knowledge, represents the first detailed evaluation of the TAPSE/SPAP ratio as a non-invasive surrogate of pulmonary circulation coupling in healthy male elite athletes of two different age groups.the TAPSE/SPAP ratio was significantly higher in athletes aged 30–39 years compared to their younger peers aged 18–29 years;we found higher values of both TAPSE and SPAP in male elite athletes compared to the published reference values for aged-matched healthy men;TAPSE/SPAP ratio was positively correlated with the training amount per week and LV stroke volume.Our most important findings are thatUnderstanding the structural and functional adaptations in highly trained athletes is essential for differentiating physiological from pathological remodeling in the context of pre-participation evaluation , 4 and, Recently, the TASPE/SPAP ratio was identified as a powerful and easily applicable echocardiographic surrogate of pulmonary circulating coupling , 16. It E/E′ lat. ratio in our examined male elite athletes reveal these parameters as relevant indicators of the respective functional adaptations and are in line with the findings of Vriz et al. [In our study, the TASPE/SPAP ratio was calculated slightly lower in male elite athletes of both age groups compared to the published age-specific reference values . Interesz et al. . Therefoz et al.  aged 18–It is important to consider both morphological and functional RV adaptations to differentiate physiological from pathological remodeling and to understand the relatively constant pulmonary circulation coupling measures that ensure an optimal physiological coupling. Enlarged RV compared to the normal population has been demonstrated in different athletic cohorts and is particularly pronounced in endurance athletes , 31, 32.Other important factors that must be acknowledged when investigating RV morphological and functional changes in athletes are sex and examination time. Female sex was shown to be related to TAPSE, SPAP and TAPSE/SPAP ratio , furtherA wealth of studies confirmed that intense prolonged exercise is associated with both an acute RV enlargement and a reduction in RV function , whereasPre-participation screenings are usually scheduled at the beginning of the competitive season, offering an opportunity to evaluate the morphology and function of the right ventricle and measure the pulmonary circulation coupling at rest, without the confounding influences of prior prolonged exercise sessions. This very sensitive marker, which was already validated against invasive measurements, could be useful for differentiating physiological from pathological RV remodeling. However, this hypothesis should be investigated in future studies.Our study has several limitations. The number of participants limited its statistical power to reveal other associations or to determine diagnostic thresholds. The focus on male elite mixed sports athletes might limit extrapolation of the results to other sport disciplines, to an older age group, or to women. Furthermore, we did not control for diet and body composition. In addition, the TAPSE/SPAP ratio, though validated against invasive measurements, still remains a surrogate parameter to assess pulmonary circulation coupling. However, we included male elite athletes of a narrow age span, free of cardiovascular diseases and medication use, and we controlled for confounders like prior prolonged exercise sessions. Furthermore, the homogenous study cohort and the rigid design of measuring cardiovascular function must be mentioned, which strengthens our analysis.This study delivered the first reference values for the TAPSE/SPAP ratio in highly trained male athletes performing mixed-exercise sports. Reference values of TAPSE, SPAP and TAPSE/SPAP derived from our male athletic cohort can be used to interpret changes in athletes and may help to distinguish between physiological and pathological adaptations.