Severe tricuspid regurgitation (TR) is a complex condition of the right ventricle (RV) and tricuspid valve apparatus and is frequently associated with symptomatic heart failure and a significant morbidity and mortality. In these patients, left heart pathologies lead to chronic pressure overload of the RV, eventually causing progressive RV dilatation and functional TR. Therefore, TR cannot be considered as isolated heart valve disease pathology but has to be understood and treated as one component of a complex structural RV pathology and is frequently also a marker of an advanced stage of cardiac disease. In these patients, medical therapy restricted to diuretics and heart failure medication is frequently ineffective. Also, severe TR in the setting of advanced heart failure constitutes a high risk for cardiac surgery. Neither one of these treatment options has demonstrated a beneficial effect on long-term prognosis. The recent innovations in transcatheter technology led to efforts to develop interventional approaches to severe TR. Multiple innovative treatment concepts are currently under preclinical and clinical investigation to replace or repair TV function. However, up to date none of these approaches is established and there is still a lack of clinical data to support the efficacy of transcatheter TR treatment. Severe tricuspid regurgitation (TR) is a complex condition of the right ventricle (RV) and tricuspid valve apparatus and is frequently associated with symptomatic heart failure and a significant morbidity and mortality . In thesIn these patients, medical therapy restricted to diuretics and heart failure medication is frequently ineffective. Also, severe TR in the setting of advanced heart failure constitutes a high risk for cardiac surgery . NeitherThe tricuspid valve anatomy is very complex and has a greater variability than the mitral valve. It is composed of the fibrous annulus, three leaflets, three papillary muscles, and the chordae tendineae. It is embedded in the right ventricular inflow tract in the junction between the right atrium (RA) and the right ventricle (RV). The elliptical shaped fibrous annulus is a three-dimensional, highly dynamic structure. It is slightly larger and anatomically not as well defined as the mitral annulus. Its size and shape changes during the cardiac cycle due to contraction of the surrounding myocardium . The annTR (TR) is a common insufficiency typically graded in mild, moderate and severe TR. While mild TR is frequently observed in asymptomatic persons, moderate and severe TR are seen less often . As evenHowever, as TR frequently develops with the progression of left heart or pulmonary disease, the underlying disorder rather than the tricuspid valve lesion tends to dominate the clinical picture. Increased right atrial pressure is transmitted to the central and hepatic veins leading to hepatosplenomegaly and ascites, which are present in 90% of patients with severe TR .Nath et. al conducted an echocardiographic series of 5,223 patients. Moderate to severe TR was found in 16% of patients . In addiTR is most frequently “functional” in nature . It is cIn early stages RV and annulus dilatation can still be compensated and TR is not severe. A progressive dilatation leads to papillary muscle displacement and tethering of the leaflets causing severe TR. Regurgitation volume leads to increased diastolic loading which supports further RV and annulus dilatation entering a vicious circle Because right ventricular stroke volume is partially expelled backwards into the venous system, there is a resulting decrease in cardiac output and RV afterload. This decrease in right ventricular afterload in presence of TR may initially actually mask a decreased RV contractility. As right ventricular preload rises the right ventricle loses its contractility and eventually fails. As the tricuspid valve loses it function, hemodynamic parameters of the right atrium adjust to those in the right ventricle called a ventricularisation of the right atrium and finally there is a systolic backflow in the hepatic, abdominal and peripheral veins too.Primary or non-functional TR is seen less frequent. It occurs when there is damage to the tricuspid leaflets, chordae, papillary muscles, or annulus, independent of right ventricular dysfunction or pulmonary hypertension. It can be caused by infective endocarditis, congenital disease like Ebstein anomaly or atrioventricular canal, rheumatic fever, carcinoid syndrome, endomyocardial fibrosis, myxomatous degeneration of the tricuspid valve leading to prolapse, penetrating and non-penetrating trauma, and iatrogenic damages during cardiac surgery, biopsies, and catheter placement in right heart chambers . These eEchocardiography is the main tool to confirm the diagnosis, determine aetiology and assess the severity of TR. Color flow imaging can be used as a screening method. Grading of the severity should be performed in accordance to the guidelines published in 2010 by the European Society of Echocardiography and in 2017 by the American Society of Echocardiography .These guidelines recommend several structural, qualitative, semiquantitative and quantitative parameters . A simplIn moderate to severe TR evaluation of the RV and RA dimensions, RV function and the venous congestion is mandatory. The tricuspid annular plane systolic excursion (TAPSE) is easy to obtain and well validated to assess the right heart function. A TAPSE <17 mm is highly suggestive of RV systolic dysfunction.2 (>40 mm).The right heart dimensions have previously been published in an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging . Measure2. The major axis is orthogonal to the minor axis and is normally between 2.4–2.5 cm/m2. The more accurate RA volume is 21–25 mL/m2.The right atrium is assessed in the same echocardiographic window. Mostly performed are linear and volume measurements. Linear measurements include the minor and the major axis of the LA. The minor axis is should be measured as the distance between the lateral RA wall and interatrial septum in the midatrial level. A normal value is 1.9 cm/mThe atrial pressure can be estimated by the use of vena cava diameter and the percentage of decrease of diameter during inspiration. An IVC diameter <2.1 cm with a collapse >50% during inspiration suggests normal RA pressure of 3 mm Hg, whereas IVC diameter >2.1 cm that collapses <50% during inspiration suggests high RA pressure of 15 mm Hg . In caseCurrently medical and surgical therapy are the only established treatments options for patients with severe TR. Medical treatment is considered a symptomatic therapy limited to diuretics. Surgical repair or replacement is associated with a significant mortality and is therefore restricted to a selected group of patients with a suitable risk profile. Also, the timing for surgery remains controversial . AccordiToday surgical correction of TR focuses on restoring valve function by reducing annular size. However, the efforts to achieve the most durable results have resulted in an ongoing debate as to whether annular plication should be achieved by implanting either flexible or rigid rings rather than by means of a partial purse string suture technique (“DeVega-technique”). Rigid annuloplasty rings appear to have a lower incidence of recurrent TR than flexible devices or the DeVega technique. In addition, the edge-to-edge tricuspid valve repair has been suggested as providing an effective adjuvant procedure for severe residual TR following annuloplasty . The proPatients with severe TR are frequently considered inoperable due to comorbidities and surgery is therefore often refused . Thus, tThe FORMA Repair System (Edwards Lifesciences) has been designed for patients with a severe functional TR. Annulus dilatation leads to malcoaptation of leaflets and therefore to a central regurgitant jet. By advancing a spacer in the center of the regurgitant yet the regurgitant orifice area is occupied and leaflets have a new coaptation surface. Therefore, the TR Grade can be reduced. The spacer is a foam-filled polymer balloon that passively expands via holes in the spacer shaft. It is available in 12 and 15 mm both with a length of 42 mm. Two radiopaque markers help to initially position the spacer using fluoroscopy. The distal end is connected to a rail anchored at the apex of the RV whereas the proximal end is locked in the subclavian region with the extra rail length coiled into a pre-pectoral pocket.The first in men experience with the FORMA device was published in 2015. Seven high-risk patients with severe TR presenting with clinical signs of heart-failure deemed unsuitable for surgery received the FORMA device as a compassionate use. All patients had a New York Heart Association (NYHA) functional class II to IV. Device implantation was successful without procedural complications in all patients. Severity of TR could be reduced significantly to moderate TR in 3 patients and to mild TR in 4 patients. At 30 day follow-up, all patients but 1 demonstrated an improvement in NYHA functional status to class II. No complications related to the device or vascular access were observed during follow-up . RecentlThe FORMA system is an investigational device and not for sale in any country. An Early Feasibility Study is currently recruiting patients in the USA (NCT02471807). The 30 day data of the US feasibility trial were presented at the TCT 2017 by Susheel Kodali, MD . 30 patients with severe symptomatic TR from five US centers underwent implantation of the Forma device. All in all, the results proved that the device is a feasible therapy for patients with severe TR. Nevertheless, it was associated with infrequent distal anchor dislodgements and the complications thereof. The next generation of this device probably with a more predictable anchor capture without dislodgement or RV perforations is already under development.Beside the Early Feasibility Study in the USA other multicenter trials are planned in Europe and Canada.The MitraClip® system has been invented for high risk patients with mitral regurgitation which are unsuitable for surgery. It is a procedure that involves the percutaneous implantation of one or more clips grasping and approximating the edges of the leaflets at the origin of the regurgitant jet and therefore reducing it. In 2011, this procedure was presented first time by Feldman et al . Until tNevertheless, clipping the tricuspid valve is more difficult than performing a clip in mitral position. The angle between the IVC and the TV annular plane makes coaxial positioning difficult. A transjugular approach has been described but the femoral approach was favored in the above-mentioned study.The Trilign device  is a percutaneous minimal invasive annuloplasty system initially designed for the treatment of symptomatic functional mitral regurgitation. First experiences have been made with the treatment of patients with severe tricuspid regurgitation. It was inspired by the Kay bicuspidization procedure, in which the annulus is plicated along its muscular part adjacent to the posterior leaflet . With thThe first-in-man procedure was published in 2015. The Trialign device was implanted in an 89-year-old woman with right heart failure due to TA dilation and severe TR as a compassionate use. After procedure, there was a significant reduction of tricuspid annulus area (57%) and effective regurgitant orifice area (53%). Hemodynamic parameters in terms of right atrial pressure and left ventricular stroke volume also improved . There aThe TriCinch System  is a percutaneous device designed to reduce functional TR by reducing the septo-lateral distance. It is composed of two parts: a stainless-steel corkscrew and a self-expanding nitinol stent. Both are connected by a Dacron band. First, the corkscrew is delivered by a delivery system from the Inferior Vena Cava and fixated at the anteroposterior TV annulus. After the delivery system is removed a second delivery system is advanced containing the other half of the TriChinch System. Both Dacron bands are now connected with a locking mechanism. By pulling the TriChinch System tension is applied to the TVA and therefore the septo-lateral distance is reduced. If echocardiography shows the desired reduction of TR, the stent is deployed in the inferior vena cava to maintain the tension.Four stent sizes are currently available .The “first-in-man” procedure was reported in 2015. The patients was a 72-year-old woman enrolled in the PREVENT  study. She had a severe functional TR associated with tricuspid annular dilation causing multiple hospitalization. New York Heart Association functional class was III. The procedure was completed in 56 min and the patient was discharged 5 days later. No intra- or postprocedural complications were observed. TR grade could be reduced from grade 4 to grade 3. The 6 month follow-up showed an improved quality of life.At this time, enrollment of 24 patients in the PREVENT Trial is completed. Results are not published yet.The transatrial intrapericardial tricuspid annuloplasty (TRAIPTA) is a minimal invasive device for patients with functional TR. Once implanted it acts as a epicardial annuloplasty band. After a transfemoral venous approach pericardial access is obtained by puncturing the right atrial appendage.Once the delivery device is advanced in the epicardial space it opens a preformed loop that is passed around the apex of the heart and then retracted toward the base. Finally it can be tightened at the atrioventricular groove. After the procedure, the right atrial appendage must be closed with a percutaneous occluder device.The device has not yet been implanted in humans but it was applied in 16 Yorkshire swines, including 4 with functional TR. Tricuspid septal-lateral and anteroposterior dimensions, the annular area and perimeter was significantly reduced. Small postprocedural effusions  resolved completely at follow-up. There is no other trial registered at Clinical Trials.The Cardioband repair system (Edwards Lifesciences) is an approved treatment of secondary  mitral regurgitation (FMR). It has been recently used in a clinical trial in patients with severe tricuspid regurgitation caused by a dilatation of the right annulus. The cardioband system is a catheter-based device that functions as a percutaneous annuloplasty band using a transfemoral approach. Implantation of the Cardioband is performed by stainless steel anchors (6 mm long). After cinching of the Cardioband the device reduces the tricuspid annular dimensions. Studies are currently investigating the use of the Cardioband in tricuspid regurgitation .The IRIS is a complete semi-rigid annuloplasty ring that is placed via a transfemoral venous approach. After puncture of the femoral vein a delivery catheter is advanced into the right atrium. The delivery catheter places the device supra-annularly and the ring is then anchored and cinched reducing annular size and therefore valvular regurgitation. Up to date annuloplasty device is only studied in patients with mitral regurgitation (NCT02607527).The tricuspid annulus is a complex and highly dynamic structure offering little resistance for long-term fixation of orthotopic valves. Particularly under conditions of severe TR the annulus is massively dilated with a loss of anatomic landmarks. Therefore, the development of transcatheter orthotopic valve implantation is associated with specific challenges, including device fixation, paravalvular sealing, sizing and thrombogenicity in a low-flow, low-pressure circulation. The NaviGate transcatheter tricuspid valve has been developed for orthotopic correction of severe functional TR by “NaviGate Cardiac Structures Inc.. The bioprosthetic self-expanding valve with a size of up to 52 mm has been implanted successfully in compassionate cases .Severe TR leads to a systolic backflow in the hepatic, abdominal and peripheral veins causing peripheral oedema, liver cirrhosis, ascites and gastrointestinal dysfunction. Implanting a prosthetic valve in the central venous system  reduces the venous congestion leading to amelioration of peripheral signs of right heart failure . HeterotThe management of patients with severe symptomatic TR remains challenging. As patients are frequently referred for surgery late in the disease process this treatment is associated with an excessive morbidity and mortality. On the other hand, medical therapy, consisting primarily of escalating doses of diuretics is frequently ineffective as patients develop increasing diuretic resistance secondary to worsening renal function. Therefore, interventional treatment approaches are needed and multiple devices are in preclinical and clinical stages of investigation.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To quantify myocardial edema by using a T2 relaxometry approach with a dual-contrast turbo spin-echo (dcTSE) sequence in patients with acute myocarditis regarding focal late gadolinium enhancement (LGE) burden. CMR T2 relaxometry was performed in 39 patients  with LGE in a typical myocarditis pattern and in ten healthy volunteers . dcTSE sequence  was used for T2 mapping, analysis were performed on the basis of region of interest (ROI). Myocardial T2 relaxation times (T2 RT) in patients-ROI with focal LGE were significantly (p < 0.001) higher than T2 RT in patients—ROI without apparent LGE pattern (65 ms (IQR 36–95) vs. 60 ms (IQR 26–88), respectively). T2 RT in healthy volunteers [55 ms (IQR 35–71)] were significantly lower than in patients ROI with or without focal LGE-pattern . T2 RT assessed by dcTSE are significantly higher in patients segments with and without focal LGE compared to normal controls, supporting a global myocardial inflammatory process in acute myocarditis. Furthermore, this quantitative T2-mapping approach highlights the potential to identify patients with diffuse myocarditis. The diagnosis of myocarditis remains challenging in daily clinical routine due to its wide and varying range of symptoms in terms of patients clinical presentation. Acute inflammatory cardiomyopathies are responsible for 10% of sudden cardiac deaths in adults and further, are responsible for up to 40% of acute nonischemic cardiomyopathies . The diaThis retrospective study was approved by the ethics committee of Medical University of Innsbruck.We enrolled 39 patients, who were referred for clinical indications to CMR, into this study. Inclusion criteria were (1) symptoms and signs suggestive of cardiac disease , (2) evidence of myocardial injury as defined by elevated serum markers, such as creatine kinase (CK) or troponin T (TnT) and/or elevation of C-reactive protein (CRP) and (3) exclusion of coronary artery disease by angiography and / or clinical criteria and (4) apparent myocardial hyperenhancement by LGE in typical myocarditis pattern. Exclusion criteria were contraindications for CMR, hemodynamic instability, previous myocardial infarction and previous episode of myocarditis. Imaging scans were performed at a median of 4 days [interquartile range (IQR) 2–11] after symptom onset.®, Mannheim, Germany). In each case, maximum values of these biochemical markers in acute stage of disease were included in statistical analysis.CK activity, TnT, N-terminal pro brain natriuretic peptide (NT-proBNP) as well as CRP values were drawn routinely at time of patients presentation in acute cardiac care as well as daily until discharge and determined by an enzymatic assay  using a 12-channel phased-array coil.Cine imaging in 3 long axis planes  and short-axis planes covering the left ventricle (LV) were acquired using breath hold, retrospective ECG-triggered true Fast Imaging with Steady State Precession (trueFISP) bright-blood sequences. Evaluation of images was performed by an experienced observer using standard software . Contouring of LV endo- and epicardial borders was performed semi-automatically. Papillary muscles were excluded from the myocardial mass and included to the LV volume. The most basal slices were excluded from evaluation in the presence of LV outflow tract, especially on the end systolic images .dcTSE dark blood sequence (echo times (TE) 29 and 75 ms, respectively; repetition time (TR) 762), field of view (FOV) 320 × 265, Trigger pulse 2, Matrix 256 × 159, slice thickness 8 mm, Echo-train length 9, generalized autocalibrating partially parallel acquisition (GRAPPA) factor 2 were acquired in short-axis slices covering the LV in an attempted breath hold. T2 maps were generated from these images by fitting a monoexponential decay curve at each pixel.  with an infusion pump at 2–3 ml/s, we acquired LGE CMR images by using an ECG triggered phase sensitive inversion recovery (PSIR) single shot trueFISP sequence with consecutive short-axis slices as described in detail previously .R 2.10.1 (Team R Development Core (2009) R: A Language and Environment for Statistical Computing) for statistical analysis. To test for normal distribution (ND) Shapiro–Wilk test was applied. Results for continuous variables are all expressed as mean ± standard deviation (SD) if they are ND or as median with corresponding IQR if not. To test for linear correlations of continuous variables Pearson's test (ND) or Spearman's rank correlations (not ND) were calculated.We used Group differences were assessed by One-way ANOVA or the Kruskal–Wallis test, depending on data distribution, whereby significant effects were further evaluated posthoc testing with Bonferroni correction. Intra- and inter-observer variability was assessed via intra-class correlation coefficients (ICC). A two tailed p value <0.05 was considered to indicate statistical significance.Patient characteristics are summarized in Table Out of all analysed patients myocardial segments 624), 5.3% were not considerably due to qualitative impairment. Among the 591 finally included segments 26% (154) showed visible replacement LGE, whereas 437 (74%) did not. T2 relaxation times (T2 RT) in segments with replacement LGE was with 65 ms (IQR 36–95) significantly higher (p < 0.001) than T2 RT in patients myocardial segments without visually detectable LGE [60 ms (IQR 26–88)]. Myocardial T2 RT in healthy volunteers [55 ms (IQR 35–71)] were significantly lower than T2 times of patients segments with focal and more diffuse LGE (both p < 0.001). Figure 4, 5.3% wOverall median T2 RT of patients was significantly correlated with maximum cTnT levels  as well as with maximum CK levels . T2 RT were not associated with maximum CRP  and maximum NT-proBNP  values.Inverse associations between T2 RT and CMR estimated parameters of LV function  were observed, but correlation was not significant.In the present study we conducted a quantitative T2-mapping approach by using T2 weighted dcTSE sequence in dark blood preparation to identify a segmental based edematous myocardial involvement in patients with acute myocarditis and LGE—positive CMR. The main finding of this study are: (a) T2 RT in patients with LGE-positive myocarditis were significantly higher in ROI’s with focal LGE burden than in myocardial segments without LGE, (b) myocardial T2 RT in normal controls were significantly lower than in patients with myocarditis, both in segments with or without LGE burden, (c) overall mean myocardial T2 RT of myocarditis patients showed moderate but significant correlations to biomarkers of myocardial damage, (d) but neither to biomarkers of ventricular dysfunction (NT-proBNP), inflammatory markers (CRP) or myocardial function parameters.Myocarditis, commonly caused by viral infections, is an underdiagnosed cause of acute heart failure, sudden death and chronic dilated cardiomyopathy . The cliAccordingly, our patient collective exhibited increased T2 RT within all myocardial segments compared to normal controls, even within segments with no visible LGE. Consecutively, this finding highlights the potential of T2 relaxometry approaches to identify inflammatory affected myocardium even in the absence of late enhancement.Furthermore, our main finding confirms that the inflammatory process affects the whole myocardium and is also supported by a recent study investigating T2 and T1 mapping as well as extracellular volume (ECV) in patients with myocarditis, whereby the mapping methods were superior to the visual inspection . T2 mappOur results rely mainly on T2 mapping derived from the dcTSE sequence with dark blood preparation. This sequence provides diagnostic relevant images with the additional feature to calculate T2 RT . Recent In our patient cohort, we observed a moderate correlation between T2 RT and maximum deflection of cTnT as well as CK in the acute stage of disease. Consequently, increased T2 relaxation might be an adequate marker for the determination of myocardial affection reflecting biochemical severity of myocarditis.However, T2 relaxation failed to correlate with CRP, NT-proBNP and LV function. CRP as a marker of inflammatory processes is known to play a central role in the pathogenesis of atherosclerosis and its elevated plasma levels have been found to predict future cardiovascular risk , 24. HowThe study has some important limitations. First, our study comprises only data from patients with symptomatic myocarditis and focal replacement LGE in at least one of the myocardial segments. Our data however, support a widespread global myocardial inflammatory process of the whole heart, even of the LGE-negative segments in the acute stage of myocarditis. Since imaging scans were performed at a median of 4 days after symptom onset, the highlighted potential of this quantitative T2-mapping approach to identify patients with diffuse myocarditis is limited to the acute stage of the disease. The presented data can not give any statement about T2 mapping in monitoring advanced disease stages. However, recently von Knobelsdorff-Brenkenhoff et al. in a multiparametric CMR mapping approach emphasized only T2 mapping to discriminate between acute and healed stages of myocarditis .Furthermore, the presented correlations of T2 relaxation times with biochemical markers are univariate correlations.The discussion is partly based on the speculation that LGE-negative segments in our patient collective are comparable to myocarditis patient without any replacement LGE.Furthermore, this is a single-center investigation with a small sample size and therefore confirmation in larger studies would be important.In conclusion, T2 relaxometry shows significant differences between myocardial segments with and without LGE burden in patients with acute myocarditis, highlighting its potential to indicate inflammatory processes without any replacement LGE. Therefore, our results might suggest that T2 values provide additional information about the widespread global myocardial inflammatory process in the acute stage of myocarditis, which is related to the biochemical severity of myocarditis.


This study sought to explore the diagnostic insight of cardiovascular magnetic resonance (CMR)-derived wave intensity analysis to better study systolic dysfunction in young patients with chronic diastolic dysfunction and preserved ejection fraction (EF), comparing it against other echocardiographic and CMR parameters.Evaluating systolic and diastolic dysfunctions in children is challenging, and a gold standard method is currently lacking.n = 18; nine aortic stenosis (AS), five hypertrophic, and four restrictive cardiomyopathies] were compared with age-matched control subjects (n = 18). All patients had no mitral or aortic incompetence, significant AS, or reduced systolic EF. E/A ratio, E/E′ ratio, deceleration time, and isovolumetric contraction time were assessed on echocardiography, and indexed left atrial volume (LAVi), acceleration time (AT), ejection time (ET), and wave intensity analyses were calculated from CMR. The latter was performed on CMR phase-contrast flow sequences, defining a ratio of the peaks of the early systolic forward compression wave (FCW) and the end-systolic forward expansion wave (FEW).Patients with presumed diastolic dysfunction [E/E′ ratio  and FCW/FEW ratio , as well as—as expected—LAVi . In particular, patients exhibited a lower FCW  in the face of preserved EF , as well as longer isovolumetric contraction time  and ET/AT .Significant differences between patients and controls were seen in the This study shows that the wave intensity-derived ratio summarizing systolic and diastolic function could provide insight into ventricular function in children, on top of CMR and echocardiography, and it was here able to identify an element of ventricular dysfunction with preserved EF in a small group of young patients. Assessment of systolic and diastolic dysfunctions in pediatric patients poses difficulties due to the lack of a “gold standard” diagnostic biomarker. Currently, ventricular function, in particular diastolic dysfunction, is best assessed using catheter-based techniques, though these are invasive in nature and present technical limitations . EchocarIn the adult population, up to 50% of elderly patients with heart failure have a normal ejection fraction (HFNEF) . This enWave intensity represents energy flux per unit area carried by waves traveling in the cardiovascular network . This he(a)Z-score ≥ +2.0)Dilated left atrium (LA) on CMR and echocardiogram ((b)Normal EF ≥ 55% on CMR(c)No mitral valve stenosis or regurgitation(d)Vmax gradient < 30 mmHg) or aortic regurgitation.No significant AS  to treat residual AS and five patients had neonatal surgical valvotomy, followed by Ross procedure.Five patients had HCM with the evidence of dilated LA on CMR or echocardiography, normal EF on CMR (>55%), no left ventricular outflow tract obstruction, and no history of myomectomy or alcohol ablation.Four patients had idiopathic RCM based on high end-diastolic pressures (EDP) on previous catheterization, echocardiographic features reported as restrictive physiology (dilated LA and Doppler evidence of restriction), and normal EF (>55%).Eighteen subjects fitted the criteria, whereby no study patient had mitral or aortic incompetence, significant AS or reduced systolic EF:Eighteen healthy age-matched controls with no current or past evidence of phenotypic cardiovascular disorders served as our control subjects.E) and late (A) diastolic trans-mitral velocities, E/A ratio, and E-wave deceleration time (DT) were measured from the spectral Doppler signal of the mitral valve inflow, together with the isovolumetric contraction time (IVCT). Pulsed-wave TDI velocities were obtained from the septal mitral annulus . TDI measurements for each myocardial segment included peak early diastolic velocity (E′) and peak late diastolic velocity (A′). Only tracings that demonstrated a clear E′ were used. Each TDI velocity was measured on three consecutive cardiac cycles and averaged for the analysis. The ratio of peak early diastolic mitral inflow velocity and early septal TDI velocity (E/E′) was calculated. Examples of echocardiographic data are provided in Figure All patients had an echocardiographic examination as a part of their assessment. Diastolic function assessment included pulsed Doppler of the mitral inflow and tissue Doppler imaging (TDI). All measurements of diastolic variables were retrospectively re-measured by a single echocardiographer. Conventional pulsed Doppler indices of diastolic function, peak early . Inversion time was adjusted (250–350 ms) in order to null the normal viable myocardium. All postprocessing was carried out using in-house written plug-ins .Cardiovascular magnetic resonance data were acquired with a 1.5-T scanner . Flow quantification was performed using phase-contrast sequences, with through-plane flow data acquired with the use of retrospective cardiac gating. Appropriate velocity-encoding values were set ~250 cm/s for through-plane flow quantification. Indicative parameters for the flow phase-contrast sequences were TR/TE = 27/3 ms, flip angle = 30°, and pixel size = 1.25 × 1.25, with a field of view = 240 × 320 or smaller. Acquisition parameters were adapted if necessary to optimize the quality of the scan for each case. Retrospectively gated, balanced, steady-state free precession cine images were acquired in the vertical long-axis (two-chamber), four-chamber, and the short-axis covering the entirety of both ventricles (9–12 slices). Myocardial late gadolinium enhancement for tissue characterization was performed in the long- and short-axis planes, using inversion recovery prepared gradient recalled echo sequence 10–15 min after injection of gadolinium (DotaremL is the shorter of the two LA length measurements (L2Ch and L4Ch) from these views . The stroke volume, EF, and cardiac output were derived from these measurements. On top of the functional data, LA area and length were also measured from the two-chamber and four-chamber views, respectively, at the end of ventricular systole. The LA area was obtained by tracing its endocardial border excluding the pulmonary veins, LA appendage, and mitral valve recess. These parameters were used to calculate LA volume (LAV) using the formula , 13:LAVLAV=8Ach(A4ch)3The aortic velocity waveforms were used to compute peak velocity, acceleration time (AT), and ejection time (ET).A) and velocity (U) differentials, i.e. dI = dUdlnA, as opposed to the traditional pressure-based formulation, i.e., dI = dPdU, the analysis can be performed non-invasively based on CMR phase-contrast acquisitions. Wave intensity information was derived from CMR data using a previously proposed methodology  at systolic ejection and a forward expansion wave (FEW) at end systole , suggesting dI as a clinically useful parameter for concurrently assessing LV systolic and early diastolic performance  and AT/ET from CMR; and FCW/FEW. Aortic distensibility (D) was inferred from wave speed (c) according to the Bramwell–Hill formula, c2 = 1/ρD, with ρ = density of blood and c estimated as a part of the CMR-based wave intensity analysis.All data processing was carried out in Matlab . Healthy controls and patients were compared for the following parameters: t-test, or Mann–Whitney U test for non-parametric data. Linear correlation among different variables was assessed using the Pearson r coefficient. A value of p < 0.05 was regarded as statistically significant.Statistical analysis was carried out with commercial software . Data are presented as mean ± SD. Comparisons of continuous variables of unpaired samples between groups (controls vs. patients) were performed using unpaired two-tailed Student’s p = 0.259). There were no blood pressure differences between the two groups.Baseline characteristics, CMR, echocardiography, and wave intensity data between patients and healthy control subjects are presented in Table E/A ratio and DT between patients and healthy controls. E/E′ showed a statistically significant difference between patients and controls (8.7 ± 4.0 vs. 5.1 ± 1.3 p = 0.001). IVCT was significantly longer in patients compared to controls .Indices of conventional pulsed-wave Doppler across the mitral valve and TDI are listed in Table p = 0.392) between patients and controls. The LAVi, as expected, was significantly larger in patients with presumed diastolic dysfunction compared to healthy controls .Left ventricular functional assessment showed no significant differences of the indexed volumes (LV ESVi and LV EDVi) and EF , while peak FEW was not significantly different . The ratio FCW/FEW was thus significantly lower in patients . Pearson correlation of the FCW/FEW with well-known echocardiographic and CMR biomarkers of diastolic dysfunction is shown in Table E/E′  and a significant negative correlation with presence of EFE , while the correlation with LAVi was just above the significance threshold . Furthermore, a significant negative correlation was found between FCW and IVCT measured from echocardiography  and between FCW and AT/ET derived from CMR aortic velocity data .Peak FCW was significantly lower in patients compared with normal healthy controls  provided insight into an element of load-independent systolic dysfunction in children with normal EF and chronic diastolic dysfunction. This observation was corroborated by prolonged IVCT on the face of normal diastolic blood pressure; however, IVCT on its own is limited by the fact that invasive pressure data is needed in order to comment on systolic function. The systolic impairment was further confirmed by observing aortic velocity waveforms, whereby peak velocity is significantly lower in patients who concurrently exhibit a longer AT. This indicates that peak aortic acceleration was lower, i.e., lower inotropy . OverallWe have shown that the FCW/FEW ratio provided insight in the physiology of patients with chronic diastolic dysfunction despite normal EF when compared with more conventional non-invasive parameters. Such a non-invasive measurement may prove particularly useful in the pediatric population, as diagnostic tools that are adequate for use in adult populations for the diagnosis of diastolic dysfunction fail to do so in pediatric patients, including echocardiographic parameters routinely used in the clinic .Potential confounders for abnormal diagnostic tests were purposefully eliminated in this study. All patients with mitral valve disease, aortic incompetence, or residual stenosis and those with reduced LV EF were excluded in an attempt to make the study group more homogenous. Our primary objective was to test the potential of the wave intensity data for assessment of sub-clinical ventricular dysfunction. There was no difference in EF between patients and control subjects but significantly increased LAVi in the patient group. This is important as there is a significant relationship between increased LAVi and elevated LV EDP as well as echocardiographic indices of diastolic dysfunction, as shown in adult patients , 21. We E/E′ was significantly different between patients and healthy control subjects , providing additional and complementary information on combined systolic and diastolic performances.Informed consent for the use of imaging data was obtained from all parents of patients who were imaged as a part of the patient clinical follow-up. The study was carried out in accordance with the ethical guidelines of the 1975 Declaration of Helsinki, as reflected in prior approval by the institutional and research ethics committee.HN, RC, PC, VM, SS, JM, KP, AT, and GB designed the study, contributed to the data acquisition, analysis, and data interpretation; drafted the article; contributed to the data acquisition, analysis, and interpretation of results and revised critically the article. All authors read and approved the final article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Left ventricle and left atrium are and have been practically always analyzed separately in common clinically and non-clinically oriented cardiovascular investigations. Both classic and speckle tracking echocardiographic data contributed to the knowledge about deformational impairments occurring in systo-diastolic differences. Recently new trajectory based approaches allowed a greater awareness about the entire left ventricle or left atrium revolution and on their deficiencies that take place in presence of hypertrophic cardiomyopathy. However, surprisingly, the concomitant function of the two left heart chambers has not been analyzed for their geometrical/mechanical relationship. For the first time we study here, by acquiring left ventricle and left atrial geometries on the same heartbeat, the trajectory attributes of the entire left heart treated as a whole shape and the shape covariation of its two subunits. We contrasted healthy subjects with patients affected by hypertrophic cardiomyopathy. We found impaired left heart trajectory mainly in terms of orientation and size. More importantly, we found profound differences in the direction of morphological covariation of left ventricle and left atrium. These findings open to new perspectives in pathophysiological evaluation of different diseases by allowing the appreciation of concomitant functioning of both left heart whole geometry and of its two chambers. In particular, easy accessibility, non-invasive approach and fast acquisition of 2D and 3D Speckle Tracking Echocardiography  made these tools among the most common instruments in cardiology10. Alternatively, Cardiac Magnetic Resonance (CMR) can be used to acquire precise heart geometry during its functioning13. However, CMR is much more invasive than 2DSTE or 3DSTE and does not enable the concomitant acquisition of electrical heart activity. A large amount of scientific literature (whose complete review if far beyond the scope of the present paper) investigated a variety of pathologies and highlighted geometrical and mechanical properties of different diseases by means of 3DSTE whose output variables comprehend different mean strain measures20. Recently, a new approach was proposed, based on the analysis of the landmarks’ cloud upon which 3DSTE strains are computed, so that heart deformation during its revolution in physiological and patho-physiological states can be easily investigated25. Thus, translational contributions of differential geometry and clinical cardiology led to the application of Parallel Transport (PT) to atrial or ventricular geometries aimed at studying pure deformational patterns irrespective of the actual starting inter-individual heart shape differences16. Exploration of not only deformation per se but also of the shape of heart trajectory itself was therefore possible to provide a precise characterization of the motion trajectory per se. This is conceivable trough the introduction of temporal homology’ notion. Heart shapes are then evaluated (via spline-interpolation) at specific electro-mechanical homologous times such as R peak of the electrocardiogram or mitral valve opening (among others). Using common ordination methods, such as Principal Components Analysis (PCA), the “landmarks” of a trajectory shape are represented by the coordinates of dominant PC scores (PCs) i.e. the main deformation modes.In recent years, the use of three-dimensional analyses in cardiological diagnosis and pathophysiological investigations became very common in scientific literaturecovary one with each other during cardiac revolution, hence forming LH dynamical change in time. Moreover, the entire LH can be viewed in two different ways: a structure composed of two, highly integrated, sub-units (LV and LA) and a sole one structure having its own shape and its own motion trajectory that can be studied with methods briefly explained above.One of the most salient features of the abovementioned studies was that they focused on left ventricle (LV) or on left atrium (LA) only. To the best of our knowledge, there are no simultaneous investigations on the two chambers together which explore the Left Heart (LH) in its entirety. On the other hand, LV and LA indissolubly 26 and about 1400 mutations carried by more than 13 genes were identified28. The attributes of HCM trajectory  appeared to be very effective in recognizing HCM for both LV16 and LA8. Here, we first hypothesize that the entire LH presents impaired motion attributes in HCM. Then, we hypothesize that the integration of the two LV and LA subunits, i.e. the way they covary in time, is also impaired. In particular, we investigate two attributes of morphological integration, strength and direction, trough recently proposed techniques exploiting Partial Least Squares analysis (PLS) capabilities29. Eventually, we also explore the covariation patterns between the shapes of LV and LA trajectories.Here we focus on hypertrophic cardiomyopathy (HCM) and we show how LH’ investigation introduce new directions in studying heart diseases. HCM is the most common genetically-based heart disease with dominant autosomal transmission and complete or incomplete penetrance although it presents a highly variable phenotypic, clinical and prognostic heterogeneityIntra-observer variability analysis shows that the reproducibility of our results is always very high . Traditional global 3DSTE parameters of the left ventricle show a very good coefficient of variation: Volume: 1.56%; Radial Strain global: 0.84%; Circumferential Strain global: 0.79%; Longitudinal Strain global: 0.81%; Rotation global: 1.18%; Twist global: 0.96%; Torsion Regional global: 0.84%; Torsion Basal global: 0.96%; Strain 3D global: 0.79%; Radial Displacement global 0.64%; Longitudinal Displacement global 1%. The same emerges from the distances between cycles shape replicas of the same subject parameterized on pi/2: mean: 0.00991; sd: 0.01605. Inter-observer variability returned also a very good performance being coefficient of variation of traditional global 3DSTE parameters of the left ventricle always smaller than 5%.Figure Figure Figure p-value: 0.00002). At positive PC1 values, were HCM places, the trajectory is flat while at negative ones, where Control stays, the trajectory shape is more rounded.Figure p-value: 3.9e-5) as well as a significant different orientation of both angles .Results relative to size and orientation of LH trajectory highlights that Control presents a significant larger size in comparison to HCM . These values indicate that LH is, as expected, a highly integrated structure when taken as a whole shape and that the two categories show the same degree of integration. A coherent result is found when using PLS on LV and LA blocks. Figure LA~SW1LV.The mean slopes of disintegration analysis do not differ among groups , while the directions are very different as illustrated by mean covariation trajectories and MA slope stacks . Figure When PLS analysis was applied to the shapes of trajectories themselves we found no significant differences in both strength and direction of covariation . The opposite holds for HCM with a mean slope smaller than 1. This result deserves special attention. As the analyses were performed in SS, any aspects of pure size are filtered out differently from what done previously16. The higher rate of LA shape change per LV shape change in Control leads to the conclusion that the non-homothetic affine (or deviatoric in continuum mechanics vocabulary) and non-affine components of shape change are larger in LA than in LV that is more dominated by size. The reverse happens in HCM. It is well known30 that in HCM the LA is hyper-dilated and that its ejection fraction is reduced. On the opposite, the absolute booster pump function is significantly augmented. It means that the pure volumetric component becomes more important in HCM’s LA, while the deviatoric and non-affine components turn out to be less significant.To our best knowledge we presented the first combined analysis of functional covariation of LV and LA as well as the investigation of the entire LH treated as a whole shape. The analysis applied to the comparison of Control and HCM allowed to augment our knowledge about HCM pathophysiology which had been investigated solely at the one-chamber-level of LVThe deformational indicators we presented in this study show a very good classification power Table . The besshape and size-and-shape might evolve in transition from healthy to pathological condition and specifically how LA-LV mechanical covariation behaves. Indeed, healthy LV is dominated by size whereas in presence of shape changes there might be a rapid evolution towards pathology31. LA might be instead more compliant in terms of both size and shape and we had shown8 that in HCM the pure size component is augmented as expected, provided its absolute booster pump function is concomitantly increased30.In order to derive potentially useful and/or applicable conclusions for clinics it is important to underline how functional homeostasis of heart organ that, while functioning in a living subject, cannot deviate from a given covariation constraint even in diseased conditions whose departure could be incompatible with life. The second one indicates clearly that this functional homeostasis cannot occur without a cost.Architectural, cellular and molecular structures are intimately connected to heart form in accordance to Laplace’s law: LV wall size and elastance compensate for LV internal radius and related end-diastolic volume (EDV), thus minimizing LV end-diastolic pressure. So it is tempting to speculate that the above mentioned structures are normal determinants of cardiac performance whose function is regulated by physiological and biochemical mechanisms. When these mechanisms fail, LV form and function are no more correlated to each other as in the normal state. As a consequence, LA follows LV impairment in HCM. This has two different outcomes: the strength of the two chamber’s covariation is maintained and the direction of this covariation is impaired. The first evidence must be interpreted in terms of et al.32, it was Claude Bernard to hypothesize the “homeostasis” concept in 1865: he postulated that the body possesses an intrinsic capability to preserve its milieu interieur, i.e. its internal stability in front of a perturbation33. Successively, Cannon34 presented the term “homeostasis” to meet original Bernard’s concept of internal stability. Quoting32 “Homeostasis reflects the body’s natural power of adaptation, i.e. a continuous cooperation and integration between the internal environment with external surroundings”. Very often the concept of homeostasis is referred to temperature, or hormone and ion concentration. We tentatively try to use it by referring to the structural and geometric compensation that LA experiences in presence of HCM augmented LV filling pressure. In HCM, in fact, LA pump function is increased to help ventricular filling. As mentioned above, while the maintenance of the strength of covariation could be interpreted in terms of functional homeostasis, the fact that we found a shift in its direction could be interpreted in terms of functional “dyshomeostasis” following Kamalov et al.’s vocabulary32. Dyshomeostasis can be defined as an inappropriate, deficient or excessive counter-regulation in response to the perturbation. The differences in the direction of covariation we found in this study can fall into these categories. The changing in slope could lead, in extreme conditions, to a potentially lethal state thus making this dyshomeostasis fatal. For example, other types of pathologies, such as aortic regurgitation or congestive heart failure, might present different, possibly more dyshomeostatic, LV-LA covariations. Another example of functional homeostasis followed by dyshomeostasis can be found in35 where the authors, studying HCM, found an increased duration of LV twist consequent to the inverse relationship of longitudinal strain rate and twist rate. This is viewed as a compensation  to preserve ejection fraction ( = systolic function). However, the increased duration of systolic twist induces an untwisting delay, with elevated LV early diastolic pressures, reduced transmitral pressure gradient and impaired LV early diastolic filling ( = dyshomeostasis). More in general, referring to other diseases different from HCM, our results suggest that the pure size and shape change evaluated not only in terms of classical 3DSTE parameters  could provide important descriptors for interpreting not only frank pathology but also incumbent disease. While the volumetric indicator, either atrial or ventricular, has been always used to describe a great number of pathologies37 in terms of ejection fraction, the new era of echocardiography, represented by 2DSTE and 3DSTE, introduced the possibility to study a large number of traditional-echocardiographic and new-deformational parameters. However, this frequently becomes a sort of boomerang as the huge plethora of parameters is often difficult to present, interpret and, above all, to export in common clinical practice. Coupling the main deformational parameters with the synthetic ones we proposed here and using them for describing the whole LH functioning and covariation could help in interpreting pathology and its mechanical and geometry-driven functional consequences.Following Kamalov 16 we acquired data using PST–25SX Artida device, Toshiba Medical Systems Corp., Tokyo, Japan. We enrolled a total of 74 Control subjects found healthy after an accurate cardiological visit and 32 HCM patients. We then excluded all acquisitions with poor image quality and with ultrasonic windows not including completely both the left atrium and the left ventricle. After this selection the Control group was constituted by 46 subjects and 20 HCM patients . Inclusion criteria for HCM patients were determined by a left ventricular septum having a thickness larger than 13 mm. Table Followingsame 3DSTE clip. This ensures that the two LH chambers are acquired during the same heart beat and according to their reciprocal anatomical position and concomitant function. It was possible to obtain the landmark cloud  by an unlocked version of the software equipping our PST–25SX Artida device, thanks to a special opportunity provided in the context of an official research and development agreement between the Dipartimento di Scienze Cardiovascolari, Respiratorie, Nefrologiche Anestesiologiche e Geriatriche, “Sapienza” Università di Roma and Toshiba Medical System Europe, Zoetermeer, The Netherland.LH, constituted by LV and LA geometries, was reconstructed starting from 6 homologous landmarks for LV and 6 for LA. These were manually identified by the operator for each subject. The same operator (AE) was involved in LH reconstruction. The final geometry of any subject is a time-sequence of 16 shapes (see the homologous times interpolation method below), each one constituted by 2594 landmarks (presumed to be homologous) for endocardial surface, including LV and LA. LV and LA are individually composed by 1297 landmarks positioned along 36 horizontal circles, each composed of 36 landmarks, plus the apex. It is critical to specify here that LV and LA were digitized on the As the same operator (AE) was involved in geometry reconstructions, we performed an intra-observer reproducibility analysis. The left ventricles of 7 randomly chosen Controls and 3 (randomly chosen) HCM patients were reconstructed twice at a temporal distance >1 year (long-term). As first, we calculated the coefficient of variation of traditional 3DSTE global strains and volumes of left ventricles that possess larger systo-diastolic differences in comparison to left atrium using not only the systolic values but also those corresponding to all frames acquired by the device during one cycle. Then, as we propose here some novel indicators built using the Geometric Morphometrics paradigm (see below), we applied to each replica’s couple of acquisitions the deformation analysis presented below. We then evaluated the shape distance  between cycle’ shapes (using the first three PC scores as explained below) of each replica of the same subject parameterized on the maximum value it can assume on the tangent space that is pi/2. Coefficient of variation in percentage (i.e. standard deviation divided by the mean*100) applied to absolute difference between the two replicas of each subject for the global 3DSTE parameters was used as measure of goodness for reproducibility of classical 3DSTE variables. Tentatively one of us (GE) digitized the same subjects used for intra-observer reproducibility twice (short-term) at one day of temporal distance between the two replicas. These data were used for a preliminary assessment of inter-observer variability.The study was conducted after the approval of the “Dipartimento di Scienze Cardiovascolari, Respiratorie, Nefrologiche, Anestesiologiche e Geriatriche, “Sapienza” Università di Roma and in accordance with the ethical guidelines of the Declaration of Helsinki. Written informed consent was obtained from each subject.16 the set of homologous times refer to LV or LA only, in this study we needed to set them according to the concomitant function of both chambers. Figure Each subject is acquired with a different number of frames depending on the frame rate, automatically set by the machine at each acquisition (mean frame rate: 41.6 ms), and on the beat rate  in the size and shape space (SSS) for the entire LH geometry taken as a whole shape on the shapes recorded for each individual and we interpolated them via cubic spline at the above mentioned homologous times. The use of SSS is justified here because at this step size is still maintained differently from successive analyses. The resulting dataset is constituted by 16 shapes, each composed by 2594 landmarks (1297 for LV and 1297 for LA), for any of the 66 subjects (46 Control and 20 HCM) under study.16. In order to deal only with pure deformations, we applied the PT geometrical tool. Basically, it estimates deformations within the cycle of each subject between observed shapes and a properly chosen local template (LT). Then all deformations are “transported” toward a common template (CT). After that a common GPA is performed. In this way, starting inter- individual shape differences are filtered out and the sole deformations can be studied. PT can be performed on the curved Riemannian manifold using sophisticated Riemannian geodesics estimation38 or on the Euclidean tangent plane to the CT by means of the so called “Linear Shift” (LS)39 where geodesics are computed via simple subtraction and addition. It is important, however, properly managing rotations as explained in39. In16, it was shown that LS approximation is fairly acceptable for the type of data used here and we thus adopted this strategy. It is important to note that LTs and CT were set as the local means of each individual and the grand mean of the entire sample, respectively. Further technical details about LS can be found in39. After PT via LS, common ordination methods such as PCA can be performed. Motion trajectory is identified, for each subject, by the scores of the first three PCs. These will represent the “landmarks” of trajectory shape whose homology is ensured by the physiological temporal homology of times at which shapes were interpolated. Trajectory shape is studied by performing GPA + PCA on motions shapes; trajectory size is represented by trajectories centroid size (CS); trajectory angles are evaluated by computing the angle of vectors connecting PC scores values corresponding to end-diastole and those corresponding to end-systole. Both PC1/PC2 and PC1/PC3 angles are evaluated. These attributes were subjected to ANOVA (CS and angles) and MANOVA (shape) using Control/HCM as two-level factor variable.LH was treated as a whole shape and its motion was studied according toIt could be possible to use more than three PCs for building trajectories shapes but this would lead to the identification of hypershapes hardly representable. The first three PCs identify an elliptical trajectory shape and they explain a large amount of variance (see Results) thus making their use fairly acceptable.16 using local means as LTs and the grand mean as CT, allows appreciating both systole and diastole as deformed states. On the contrary, in fact, in classic 2D and 3D echocardiographic studies, end-diastole is a sort of “zero” from which deformations are computed. Our approach, instead, permits to identify possible impairments even if occurring during late diastolic phase.As already highlighted inwithin each individual: the 16 LH shapes that constitute each individual cycle identify a specific covariation trajectory. All covariation trajectories can then be compared in terms of the strength and direction of covariation. One of the most used techniques to study the covariation between two blocks of variables  is the Partial Least Squares Analysis (PLS)40. This approach treats blocks symmetrically without an a priori attribution of dependence-independence relationship. PLS returns two sets of paired singular vectors (SW) that maximize the covariance between blocks: one set for block A and one set for block B. These sets must be evaluated by plotting pair by pair the same SWs of both blocks. In the SW space the covariation trajectory can be evaluated in terms of strength and direction. Recently29 proposed a new strategy to compare the strength of PLS focusing on the first SW pair. They proposed a standardized test statistic (a z-score) for measuring the degree of morphological integration between sets of variables. The z-scores can be used to test for differences (via ANOVA) among groups. We then performed, on deformational data coming from LS procedure, separate PLS analyses for each individual using its proper 16 LV and LA shapes. We then used compare.pls function from the R package “geomorph”41 in order extract z-scores  to be used in ANOVA using Control/HCM as factor. This looks for differences in the strength of covariation, whereas nothing is known about its direction. In fact, in the SW space, two covariation trajectories could show the same strength in terms of effect size still having different orientations. The orientation of trajectory in SW space can be interpreted as the shape change rate of one module relatively to the shape change of the other. This aspect is very important as it is exactly related to the way the two modules (LV and LA) work in realizing LH functioning.Being LH organized into two highly interacting modules (LV and LA), the integration and covariation between them at different levels of organization can be studied. The first one is that occurring within each individual, as one individual is represented by one single trajectory shape. Here covariation within any category (Control and HCM) is estimated using each individual trajectory shape as a single observation. LA and LV trajectory shapes were subjected to PLS analysis and the significance of difference in z-scores was evaluated via permutation analysis. Differences in direction were evaluated using MA regression as described above. This time, however, MA regression was performed on Control and HCM categories rather than on single individuals.In order to investigate this issue, we performed separate Major Axis (MA) analyses on individual covariation trajectories on the space identified by the first pair of SWs. MA is necessary being it “symmetrical”, i.e. residuals are computed orthogonally to the line of best fit, and, coherently with the symmetry intrinsic to PLS, does not require the classic assumption of dependence-independence relationship. MA slopes are then contrasted in the usual ANOVA using Control/HCM as factor. A second-order level of covariation is that occurring between the shapes of trajectory themselves. In this case, we don’t analyze data 42 it was proposed a new, alternative way to look at the integration intrinsic to a special set of shapes. This approach does not compare two or more modules. Actually, it examines the regression coefficient for log partial warp variance against log of its proper bending energy in the standard thin-plate spline setup41. If the coefficient equals −1 the shape series can be considered as “self-similar” while if it is smaller the series is considered as “integrated”. When it results larger than −1 (e.g. close to 0) the series can be considered “disintegrated”, i.e. does not correspond to any biological meaningful explanation which is to say, incompatible with life. The more negative the coefficient the larger the integration. We thus performed such kind of analysis using globalIntegration function in “geomorph” R package for each individual present in our dataset. Resulting slopes were subjected to ANOVA using Control/HCM as factor variable.Recently, in16.We used the indicators coming from LS analysis and trajectory analysis in a classification exercise in order to assess the clinical value of whole LH deformation as previously done inTo achieve this we adopted the same strategy used in ref. Supplementary Figure S1Supplementary Figure S2


Catestatin was discovered as a potent inhibitor of catecholamine secretion and plays important roles in the cardiovascular system. Our previous study demonstrates a close relationship between catestatin levels and prognosis of ST-elevation myocardial infarction (STEMI). Using the same population, the goal of this study is to investigate the ability of catestatin to predict left ventricular (LV) remodeling in STEMI patients. 72 patients and 30 controls were included. Catestatin was sampled after admission to the emergency room (ER), at day3 (D3), and day7 (D7) after STEMI. Echocardiography was performed at D3 and after 65 months for evaluation of LVEDD, EF, IVS, LVPW, E, A, E’, E/A, and E/E’. The changes of these parameters from D3 to 65 months were used to reflect the changes of ventricular structure and function. We found that plasma catestatin levels at D3 were highly correlated with the changes of LVEDD, EF, E, A, E’, E/A, as well as E/E’. Patients with higher catestatin levels developed worse ventricular function during the follow-up period. Single-point catestatin was effective to predict LVEDD change. And concurrently increasing catestatin and NT-proBNP levels predicted the highest risk of LV remodeling. This study suggests an important prognostic information of catestatin on LV remodeling. Left ventricular (LV) remodeling refers to the process by which ventricular size, structure and function are regulated by mechanical, neurohormonal, and genetic factors 1113The baseline demographics, echocardiography and other laboratory findings are detailed in We have earlier reported that plasma catestatin achieved its highest level at D3 after STEMI , which wFirst, patients were divided into 2 groups based on the median level of catestatin at D3 (28.71 ng/ml); the changes of echocardiography parameters as well as other characteristics listed in We performed ROC analysis of catestatin levels at D3 for prediction of LV remodeling, as illustrated by the following echocardiography parameters: ΔLVEDD, ΔEF, ΔE, ΔA, ΔE’, ΔE/A, ΔE/E’ . The AUCPatients were grouped according to the catestatin and NT-proBNP median values . Multivariate logistic regression found that concurrent increases in catestatin and NT-proBNP predicted the greatest risk [OR = 24.645 ] .In STEMI, timely reperfusion therapy can reduce infarct size, preserve left ventricular function and improve clinical outcomes. However, as one of the strongest predictors of subsequent mortality, LV remodeling occurs in an appreciable proportion of patients with AMI, even those successfully treated with pPCI. Early identification of high-risk patients allows for early intervention with targeted treatment strategies and close follow-up. But currently, a major challenge in clinic is to discriminate between patients with reversible dysfunction and those who will experience little functional recovery accompanied by LV remodeling, which necessitates the development of new strategies to predict adverse events at early stages. It has been shown that the plasma concentration of catestatin is altered during the course of AMI, and it is associated with poor prognosis such as heart failure and deathAs a follow-up of our previous studyet al. confirmed this effect using isolated adult rat cardiomyocytes undergoing simulated ischemia/reperfusion injury, and determined PI3K/NO/cGMP pathway as well as preservation of mitochondrial membrane potential were involvedCardiac remodeling is generally accepted as a determinant of the clinical course of heart failure (HF), which can be considered a primary target for treatment and a reliable surrogate for long-time outcomes. It is manifested clinically as changes in structure and function of the heart resulting from cardiac load or injury, such as AMI. Using noninvasive imaging like echocardiography, physicians and researchers are able to analyze the mechanisms by which biochemical and cellular events contribute to these changes during remodeling. In the current study, the myocardial functions can be assessed through the following parameters: EF for systolic function; E, A, E’, E/A, and E/E’ for diastolic function. We found that patients with higher catestatin levels at D3 developed worse systolic as well as diastolic function during the follow-up period. It has been shown that in isolated avascular frog heart, catestatin dose-dependently decreased stroke volume and stroke work, noncompetitively inhibited the positive inotropic action of isoproterenol and the positive inotropic effect of endothlin-1Apart from the worsening of myocardial functions, our results also showed that catestatin levels at D3 were positively associated with the increase of LVEDD, a parameter indicating cardiac structure change. Because cardiomyocytes and extracellular matrix (ECM) are two essential components of the myocardium, the pathological alterations of them will provide insights into the remodeling process. For cardiomyocytes, the most important change after AMI is hypertrophy. Cardiomyocyte hypertrophy is characterized by an increase in cell size, enhanced protein synthesis, and heightened organization of the sarcomere2426et al. demonstrated that catecholamine activation in patients with AMI, as measured by plasma adrenaline and noradrenaline, showed an early and rapid increase in the first 3 days and was restricted to the first 5 days, with values unchanged after 1 year compared to those at discharge, at day 6Petersen To the best of our knowledge, this is the first study presenting that catestatin might be a novel marker reflecting LV remodeling in the myocardium following AMI. In summary, we observed a positive association between catestatin concentrations at D3 and LV remodeling. However, despite the findings, there are still some limitations in the current study. First, the sample size was relative small. Second, this was a one-center study. Third, we just assessed the changes of echocardiographic parameters instead of giving a certain definition of LV remodeling, which might cause obscuration when making clinical decisions. Therefore, further large-scale investigations and careful comparisons are required to confirm the predictive ability of catestatin in LV remodeling in AMI patients.A total of 117 consecutive patients with the first AMI admitted to the Department of Cardiology, Peking University Third Hospital, from June 2008 to April 2009 were included, 17 of them were lost to follow-up. In the rest of the 100 patients, we were able to get echocardiography parameters at D3 and 65 months from 72 of them, so this study is based on the information of these 72 patients. All patients received successful primary percutaneous coronary intervention (pPCI) within 12 h from the AMI symptoms onset. The ST segment elevation myocardial infarction (STEMI) was diagnosed according to the American College of Cardiology/American Heart Association guideline in 2004At the acute phase of AMI, blood samples were obtained from an antecubital vein without stasis in all patients immediately after admission to the emergency room (ER), and in the morning of the third day (D3) and the seventh day (D7) after AMI (n = 72). In the control subjects, blood samples were obtained from the antecubital vein in the morning of the same day when angiography was performed (n = 30). The blood samples, anticoagulated with ethylenediaminetetraacetic acid (EDTA), were immediately centrifuged at 3000 rpm for 10 min at 4 °C. An aliquot of the EDTA plasma was stored at −80 °C till analysis. Repeated freeze-thaw cycles were avoided.Plasma levels of catestatin were measured by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instruction . The minimal detection limits for catestatin was 0.06 ng/ml. Serum NT-proBNP levels were measured by a two-site sandwich electrochemiluminescence immunoassay . These assays were performed by an investigator blinded to the sources of the samples.All patients underwent an echocardiography examination at D3 and 65 months after AMI in our hospital. A VIVID 7  scanner with a 3.3-MHz multiphase array probe was used for the Doppler echocardiography studies, which was conducted under the supervision of experienced cardiologists. The study commenced with each patient lying in the left decubitus position for probe insertion. The echocardiographic techniques were performed and cardiac dimensions and volumes calculated in accordance with the guidelines of the American Society of Echocardiography65 months-LVEDDD3). All results are expressed as the mean ± SD. Differences between groups were assessed by Student’s t-test and chi-square test. A Pearson or Spearman correlation was used to explore associations between catestatin levels and parameters. The sensitivity and specificity of catestatin concentration for predicting outcomes were determined, and receiver operating characteristics (ROC) curves were constructed. Univariate and multivariate logistic regression were performed to examine predictors of LV remodeling. p < 0.05 was considered statistically significant.Outcome measures were left ventricular end-diastolic dimension (LVEDD), ejection fraction (EF), interventricular septal end diastolic dimension (IVS), left ventricular posterior wall thickness (LVPW), E, A, E’, E/A, E/E’, and changes of them from D3 to 65 months .Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


To investigate the association between diastolic function and the different beneficial effects of cardiac resynchronization therapy in patients with heart failure due to different causes.The 104 enrolled patients were divided into an ischemic cardiomyopathy group (n=27) and a non-ischemic cardiomyopathy group (n=77) according to the cause of heart failure. Before implantation, left ventricular diastolic function was evaluated in all patients using echocardiography. After six months of follow-up, the beneficial effects of cardiac resynchronization therapy were evaluated using a combination of clinical symptoms and echocardiography parameters.The ischemic cardiomyopathy group included significantly more patients with restrictive filling than the non-ischemic cardiomyopathy group. The response rate after the implantation procedure was significantly higher in the non-ischemic cardiomyopathy group than in the ischemic cardiomyopathy group. Degrees of improvement in echocardiography parameters were significantly greater in the non-ischemic cardiomyopathy group than in the ischemic cardiomyopathy group. Multivariate regression analysis showed that a restrictive filling pattern was an independent factor that influenced responses to cardiac resynchronization therapy.This study again confirmed that the etiology of heart failure affects the beneficial effects of cardiac resynchronization therapy and a lower degree of improvement in ventricular systolic function and remodelling was observed in ischemic cardiomyopathy patients than in non-ischemic cardiomyopathy patients. In addition, systolic heart failure patients with severe diastolic dysfunction had poor responses to cardiac resynchronization therapy. Ischemic cardiomyopathy patients exhibited more severe diastolic dysfunction than non-ischemic cardiomyopathy patients, which may be a reason for the reduced beneficial effect of cardiac resynchronization therapy. Cardiac resynchronization therapy (CRT) can improve symptoms, increase quality of life, reduce the risk of hospital readmission, and decrease the mortality of chronic heart failure patients Consecutive patients who were scheduled to receive CRT pacemaker/defibrillator (CRT-P/D) treatment for chronic heart failure at Provincial Hospital Affiliated with Anhui Medical University from April 2013 to January 2015 were selected. Patients who met the following criteria were enrolled in the study The NYHA functional classification of patients was determined before implantation, and the disease course of heart failure, medications, and serum creatinine values were recorded. All patients underwent 12-lead electrocardiography (ECG) to determine heart rhythm, QRS duration, and morphology as well as echocardiography to evaluate cardiac structure and systolic and diastolic function. Six months after implantation, the NYHA functional classification was re-evaluated, and ECG and echocardiography were performed to assess the changes.Each patient underwent conventional echocardiography before implantation and at six months after implantation. A Philips iE33 ultrasound system with an S5-1 probe was used (1.0-5.0 MHz).Left atrial as well as LV end-systolic and end-diastolic diameters  were obtained in M mode. LV volumes and the ejection fraction  were assessed using the biplane Simpson’s rule. The LV outflow tract-velocity time integral (LVOT-VTI) was measured within 0.5-1 cm below the aortic valve, and the systolic pulmonary artery pressure (SPAP) was estimated based on the tricuspid regurgitation velocity. LV dyssynchrony was assessed using the standard deviation of the time to peak systolic velocity in 12 LV segments (Ts-SD) derived from tissue Doppler images The degree of mitral regurgitation (MR) was evaluated according to the ratio between the maximal mitral regurgitant jet area and the left atrial area as follows: mild (Grade 1) <20%, moderate (Grade 2) 20-40%, and severe (Grade 3) >40%.Diastolic function was assessed by transmitral Doppler and tissue Doppler. Pulse Doppler was used to acquire the diastolic mitral valve flow spectrum and record peak early diastolic velocity (E), peak late diastolic velocity (A), and diastolic early filling deceleration time (DT) and to calculate the E/A ratio. Tissue Doppler was used to acquire mitral annular velocity curves corresponding to the lateral wall and interventricular septum, to record mitral annular early diastolic peak velocity , and to calculate the mean Em value and E/Em ratio. According to the mitral valve flow spectrum and the tissue Doppler spectrum of the mitral annulus, patients were divided into restrictive filling pattern (RFP)  and non-RFP  groups CRT was placed using the transvenous approach. Subclavian vein puncture was performed. After coronary sinus intubation, retrograde angiography was performed to fully display all branches of the coronary veins. The LV electrode lead was placed in the lateral or posterolateral cardiac vein to ensure pacing capture, with high voltage (10 V) used to demonstrate a lack of phrenic nerve stimulation. The right ventricular electrode lead was placed in the right ventricular apex or septum. The right atrial electrode lead was conventionally placed in the right atrial appendage. After the pacing tests were completed, the electrode leads were connected to a pulse generator and embedded in a subcutaneous or a deep to pectoralis major pouch in the chest wall. The incision was sutured in layers.Within one week of implantation, atrioventricular (AV) delay and interventricular (VV) delay optimization were performed under echocardiographic guidance. AV delay optimization was conducted using the iterative method. In particular, the optimal AV delay was determined based on the maximum left ventricular filling times at 6 selected AV delays: 180, 160, 140, 120, 100, and 80 ms. VV delay optimization was performed after AV delay optimization; the optimal VV delay was determined using the maximum left ventricular outflow tract velocity time integral at peak velocity (LVOT-VTImax) Six months after implantation, a ≥15% reduction in LVESV compared with the preoperative value was defined as a CRT response.x2 tests. Influencing factors on CRT responses were analyzed using univariate and multivariate logistic regression models. A value of p<0.05 indicated a statistically significant difference.The statistical analysis was performed using SPSS 19.0 software. Continuous variables are presented as the mean±standard deviation. Categorical variables are presented as frequencies and percentages. Comparisons of data within groups were performed with paired Student's t-tests (continuous variables) and Wilcoxon signed-rank tests . Comparisons of data between groups were performed with unpaired Student's t-tests (continuous variables) and Mann-Whitney U tests . Comparisons of gender and CRT response rates between groups were performed with Baseline information . The RFP was significantly higher in patients in the ICM group than in patients in the NICM group . One week after implantation, the AV delay optimization was not significantly different between the ICM group (119.3±19.6 ms) and the NICM group (123.1±17.2 ms).1. ormation . In thisCRT response rate. Six months after the implantation procedure, 66 out of the 104 patients (63.5%) exhibited responses to CRT. The CRT response rate was significantly higher in the NICM group than in the ICM group .2. Clinical beneficial effects of CRT. NYHA functional classification, LAD, LVEDV, LVESV, LVEF, FS, and LVOT-VTI were improved six months after the implantation procedure relative to before implantation . The degree of MR was lower than before implantation (p<0.05). The SPAP did not change significantly. A comparison of parameters before and after CRT is presented in 3. p<0.001); the degrees of SPAP and MR were both lower than those recorded before implantation (both p<0.05). In the ICM group, the postoperative NYHA functional classification, LVESV, LVEF, FS, and LVOT-VTI were all significantly improved , whereas the LAD, LVEDV, SPAP, and MR did not exhibit significant changes.In the NICM group, the postoperative NYHA functional classification, LAD, LVEDV, LVESV, LVEF, FS, and LVOT-VTI were all significantly improved compared with the values recorded before implantation . A comparison of parameters between the NICM and ICM groups is shown in Six months after implantation, the differences in echocardiography parameters  between the two groups were significant (all Factors that influence the CRT response (4. response . The uniThis study showed that Many randomized controlled trials and observational studies Although diastolic function is an important component of overall cardiac function, it has long received much less attention than systolic function. Abnormal diastolic function is important for the development of heart failure symptoms and signs. Even during systolic heart failure, increased LV filling pressure is closely associated with exercise limitation and is independent of the degree of systolic dysfunction 2+ pump activity, Ca2+ uptake into the sarcoplasmic reticulum, and Ca2+ outflow decrease, and myosin-actin complex dissociation disorder occurs, resulting in a delayed and incomplete active diastole Diastolic dysfunction is a typical presentation of ICM. Abnormal diastolic function occurs at the early stage of myocardial ischemia, even earlier than systolic dysfunction This study is subject to the following limitations. In summary, this study again confirmed that the etiology of heart failure affected the curative effects of CRT and that a lower degree of improvement of ventricular systolic function and remodeling was observed in ICM patients than in NICM patients. In addition, systolic heart failure patients with severe diastolic dysfunction showed poor CRT responses. ICM patients exhibited more severe diastolic dysfunction than NICM patients, which may be a reason for the reduced beneficial effect of CRT. The findings of our study are similar to those published as long as a decade ago, but the intervening period has seen little attention to this important aspect of the CRT response. We feel that it may now be reasonable to refocus on this aspect of CRT and that a study from an Asian country may reignite interest.Wang Q, Chen KY and Yan J conceived and designed the study. Wang Q and Chen KY drafted the manuscript. Wang Q, Hu Y and Yang DM were responsible for the acquisition of data. Chen KY, Yu F, An CS and Su H were responsible for the analysis and interpretation of data. Yan J was responsible for the administrative support. Xu J, Su H and Yang DM were responsible for the critical revision of the manuscript for important intellectual content. All authors have read and approved the final version of this manuscript.