FRDA manifests with multiple symptoms, which may include ataxia, cardiomyopathy and diabetes mellitus. Expanded GAA tracts are genetically unstable, exhibiting both expansions and contractions. GAA length correlates with severity of FRDA symptoms and inversely with age of onset. Thus, tissue-specific somatic instability of long GAA repeats may be implicated in the development of symptoms and disease progression. Herein, we determined the extent of somatic instability of the GAA repeats in heart, cerebral cortex, spinal cord, cerebellar cortex, and pancreatic tissues from 15 FRDA patients. Results demonstrate differences in the lengths of the expanded GAAs among different tissues, with significantly longer GAA tracts detected in heart and pancreas than in other tissues. The expansion bias detected in heart and pancreas may contribute to disease onset and progression, making the mechanism of somatic instability an important target for therapy. Additionally, we detected significant differences in GAA tract lengths between lymphocytes and fibroblast pairs derived from 16 FRDA patients, with longer GAA tracts present in the lymphocytes. This result urges caution in direct comparisons of data obtained in these frequently used FRDA models. Furthermore, we conducted a longitudinal analysis of the GAA repeat length in lymphocytes collected over a span of 7–9 years and demonstrated progressive expansions of the GAAs with maximum gain of approximately 9 repeats per year. Continuous GAA expansions throughout the patient’s lifespan, as observed in FRDA lymphocytes, should be considered in clinical trial designs and data interpretation.Friedreich’s ataxia (FRDA) is a genetic neurodegenerative disorder caused by transcriptional silencing of the  In FRDA patients, the expanded GAA repeat tracts are associated with locus-specific chromatin changes leading to transcriptional silencing .Reactions utilized the FailSafe PCR System with mix D  or JumpStart® CA-630, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate (SDS), 50mM Tris-HCl, pH 8, and a protease inhibitor cocktail . The Bradford Protein Assay Kit  was used to determine protein concentration. Fifty micrograms of tissue protein lysate were electrophoresed on NuPAGE™ 4–12% Bis-Tris protein gels  and transferred onto nitrocellulose membranes . Human frataxin was detected with the anti-frataxin polyclonal H-155 antibody  and human voltage dependent anion channel (VDAC) was detected with the anti-VDAC polyclonal antibody , both used at 1:1,000 dilutions. Human heat shock protein (Hsp) 60 was detected with the anti-Hsp60 D307 antibody  at 1:2,000 dilution. GAPDH was detected with the anti-GAPDH antibody  at 1:25,000 dilution. Primary antibody incubation was performed for at least 12 hours at 4°C. Sheep anti-mouse immunoglobulin  and donkey anti-rabbit immunoglobulin , linked to horseradish peroxidase, were used as secondary antibodies at a 1:5,000 dilution for 1 hour at room temperature. Signal was exposed using Amersham ECL Prime Western Blotting Detection Reagent  or SuperSignal® West Dura Extended Duration Substrate  and measured using Image Lab 5.0. Quantification was performed using ImageJ software .Lysates were prepared using a RIPA buffer containing 150 mM NaCl, 1% IGEPAL® SPSS® Statistics Version 24 and Excel 2016 software. A p-value less than 0.05 was considered significant for all analyses.Statistical analyses were done using IBMFXN gene in FRDA patient tissues, we analyzed sizes of the repeats in heart, cerebral cortex, spinal cord, cerebellar cortex, and pancreas samples from 15 patients  in the majority of samples due to the high level of somatic instability, we developed an unbiased GAA length analysis protocol based on defining the minimum, maximum, and mean GAA size of the repeat tracts detected in each sample (Methods). The mean GAA repeat sizes among 15 FRDA patients and 5 different tissues were between 428 and 914 GAAs  Is there a correlation between the sizes of expanded GAA tracts and tissue type, especially tissues primarily affected in the disease? (ii) Is the number of GAA repeats identical in different tissues? (iii) Do contractions or expansions of the GAA tracts accumulate over time in tissues? To answer these questions, we thoroughly characterized GAA tracts in a large number of different FRDA and control tissue samples.FXN gene and differences in the activity of various DNA repair systems could be responsible for the significantly longer GAAs detected in pancreas and heart tissues. Interestingly, quantitative Western blot analyses of frataxin expression in different tissues from FRDA patients and unaffected controls indicate a remarkably low level of frataxin in FRDA cardiac tissue relative to nervous system tissue  system is considered a major factor contributing to GAA repeat instability in human cells. Expansions of the GAA repeats in iPSCs reprogrammed from patient fibroblasts have been correlated with increased expression of the MMR enzymes when compared to the parental fibroblast cells , 37 and m tissue . DevelopTranscriptome analyses conducted using FRDA mouse models demonstrated a global decrease of gene expression in frataxin deficient tissues . Also, rInterestingly, results of the longitudinal analyses of the GAA tract in lymphocytes, although conducted on a relatively small pool of expanded alleles, demonstrated a strong, length-dependent bias towards repeat expansions. Eight of 10 alleles analyzed increased in GAA length by up to 64 repeats over a period of 7–9 years. This result contrasts with prior in vitro studies on immortalized lymphoblast cells where a predominance for contractions, frequently large, was observed . In factHFE) gene [Results of our longitudinal studies also indicate that comparative analyses of the GAA length between patients need to be interpreted cautiously as expanded tracts change dynamically over a patient’s lifetime. Considering the extreme case of a 15% increase over 7 years , substanFE) gene .FXN GAA tract evolved from G/A rich sequences of the ancient Alu elements. It is highly likely that long GAA sequences constantly evolve and change, resulting in introduction of point mutations (interruptions) into the pure GAA motifs. Examples of such interruptions have been recurrently reported in the literature but their actual detailed structure and frequency in FXN alleles is unknown. Disturbance of the GAA repeat purity can affect not only expression of the FXN gene but also can significantly influence instability of the repeat tract, especially the propensity for continuous expansions. Although technically challenging, future studies addressing the role of GAA tract interruptions in FRDA heterogeneity are necessary.Length polymorphism and somatic instability of the expanded GAA repeat tracts in different tissues represent the first layer of complexity responsible for differences in frataxin expression that can translate to clinical variability between FRDA patients. It has been estimated that the length of the repeat tract accounts for only 36% of the variability in the age of onset with other contributing factors being genetic, epigenetic, or environmental in nature . The FXNcis and trans acting factors affecting this process need to be further investigated.Expanded GAA repeats are unstable in FRDA, and expansion bias detected in heart and pancreas is likely to contribute to symptom development and disease progression, making the mechanism of somatic instability an important target for therapy. Differences in the size of the GAA tracts between lymphocytes and fibroblasts urge caution in direct comparisons of data obtained using different model systems. Continuous GAA expansions over time as observed in FRDA lymphocytes should be considered in clinical trials design and data analyses. The kinetics of longitudinal changes in GAA repeat number and potential S1 FigA,D) heart,  cerebral cortex, and  cerebellar cortex tissues. Frataxin expression values were normalized using the mitochondrial HSP60 protein. Patient F9 exhibited very low HSP60 expression in cerebellar cortex tissue, therefore GAPDH was used for normalization.Western blots probed for FXN were performed on ((PDF)Click here for additional data file.S2 FigFXN gene downstream of the GAA tract as control for genomic DNA quality (bottom panel). (-) represents no-template control and (+) represents positive control (genomic DNA isolated from FRDA fibroblasts). (A) F1, (B) F4, (C) F5, (D) F3, (E) F6, (F) F8, (G) F9, (H) M1, (I) M2, (J) M3, (K) M5, and (L) M4 as described in Genomic DNA was extracted from heart (H), cerebral cortex (Cc), spinal cord (Sc), cerebellar cortex (Cb) and pancreas (P) tissues. Results of PCR analyses of GAA repeat length in FRDA patient tissues (top panel). Analyses of GAA repeat instability in the 5q23 locus in patient tissues (middle panel). Amplification of an intron 1—exon 2 fragment of the (PDF)Click here for additional data file.S3 FigFXN gene were amplified from genomic DNA extracted from heart (H), cerebral cortex (Cc), spinal cord (Sc), cerebellar cortex (Cb) and pancreas (P) tissues isolated from FRDA patients. The band intensity of the PCR products along with the repeat sizes are shown. Solid vertical lines represent the mean of GAA repeat sizes detected across all tissues analyzed. (A) F1, (B) F4, (C) F5, (D) F3, (E) F6, (F) F8, (G) F9, (H) M1, (I) M2, (J) M3, (K) M5, and (L) M4 as described in The expanded GAA repeats in the (PDF)Click here for additional data file.S4 FigFXN gene were amplified from genomic DNA extracted from heart (H), cerebral cortex (Cc), spinal cord (Sc), cerebellar cortex (Cb) and pancreas (P) tissues isolated from FRDA patients in two independent reactions. Analyses of GAA repeat instability in tissues of FRDA patient F2; (A) experiment 1, (B) experiment 2 and in tissues of FRDA patient M5 (C) experiment 1, (D) experiment 2. Sizes of the individual PCR products were calculated for each tissue and experiment. No significant differences were observed between sizes of the GAA tracts determined in two independent experiments .The expanded GAA repeats in the (PDF)Click here for additional data file.S5 FigFXN gene using genomic DNA extracted from the cerebral cortex (Cc) and cerebellar cortex (Cb) tissues of unaffected individuals. (-) represents no-template control and (+) represents positive control (genomic DNA isolated from control fibroblasts).PCR analysis of the GAA repeat region in the (PDF)Click here for additional data file.


Echocardiographic studies have shown a reduction in global left ventricular (LV) ejection fraction (LVEF) in patients with isolated left bundle branch block (LBBB). This is likely due to altered electromechanical activation and resultant loss of septal contribution to LV systolic function. We sought to characterize LV volumes and global systolic function in adult subjects with an isolated (not related to infarct or cardiomyopathy) LBBB and compared these data to matched adults without LBBB and were free of clinical cardiovascular disease, using Cardiac Magnetic Resonance (CMR) imaging.Subjects with isolated LBBB  were identified from the hospital echocardiographic database and invited to undergo CMR. Age-, sex-, and body-surface area (BSA)-matched controls (n=18) were identified from a large community-dwelling cohort who had undergone CMR, as part of a population study, on the same CMR scanner using the same SSFP sequence. Ten-mm thick contiguous slices in the LV short-axis orientation encompassing both ventricles were obtained. Right and left ventricular endocardial borders were manually segmented by a trained observer and volumes were determined in the standard fashion using a modified summation of disks method. Ejection fraction was computed as stroke volume divided by end-diastolic volume in each ventricle. Differences between the LBBB group and matched controls were assessed using the Wilcoxon paired signed rank test; a p < 0.05 was considered significant.LBBB subjects ranged in age from 37 to 82 years. Left ventricular end-diastolic volume (EDV) and end-systolic volume (ESV) were larger in the LBBB group (p < 0.01), but LV stroke volume (p=0.13) and cardiac output (p=0.18) did not differ between LBBB subjects and controls. Subjects with isolated LBBB had significantly lower LVEF (56 ± 7%) than controls (68 ± 6%), p = 0.0002. Right ventricular volumes and ejection fraction did not differ between isolated LBBB and control groups.Using the reference standard of volumetric CMR, our study demonstrates that adults with an isolated LBBB have greater LVEDV and LVESV than age, sex and BSA-matched individuals without LBBB. While LV stroke volume and cardiac output did not differ between groups, LVEF was significantly lower in subjects with LBBB. Right ventricular volumes and ejection fraction did not differ between groups. These data are important for the clinical interpretation of left and right ventricular volumes and ejection fraction in LBBB patients referred for CMR.


Mechanics of the left ventricle (LV) are important indicators of cardiac function. The role of right ventricular (RV) mechanics is unknown due to the technical limitations of imaging its thin wall and complex geometry and motion. By combining 3D Displacement Encoding with Stimulated Echoes (DENSE) with a local coordinate system analysis, it is possible to quantify RV strain, torsion, and synchrony. In this study we sought to characterize RV mechanics in healthy individuals and compare these values to their LV counterparts.Spiral cine DENSE was performed on 40 healthy subjects  at 3T (Siemens Trio). Short-axis images spanning both ventricles at end-diastole were acquired with displacements encoded in three dimensions. Acquisition parameters included: 12 spiral interleaves, 360 × 360 mm2 FOV, 180 × 180 image matrix, 8 mm slice thickness, TE/TR = 1.08/17 ms, 0.04 cycles/mm encoding frequency. For each cardiac frame, the 3D displacements were fit to continuously differentiable radial basis functions, allowing for computation of the 3D Cartesian Lagrangian strain tensor at any myocardial point. The geometry of the RV was extracted via a surface fit to manually drawn endocardial contours  in the outflow region Figure . Ell var3D spiral cine DENSE is capable of resolving both the complex geometry and 3D motion of the RV. In healthy subjects, regional variations in Ecc and Ell exist within the RV, however they have comparable global magnitudes. RV torsion was similar to torsion seen in the LV and the RV was found to contract later but more synchronously than the LV.


To analyze alterations in left ventricular (LV) myocardial T1 times in patients with pulmonary hypertension (PH) and to investigate their associations with ventricular function, mass, geometry and hemodynamics.Fifty-eight patients with suspected PH underwent right heart catheterization (RHC) and 3T cardiac magnetic resonance imaging. Ventricular function, geometry and mass were derived from cine real-time short-axis images. Myocardial T1 maps were acquired by a prototype modified Look-Locker inversion-recovery sequence in short-axis orientations. LV global, segmental and ventricular insertion point (VIP) T1 times were evaluated manually and corrected for blood T1.p < 0.0001; lateral, 1190 ± 45 ms vs. 1150 ± 33 ms, p = 0.0003; global, 1220 ± 52 ms vs. 1171 ± 29 ms, p < 0.0001; VIP, 1298 ± 78 ms vs. 1193 ± 31 ms, p < 0.0001). In PH, LV eccentricity index was the strongest linear predictor of VIP T1 (r = 0.72). Septal, lateral and global T1 showed strong correlations with VIP T1 .Septal, lateral, global and VIP T1 times were significantly higher in PH than in non-PH subjects (septal, 1249 ± 58 ms vs. 1186 ± 33 ms, In patients with PH, T1 times in VIPs and in the entire LV myocardium are elevated. LV eccentricity strongly correlates with VIP T1 time, which in turn is strongly associated with T1 time changes in the entire LV myocardium.• Native T1 mapping detects left ventricular myocardial alterations in pulmonary hypertension• In pulmonary hypertension, native T1 times at ventricular insertion points are increased• These T1 times correlate strongly with left ventricular eccentricity• In pulmonary hypertension, global and segmental myocardial T1 times are increased• Global, segmental and ventricular insertion point T1 times are strongly correlated Patients with pulmonary hypertension (PH) are at risk for progressive heart failure , 2. The Myocardial T1 relaxation time mapping is an emerging technique for tissue characterization that provides information about tissue composition on a standardized scale , 10. IncThe aim of the present study was, therefore, to assess LV global, segmental and VIP T1 times in patients with normal and elevated mean pulmonary arterial pressure, and to investigate their correlations with ventricular function, mass, geometry and hemodynamic parameters.This prospective, explorative study was approved by the local ethical review board, and all subjects gave written informed consent. Patients with contraindications to magnetic resonance imaging were not enrolled.From November 2012 to January 2015, a total of sixty-four patients with suspected PH underwent right heart catheterization (RHC) and non-contrast CMR imaging. Patients with known cardiomyopathies or PH owing to left heart diseases . LVEI remained the strongest correlate of non-normalized VIP T1 time for patients with PH .Correlation coefficients of non-normalized VIP T1 time with septal, lateral and global non-normalized myocardial T1 times remained similar to the blood normalized values [all patients, The major findings of the present study were that 1) septal, lateral, global and VIP T1 times were significantly higher in patients with PH than in those without PH; 2) VIP T1 time was the strongest linear predictor of septal, lateral and global T1 times; and 3) in patients with PH, LVEI was the strongest linear predictor of VIP T1 time, and RVCI was the only additional significant parameter in bilinear regression.As a consequence of ventricular interdependence, PH impairs both RV and LV function –24: ProgAccordingly, we presume that the significantly higher VIP T1 times found in patients with PH can be explained by focal myocardial remodelling in all (anterior and posterior) VIPs at the basal, mid-ventricular and apical levels.To lessen the impact of interobserver variability, analysis was restricted to mean VIP T1 times. In agreement with relationships previously reported between LGE volume and hemodynamic, function, mass and geometry parameters –5, 29, uIn our study, alterations of LV myocardial T1 times in patients with PH were not limited to the VIPs and IVS. T1 times were higher in PH patients in all LV segments, whereas significance was reached for all but the apical lateral segment. Segmental averaging reduced variances of determined T1 times, such that septal, global and lateral T1 values were all significantly higher in patients with PH than in patients without PH. No differences were found between PAH and non-PAH PH patients. We conjecture that the presence of higher T1 times throughout the LV myocardium in patients with PH could be related to interstitial fibrosis; in turn, such fibrosis could explain the increased LV wall stiffness, the reduced LV longitudinal contractility and the reduced circumferential strain even at LV non-septal segments reported in patients with chronic PH , 20, 21.The current study cannot unmask the underlying mechanisms leading to LV tissue alterations. However, given that VIP T1 time was strongly correlated with septal, global and lateral T1 times and no simple multilinear model of hemodynamic, ventricular function, mass and geometrical parameters could similarly predict these T1 values, it appears that PH involves the total LV myocardium to a large extent in parallel. This is compatible with the fact that VIP, septal, global and lateral T1 times showed similar significances in univariate correlations with hemodynamic, ventricular function, mass and geometrical parameters. Especially, significant correlations of lateral T1 times with RVMMI, RVEDVI, RVESVI and RVEF can be understood in this context, as these RV parameters are related to mPAP and PH. Moreover, consistently, neither PAWP as a surrogate for left atrial pressure, nor LV functional parameters exhibited dominant association with septal, global or lateral T1 times similar to the association of these parameters with VIP T1 times.k = 0.30 derived from healthy volunteers at 3T was expectedly different from the one at 1.5T [Segmental, myocardial and VIP T1 times were normalized to the mean blood T1 time of the study population. The blood normalization coefficient  at 1.5T . Blood nThe present study had a number of limitations. A non-contrast CMR protocol was applied, and, therefore, LGE and post-contrast T1 times could not be assessed. Analysis of LGE volume would have allowed proving the association of VIP T1 with the extent of LGE at VIPs. Post-contrast T1 and calculation of ECV might have provided additional information on the underlying nature of tissue alterations observed in native T1, as a recent pre-clinical study  suggestsIn patients with PH, T1 times in VIPs and also in the entire LV myocardium are elevated. LV eccentricity strongly correlates with VIP T1 time, which in turn is strongly associated with T1 time changes in the entire LV myocardium. Further research is needed to determine if elevated LV T1 times have prognostic importance in patients with PH.


This article presents the case of a 53-year-old man who presented with acute right superficial femoral and popliteal arterial thrombosis for which he underwent an emergent uncomplicated thrombectomy. He denied preceding cardiovascular or neurologic symptomatology and had no history of coronary or peripheral arterial disease, trauma, hypercoagulability, or malignancy. However, he reported having several days of intense emotional stress prior to presentation. His cardiac exam was normal, his electrocardiogram showed normal sinus rhythm and nonspecific ST-T wave abnormalities, and his troponin levels were normal. Transthoracic echocardiography (TTE) revealed a large (2.4 × 2 cm) apical left ventricle (LV) thrombus, LV apical akinesis, and LV ejection fraction of 40% to 45%. Coronary angiography revealed only luminal irregularities. A repeat TTE performed 3 days after initiating unfractionated heparin revealed complete resolution of the LV thrombus. The patient had an uneventful clinical course and was discharged home in stable condition on oral anticoagulants. The lower incidence of LV thrombus in takotsubo cardiomyopathy (TC) of 1.3% in comparison to 4% to 8% in acute myocardial infarction due to coronary artery disease in the current era of early reperfusion may be explained by the lower extent of ischemic myocardial necrosis associated with TC. This case suggests that the lower extent of myocardial necrosis in TC may also lead to faster resolution of LV thrombus. Therefore, earlier follow-up with TTE (within 2 weeks) and shorter duration of anticoagulation (<3 months) may be considered in patients with TC complicated by LV thrombus formation with or without systemic embolism. These features make distinguishing TC from ACS a diagnostic challenge. Therefore, patients typically undergo emergent coronary angiography to exclude obstructive epicardial CAD. LV angiography and echocardiography demonstrate characteristic mid to apical ballooning of the LV with hyperdynamic basal segments.514Electrocardiographic abnormalities in TC include ST-segment changes, predominantly ST-segment elevation in the precordial leads.51521The overall prognosis of patients with TC is similar to that of patients with ACS. TC can be complicated by LV thrombus formation with or without systemic embolism, ventricular tachyarrhythmias, heart failure, cardiogenic shock due to significant LV systolic dysfunction, or less commonly due to obstructive cardiomyopathy-like pathophysiology caused by hypercontractile basal segments of the LV, ventricular rupture, or death.We present the case of a 53-year-old male patient with a history of hypertension, hyperlipidemia, and obstructive sleep apnea that presented with acute right lower extremity pain and was diagnosed with right superficial femoral artery and popliteal artery thrombosis.He denied having any preceding chest pain or any other cardiac or neurologic symptomatology. He had no history of CAD, peripheral arterial disease, trauma, hypercoagulability, or malignancy. However, he reported having several days of intense emotional stress prior to presentation. His cardiac exam was normal and his electrocardiogram (ECG) revealed nonspecific ST-T wave abnormalities. His laboratory data and troponin levels were normal. The patient underwent an emergent uncomplicated femoral and popliteal arterial thrombectomy.Postoperative echocardiogram on day 1 of hospitalization demonstrated LV apical akinesis, an estimated LV ejection fraction of 40% to 45%, and a large (2.4 × 2 cm), pedunculated, and mobile apical LV mass suggestive of an LV thrombus  and B. COn day 3 of intravenous unfractionated heparin a repeat transthoracic echocardiography (TTE) to further characterize the LV thrombus with 3D imaging revealed complete resolution of the LV thrombus with persistent LV apical akinesis  and D. TTo the best of our knowledge, this is the first case of TC complicated by peripheral arterial embolism and a large apical LV thrombus that resolved completely within 3 days of intravenous unfractionated heparin.2224 Our patient’s clinical, laboratory, and imaging data did not fit any of the last 5 clinical conditions. He denied any tobacco use, had a negative drug screen, a negative hypercoagulable state, his coronary arteries were angiographically nearly normal, had no other cardioembolic source seen on echocardiography, was in normal sinus rhythm throughout his hospital stay, and the absence of myocardial inflammation on MRI and segmental rather than global LV dysfunction on MRI and echocardiography were inconsistent with myocarditis.The differential diagnosis of myocardial infarction with nonobstructive CAD includes the following: (1) TC, (2) coronary vasospasm due to Prinzmetal’s angina (more common in young women) or drug-induced vasospasm secondary to the use of cocaine or amphetamines, (3) a hypercoagulable state with in situ coronary thrombosis, (4) vasculitis with or without in situ thrombosis, (5) coronary embolism from infective or noninfective valve vegetations or atrial fibrillation, or (6) myocarditis.2527 This case fulfils the revised Mayo Clinic criteria listed below.The initial diagnosis of TC in our patient was challenging because of the absence of chest pain and lack of diagnostic ECG changes and no troponin elevation. However, the patient did report having several days of intense emotional stress prior to presentation. Since TC can often represent a diagnostic challenge for clinicians, specific diagnostic criteria for TC have been proposed.Transient hypokinesis, akinesis, or dyskinesis of the LV mid segments with or without apical involvement; the regional wall motion abnormalities extend beyond a single epicardial coronary vascular distribution; a stressful trigger is often, but not always present.Absence of obstructive CAD or absence on angiography of acute coronary plaque rupture.New ECG abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin enzymes.Absence of pheochromocytoma or myocarditis.1316 Thrombus formation is more common in the LV apex, but can infrequently affect the RV. The clinical presentation of thromboembolism can occur at initial presentation or any time during the course of the disease.1517Left ventricular thrombi has been identified in 1.3% of patients with TC and about 1% of patients have cardioembolic complications.1528The pathogenesis of LV thrombus formation in TC is presumably due to the contact of blood with the endothelium-denuded endocardium and the actively inflamed and necrotic subendocardium compounded by blood stasis in the presence of mid to apical wall motion abnormalities or LV aneurysm.15 Cardiac MRI and computed tomography may also be used to identify and further characterize an LV or RV thrombus.30 However, these imaging techniques are rarely used for this purpose since the sensitivity of TTE for detection of LV thrombus is >95%.LV apical thrombus in TC is usually detected with noncontrasted and sometimes contrasted echocardiography.1521 Therefore, anticoagulation therapy is indicated in specific subsets of patients with TC to prevent LV thrombus formation and systemic embolism.TC complicated by thromboembolism is associated with an increase in morbidity and mortality.3133 In those studies, anticoagulation for a period of 3 to 6 months was associated with a reduced rate of embolization. The duration of anticoagulation may be modified based on the rate of recovery of cardiac function and resolution of the LV thrombus.The recommendations for anticoagulation to prevent embolization in patients with TC and LV thrombus are derived from observational studies in patients with LV thrombus after CAD-related myocardial infarction.153133Also, limited specific data are available to guide anticoagulant therapy to prevent LV thrombus formation and thromboembolism in patients with TC. For patients without LV thrombus but with significant anteroapical segmental wall motion abnormalities (akinesis or dyskinesis) or LV apical aneurysm, and/or severe LV systolic dysfunction (ejection fraction <30%), anticoagulation with warfarin for at least 3 months, or until LV akinesis or dyskinesis has resolved is considered reasonable.3133 Also the lower extent of myocardial necrosis and rapid recovery of LV function in TC may also lead to faster resolution of LV thrombus. As illustrated in this case, the rapid resolution of the LV thrombus suggests that repeating an echocardiogram earlier (perhaps within 2 weeks) to reassess LV wall motion abnormalities and LV thrombus regression may be appropriate in patients with TC. This strategy may shorten the duration of and decrease the potential risks associated with oral anticoagulation. However, a prospective cross-sectional and longitudinal study using serial echocardiography in patients with TC complicated by LV thrombus is needed to confirm this hypothesis.In conclusion, the lower incidence of LV thrombus in TC of 1.3% in comparison to 4% to 8% in acute myocardial infarction due to CAD in the current era of early reperfusion may be explained by the lower extent of ischemic myocardial necrosis associated with TC.


Pulmonary arterial hypertension (PAH) is a chronic pulmonary vascular disease characterized by increased pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Autonomic nervous system involvement in the pathogenesis of PAH has been demonstrated several years ago, however the extent of this involvement is not fully understood. PAH is associated with increased sympathetic nervous system (SNS) activation, decreased heart rate variability, and presence of cardiac arrhythmias. There is also evidence for increased renin-angiotensin-aldosterone system (RAAS) activation in PAH patients associated with clinical worsening. Reduction of neurohormonal activation could be an effective therapeutic strategy for PAH. Although therapies targeting adrenergic receptors or RAAS signaling pathways have been shown to reverse cardiac remodeling and improve outcomes in experimental pulmonary hypertension (PH)-models, the effectiveness and safety of such treatments in clinical settings have been uncertain. Recently, novel direct methods such as cervical ganglion block, pulmonary artery denervation (PADN), and renal denervation have been employed to attenuate SNS activation in PAH. In this review, we intend to summarize the multiple aspects of autonomic nervous system involvement in PAH and overview the different pharmacological and invasive strategies used to target autonomic nervous system for the treatment of PAH. The autonomic nervous system is composed of sympathetic and parasympathetic divisions and is often divided by neural and endocrine regulatory components. The sympathetic nervous system (SNS) originates from the thoracolumbar region of the spinal cord Fig. . Short pThe pulmonary vasculature is innervated by sympathetic, parasympathetic, and sensory nerve fibers. Increased vascular resistance is mediated by α-adrenoreceptors upon sympathetic nerve stimulation . NoradreThe heart is also innervated by both parasympathetic and sympathetic fibers Fig. . The parPatients with PAH often have normal systemic blood pressures and lung volumes. However, they may suffer from hypoxia, hypercarbia, acidosis, and, in later stages, RV hypertrophy and failure. Neural pathways controlling the heart and lungs are described in detail within current scientific literature .PAH is a clinical syndrome characterized by pathologic pulmonary 1) vasoconstriction, 2) vascular remodelling, and 3) thrombosis. Progressive sequelae include increased pulmonary vascular resistance (PVR), RV hypertrophy and dysfunction, and ultimately death. The extent of involvement of the autonomic nervous system in the pathogenesis of PAH is not fully understood. It is postulated that the patients with PAH often have a low cardiac output and may compensate for that by upregulation of neurohormonal systems such as SNS and renin-angiotensin-aldosterone system (RAAS)  There is an increasing body of evidence linking autonomic nervous system involvement in the pathogenesis of PAH. Here we review the available literature on SNS activation, heart rate variability, baroreflex sensitivity and arrhythmias, and RAAS dysregulation in PAH. We also summarize the therapeutic strategies for modulating the autonomic nervous system and RAAS in PAH.Over the last 30 years, accumulating evidence has supported the involvement of the autonomic nervous system in PAH, strengthening the hypothesis for the role of SNS activation in PAH development. Microneurography was used to compare the muscle sympathetic nerve activity (MSNA) between patients with PAH and healthy controls and showed increased sympathetic nerve traffic in PAH patients . MSNA waIncreased SNS activity in PAH was also assessed by neurohormonal activation, despite conflicting results between studies. In a small clinical study comprising 32 patients with PAH, plasma norepinephrine concentration was strongly correlated to PVR and was associated with poor estimated 5-year survival . Some otBristow and colleagues  were the2+ sensitivity, thus impairing RV relaxation and contributing to RV stiffness .Fig.Fig54].F1 receptor antagonism using losartan significantly delayed disease progression in MCT-induced PH rats by reducing RV afterload, restoring ventricular–arterial coupling, and improving RV diastolic function. Furthermore, losartan significantly reduced pulmonary vascular remodeling in treated-rats but without any change in RV hypertrophy . A . A 60]. Another method to counter the vasoconstrictive and proliferative ACE/angiotensin II/AT1 receptor axis in PAH was demonstrated by activating the vasoprotective ACE2/Angiotensin-(1–7)/Mas axis of the RAAS. Ferreira and colleagues  administAnother key player of RAAS is the steroid hormone aldosterone. Maron and colleagues  found ann = 5) and treatment-naïve PAH patients (n = 6), aldosterone levels also positively correlated with PVR and transpulmonary gradient and inversely correlated with cardiac output. Maron and colleagues [n = 57), patients in whom spironolactone therapy was reported during the trial (n = 10) had a trend toward further improvement in 6-MWD, a 1.7 fold increase in B-type natriuretic peptide plasma levels, as well as improvement in World Health Organization functional classification. However, a recent and larger study showed no association between B-type natriuretic peptide levels, 6-MWD, Borg dyspnea score, RV systolic pressure, cardiac output, or cardiac index [In a clinical study, Maron and colleagues  confirmelleagues  also anaac index . AldosteThe activation of the SNS in PAH is well recognized, and, as seen previously, different methodologies have been considered to decrease this activation and improve PAH. Na and colleagues  investig5 compared to baseline. These changes at five minutes were completely abolished with the PADN treatment compared to baseline. Recently, the nerve distribution around the pulmonary artery has been investigated in a swine model to determine the effect of radiofrequency PADN on acute PH induced by vasoconstriction using thromboxane A2 agonist [2 agonist injection in swine treated with PADN (n = 4) compared to the sham group (n = 4). This change correlated with the number of histological denervation lesions in pulmonary arteries. Furthermore, they demonstrated that the depth of histological changes induced by radiofrequency energy delivery varied with anatomic location and wall thickness, indicating that the location is critical to successful PADN.Baroreceptors and sympathetic nerve fibers are localized in or near the bifurcation area of the main pulmonary artery. Chen and colleagues  first te agonist . Mean PAn = 13) showed significant reduction of mean PAP and PVR and significant improvement of 6-MWD, World Health Organization class, and N-terminal brain natriuretic peptide level compared to control group (n = 8). A few years later, a phase II of this study was performed in a cohort of 66 patients with mixed PH ethiologies who all underwent PADN treatment [Chen and colleagues  tested freatment . Comparen = 171) as well as in systemic hypertensive patients (n = 364) [Catheter based renal denervation is an intervention that reduces activation of the SNS and the RAAS Fig.  by destrn = 364) . Very ren = 364) . After aAlthough PAH is generally associated with increased sympathetic nervous system activation, the precise role of autonomic nervous system involvement in the pathogenesis of PAH is still not fully understood. Pharmacologic adrenergic blockade, reduction of neurohormonal activation, and novel direct methods to attenuate sympathetic nervous system activation such as renal denervation and pulmonary artery denervation may be beneficial in PAH. Further studies are needed to determine the extent of involvement of the autonomic nervous system in PAH and to assess the effectiveness and safety of targeting the autonomic nervous system and RAAS for the treatment of PAH patients.


Left ventricular (LV) diastolic dysfunction is one of the important mechanisms responsible for symptoms in patients with heart failure. The aim of the current study was to identify parameters that may be used to detect early signs of LV diastolic dysfunction in diabetic pigs on a high fat diet, using conventional and speckle tracking echocardiography. The study population consisted of 16 healthy Göttingen minipigs and 18 minipigs with experimentally induced metabolic dysfunction. Echocardiography measurements were performed at baseline and 3-month follow-up. The ratio of peak early (E) and late filling velocity (E/A ratio) and the ratio of E and the velocity of the mitral annulus early diastolic wave (E/Em ratio) did not change significantly in both groups. Peak untwisting velocity decreased in the metabolic dysfunction group (− 30.1 ± 18.5 vs. − 23.4 ± 15.5 °/ms) but not in controls (− 38.1 ± 23.6 vs. − 42.2 ± 23.0 °/ms), being significantly different between the groups at the 3-month time point (p < 0.05). In conclusion, whereas E/A ratio and E/Em ratio did not change significantly after 3 months of metabolic dysfunction, peak untwisting velocity was significantly decreased. Hence, peak untwisting velocity may serve as an important marker to detect early changes of LV diastolic dysfunction. Heart failure is a major public health problem in developed countries . Left veDiabetes mellitus is an important risk factor for the development of LV diastolic dysfunction –11. In pThe aim of the current study was to identify parameters that may be used to detect early signs of LV diastolic dysfunction in a large animal model of metabolic dysfunction, using conventional and speckle tracking echocardiography.Although it was shown in previous studies –26 that The study population consisted of 16 healthy Göttingen minipigs  and 18 minipigs with metabolic dysfunction . Diabetes was induced with intravenous (ear catheter) injections of streptozotocin (25 mg/kg/day) over 3 days . One week after diabetes induction, a high fat diet (25% of saturated fats and 1% of cholesterol) was gradually introduced for diabetic pigs, whereas control pigs continued on a normal chow diet . Pigs weEchocardiography measurements were performed at baseline and 3-months follow-up. Two-dimensional grayscale harmonic images were obtained in the right lateral decubitus position using a commercially available ultrasound system , equipped with a broadband 1–5 MHz) S5-1 transducer  . In order to assess LV apical and basal rotation, tracking points were placed automatically and could be manually adjusted afterwards on an end-diastolic frame in each parasternal short-axis image, close to the endocardium. Rotation was defined as the mean angular displacement of all tracking points, relative to the centre of a circle through these tracking points. Clockwise rotation as viewed from the apex was expressed as a positive value, counter clockwise rotation was expressed as a negative value. LV twist was calculated as the difference between LV apical and basal rotation. Data were exported to a spread sheet program  to determine peak basal and apical rotation, peak twist, peak untwist velocity, and the timing of these parameters. Also, circumferential strain and strain rate (short-axis images) and longitudinal strain and strain rate (long-axis images) were measured.Statistical analyses were performed with SAS 9.3 program , using two-way ANOVA for repeated measures, with time (baseline vs. 3-month time point) and diabetes  as factors. If significant main effects or interactions were found, pairwise differences were identified with the Tukey–Kramer post hoc correction. A p value < 0.05 was considered statistically significant. Measurements were presented as mean ± SD. A Pearson’s R correlation test was conducted to examine whether there was a relationship between parameters that changed significantly from baseline to 3 months follow-up.Baseline characteristics are shown in Table Baseline versus 3 months conventional echocardiography characteristics are shown in Table 2 = − 0.473, p = 0.111 and R2 = − 0.183, p = 0.481, respectively) or (delta) E or E/Em ratio and (delta) peak untwisting velocity . LV longitudinal and circumferential strain and strain rate did not change significantly from baseline to 3 months in diabetic pigs on a high fat diet and healthy control pigs.LV twist and untwist data are shown in Table Peak untwisting velocity was significantly decreased in diabetic pigs on a high fat diet compared to healthy animals as assessed at 3-months from metabolic dysfunction onset. To the best of our knowledge, the current study is the first to show these early changes of LV diastolic dysfunction in a large animal model. These findings suggest that peak untwisting velocity may serve as an important marker to detect early changes of LV diastolic dysfunction.Under normal physiological conditions, over 40% of diastolic LV untwisting has been completed after the first 15% of diastole, thereby contributing to the large and rapid pressure decay during the isovolumic relaxation phase . This raE-wave velocity increased significantly after 3 months of metabolic dysfunction and A-wave velocity increased in both groups. A possible explanation for this may be the increased circulating volume related to the increase in body weight over time in both groups, because the mitral inflow pattern is well-known to heavily depend on circulating volume status . HoweverAlthough E/Em ratio increased by almost 12% after 3 months of metabolic dysfunction, this group difference failed to reach statistical significance. Increased E/Em ratio is essentially a marker of increased left atrial pressure. When LV diastolic dysfunction develops, LV filling will be impaired, subsequently leading to increased left atrial pressure . Maybe tAfter the 3 month period, both diabetic pigs on a high fat diet and control pigs were randomized to either a training program or an untrained, sedentary lifestyle. Unpublished data from our laboratory indicate that in this model at 5 months E/Em ratio was increased in untrained pigs with metabolic syndrome compared to untrained controls . Therefore, development of diastolic dysfunction in the diabetic pigs on a high fat diet was confirmed by conventional echocardiography after 5 months.In previous studies, abnormal values of LV strain, especially longitudinal systolic strain, in patients with diabetes mellitus have been reported –23. Yet,The study population is relatively small. Also, it is uncertain whether the findings in this large animal model may be extrapolated to humans. Therefore, the true potential of LV untwisting as an early marker of LV diastolic dysfunction should be confirmed in a prospective clinical study, for example in patients at high risk of development of LV diastolic dysfunction but with a normal echocardiogram according to conventional parameters.In this study, based on comprehensive conventional and speckle tracking echocardiography analyses of the LV in a large animal model of metabolic dysfunction, LV peak untwisting velocity was found to be a parameter for early detection of LV diastolic dysfunction.


Objectives. Ginsenoside Rg3 is one of the ginsenosides which are the main constituents isolated from Panax ginseng. Previous study demonstrated that ginsenoside Rg3 had a protective effect against myocardial ischemia/reperfusion- (I/R-) induced injury. Objective. This study was designed to evaluate the effect of ginsenoside Rg3 on cardiac function impairment induced by myocardial I/R in rats. Methods. Sprague-Dawley rats were subjected to myocardial I/R. Echocardiographic and hemodynamic parameters and histopathological examination were carried out. The expressions of P53, Bcl-2, Bax, and cleaved caspase-3 and the levels of TNF-α and IL-1β in the left ventricles were measured. Results. Ginsenoside Rg3 increased a left ventricular fractional shortening and left ventricular ejection fraction. Treatment with ginsenoside Rg3 also alleviated increases of left ventricular end diastolic pressure and decreases of left ventricular systolic pressure and ±dp/dt in myocardial I/R-rats. Ginsenoside Rg3 decreased apoptosis cells through inhibiting the activation of caspase-3. Ginsenoside Rg3 also caused significant reductions of the contents of TNF-α and IL-1β in left ventricles of myocardial I/R-rats. Conclusion. The findings suggested that ginsenoside Rg3 possessed the effect of improving myocardial I/R-induced cardiac function impairment and that the mechanism of pharmacological action of ginsenoside Rg3 was related to its properties of antiapoptosis and anti-inflammation. The prevalence of heart failure reaches 1% of the population aged over 65 years in the world. It estimated that 37% of all cases of symptomatic heart failure worldwide were caused by myocardial ischemia . Apoptos Panax ginseng C.A. Meyer listed in the Chinese Pharmacopoeia, is widely used to treat cardiovascular disorders. Ginsenosides are the bioactive ingredients of ginseng. Studies indicated that ginsenosides had potential cardiovascular benefits through many mechanisms including the properties of antioxidation and anti-inflammation [Ginseng, the root ofammation . Ginsenoammation . Recent ammation . Up to nα and IL-1β enzyme-linked immunosorbent assay (ELISA) kits were purchased from R&D Systems, Inc. .Ginsenoside Rg3, a white amorphous powder, was provided by Department of Medicinal Chemistry, Jilin University. The chemical structure of ginsenoside Rg3 was shown in Male Sprague-Dawley rats weighing 270–290 g were obtained from the Experimental Animal Center of Jilin University. They were housed in a well-ventilated animal unit  and had free access to a standard diet. The rats were given water ad libitum. The experiments were carried out according to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health  and were approved by the local Ethics Committee of Jilin University (J130926).The rats were anesthetized with chloralose . Myocardial ischemia was produced via one-stage occlusion of the left coronary artery for 30 min followed by reperfusion as described previously . The ratAt 2 h after last treatment, transthoracic echocardiography was performed as previously described using a standard setting with a 10S scan head . Animals were anesthetized with urethane . Two-dimensional and M-mode echocardiographic measurements were conducted. A short-axis two-dimensional image of the left ventricle was first obtained at the position of the papillary muscles. Then, M-mode images were acquired at a sweep speed of 100 mm/s and stored digitally. After the left ventricular internal dimension at diastole (LVIDd) and left ventricular internal dimension at systole (LVIDs) were acquired from M-mode images, left ventricular fractional shortening (FS) and left ventricular ejection fraction (EF) were calculated automatically by the equipment. The parameters were measured by one experienced echocardiographer who was blind to the treatment.After echocardiography measurement, the right common carotid artery of the rats was cannulated with a 2 F polyethylene catheter into the left ventricle. Thereby, left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), and positive and negative maximal values of the first derivative of left ventricular pressure (±dp/dt) were measured using a hemodynamic analyzing system .TUNEL staining was assessed by the In Situ Cell Death Detection Kit, POD . After the cardiac function evaluation, the sections of rat hearts were prepared. The staining was performed according to the protocol provided by the manufacturer. Ten fields in each section were randomly selected for apoptotic cell counting in a blinded manner using an Olympus IX51-reflected light fluorescence microscope . Then the apoptosis cells were calculated.β-actin . The primary antibodies were detected with horse radish peroxidase-conjugated goat anti-mouse or goat anti-rabbit secondary antibody (1 : 2000). ECL detection reagents were used to detect the binding. For the quantitative analysis of the density of the immunoblot bands, densitometry was performed with the Gel-Pro Analyzer Version 3.0.The protein of the left ventricles was separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then transferred to the polyvinylidene difluoride membranes using an electrophoretic transfer system. The membranes were blocked for 2 h with 5% bovine serum albumin and incubated for 24 h at 4°C with primary antibody. The primary antibodies were as follows: P53 , Bcl-2 , Bax , cleaved caspase-3 , and α and IL-1β in supernatants of the left ventricles were estimated with an ELISA plate reader, using commercially available ELISA kits and following the manufacturer's protocols. Duplicate samples were analyzed for each sample.The supernatants of the left ventricles were prepared as follows. Five hundred milligrams of the left ventricles was homogenized in 9 volumes of ice-cold saline and centrifuged (1000 ×g) at 4°C for 15 min. The supernatants were removed and stored at −80°C for further analysis. The amount of protein in the supernatant was measured according to the previous method  using boP value < 0.05 was considered as statistically significant.SPSS 22.0 Statistical Software was used for the analysis. The data are expressed as the mean ± SD, and the statistical significance of the data was determined using one-way analysis of variance (ANOVA) followed by Dunnett's test. We evaluated the effect of ginsenoside Rg3 on cardiac function using echocardiography. As shown in P < 0.05 or P < 0.01, Compared with the sham group, myocardial I/R induced cardiac function impairment characterized by a significant increase of LVEDP and decreases of LVSP and ±dp/dt. Treatment with ginsenoside Rg3 at doses of 5 or 20 mg/kg alleviated the increase of LVEDP and the decreases of LVSP and ±dp/dt induced by myocardial I/R . However, treatment with ginsenoside Rg3 at doses of 5 and 20 mg/kg markedly inhibited the elevation of levels of TNF-α and IL-1β induced by myocardial I/R (P < 0.05 of P < 0.01, The levels of TNF-The incidence of myocardial infarction has decreased over the last two decades in developed countries. Because it finally developed into heart failure, myocardial infarction remained the major killer during the past decade . AlthougCardiac functions are closely associated with the ventricular systolic and diastolic functions. Studies have demonstrated that myocardial I/R injury may induce the changes of cardiac hemodynamic parameters and then affect cardiac function . Echocarα release from the cardiomyocyte. The secreted TNF-α further stimulates the release of proinflammatory cytokines from infiltrating leukocytes and endothelial cells, initiating the cytokine cascade [α and IL-1β are contributors to cardiac dysfunction. The present study revealed that treatment with ginsenoside Rg3 significantly inhibited the increases of P53, Bax, and cleaved caspase-3 and the decrease of Bcl-2 induced by myocardial I/R. It is showed that ginsenoside Rg3 also blocked the increases of TNF-α and IL-1β in myocardial I/R-rats. Therefore, these findings indicated that the mechanism of pharmacological action of ginsenoside Rg3 was related to its properties of antiapoptosis and anti-inflammation.After myocardial ischemia, apoptosis plays a critical role in both mechanical and molecular mechanisms of cardiac dysfunction . In the  cascade , 20. TNFThere are limitations in this study. Although apoptosis has been considered as a noninflammatory mode of cell death, recent studies have provided evidences that apoptotic cells are invariably noninflammatory, particularly in the context of apoptosis induced by the members of the TNF family. Cells undergoing apoptosis is also associated with the production of a range of proinflammatory cytokines and chemokines by the dying cell . HoweverIn conclusion, the findings of the present study indicated that ginsenoside Rg3 possessed the effect of improving myocardial I/R-induced cardiac function impairment and that the mechanism of pharmacological action was related to its properties of antiapoptosis and anti-inflammation. Therefore, the possible therapeutic application of ginsenoside in myocardial infarction patients at risk for heart failure is worth researching.


Atrial fibrillation (AF) is associated with increased risk of heart failure and premature death, and with resistance to treatment. Animal models of pacing-induced AF indicate that AF-induced endothelial dysfunction, impaired coronary reserve, and myocardial remodelling are important in arrhythmia maintenance; however, human AF may reflect a subclinical cardiomyopathy that develops with ageing and risk factors, persists after restoration of sinus rhythm (SR), and provides a substrate for AF recurrence. To test this hypothesis, we investigated the effect of restoring SR by catheter ablation on left ventricular (LV) function, perfusion and energetics.31Phosphorus MR spectroscopy determined LV energetics (ratio of phosphocreatine to ATP - PCr/ATP), and adenosine stress/rest CMR assessed first-pass perfusion. Ablation success was evaluated by prolonged intermittent ECG monitoring, after a 3-month blanking period. A majority of patients (n = 30) were re-assessed 7 ± 1 months post-ablation.72 subjects were recruited: 52 patients (63 ± 8 y) referred for AF ablation, and 20 age-matched controls (62 ± 7 y) in SR. Patients had symptomatic paroxysmal (n = 27) or persistent (n = 25) AF without coronary artery disease, valve disease, diabetes, uncontrolled hypertension, inflammatory disease or inadequate ventricular rate-control. CMR-derived short axis cines were analysed by an investigator blinded to rhythm and clinical status to calculate LV volumes and ejection fraction (EF). In patients compared to controls, LVEF and energetics Figure  were botIn patients with a rhythm of AF during pre-ablation CMR and SR during post-ablation CMR (n = 10), there was modest improvement, but not normalisation, in LVEF . However, energetics and perfusion reserve were unchanged despite recovery of SR (both p = ns). Furthermore, when patients were grouped based on presence/absence of recurrent AF on ECG monitoring post-ablation, LV function, energetics and perfusion reserve were all unchanged, irrespective of ablation success  of an occult cardiomyopathic process. Comprehensive therapeutic strategies that target and reverse this phenotype may reduce AF recurrence and improve clinical outcomes.


Gyrocardiography (GCG) is a new non-invasive technique for assessing heart motions by using a sensor of angular motion – gyroscope – attached to the skin of the chest. In this study, we conducted simultaneous recordings of electrocardiography (ECG), GCG, and echocardiography in a group of subjects consisting of nine healthy volunteer men. Annotation of underlying fiducial points in GCG is presented and compared to opening and closing points of heart valves measured by a pulse wave Doppler. Comparison between GCG and synchronized tissue Doppler imaging (TDI) data shows that the GCG signal is also capable of providing temporal information on the systolic and early diastolic peak velocities of the myocardium. Furthermore, time intervals from the ECG Q-wave to the maximum of the integrated GCG (angular displacement) signal and maximal myocardial strain curves obtained by 3D speckle tracking are correlated. We see GCG as a promising mechanical cardiac monitoring tool that enables quantification of beat-by-beat dynamics of systolic time intervals (STI) related to hemodynamic variables and myocardial contractility. The contraction of helically oriented muscle fibres act as an integrated force causing a coordinated wringing motion to the myocardium within each cardiac cycle2. Accordingly, the longitudinal retraction of the myocardium causes left ventricular (LV) base to move towards apex. Linear contribution of the muscle fibres contraction in the long axis of the heart is known as an indicator of ventricular systolic and diastolic mechanical function4.The heart is an intricate object which undergoes repeating changes in different dimensions and orientationset al.5 proposed an invasive method to evaluate LV performance in dogs based on multiple implanted radiopaque markers and biplane cine angiography analysis. Later, other non-invasive approaches based upon optical devices7, tagged magnetic resonance imaging (tagged MRI)8, tissue Doppler imaging (TDI)9 and speckle tracking imaging10 were introduced in order to evaluate dynamics of cardiac motion and myocardial tissue function.Monitoring of the myocardial mechanical activity requires sophisticated techniques. Over the past years, cardiac motion has been widely studied and quantitatively investigated using invasive and non-invasive techniques in both animals and humans. In 1975, Ingels 14. In principle, BCG measures the whole body recoil or ballistic forces in response to the blood ejection from aorta into the vascular tree, while the SCG measures the positional vibrations of the chest wall in reaction to the myocardial motions and respiration16. In a recent study, sophisticated in vivo experimental examinations and a complementary mathematical model revealed that BCG waves are formed due to blood pressure gradients in the ascending and descending aorta17. SCG and BCG, which are typically based on using accelerometers and force sensors, can be used for unobtrusive long term monitoring of LV to estimate hemodynamic variables, cardiac abnormalities, and breathing disorders via low-cost wearable or portable devices26. Recent studies have also briefly described the feasibility of heart monitoring using built in accelerometer and gyroscope sensors in Google glasses, wrist worn devices, smart phones, and chest worn patches30. Additionally, the body kinetic energy analysis, also known as the multi-dimensional kineticardiography (MKCG), has been recently introduced in ref. 31. Marcelli et al.33, Hyler et al.34, and Grymyr et al.35, on the other hand, reported invasive techniques based upon implantable gyroscope and accelerometer sensors in order to monitor left ventricular function and assess cardiac rotation in animals. These studies report promising results which may yield to a prospective strategy suitable for implantable devices for the continuous monitoring of cardiac function. Other studies have also showed that by using gyroscope one can improve the automated interpretation of SCG signals in order to estimate heart rate variability, cardiac time intervals and annotation of waveforms38.Ballistocardiography (BCG) — the recording of the reactionary forces of the body invented by Gordon in 1877 – and seismocardiography — the recording of chest wall vibrations invented by Bozhenko in 1961 — are non-invasive methods which have been used for cardiac mechanical monitoringComplementary to the above methods, we introduce in this paper a novel non-invasive approach for the measurement of cardiac and respiration signals we call gyrocardiography (GCG). This technique is solely based on measuring the precordial microvibrations using a microelectromechanical (MEMS) gyroscope sensor attached to the skin anterior to the sternum. GCG can be used to estimate beat-to-beat hemodynamic variables such as heart rate and the pre-ejection period, and to investigate the mechanical activity of the heart. The gyroscope measures its own angular velocity, and in this paper we present how some of the maxima or minima of these velocities correspond to physiological events such as the moments of LV valvular openings and closings. A benefit of the proposed method is that a gyroscope is a relatively cheap sensor, and is available for example in most wearable devices . However, the engagement mechanism and the transfer function from the motion of the heart to the motion of the chest are still unclear, and should be investigated more thoroughly in the future.39 in which we presented primary investigations on the GCG signal and its correspondence to the mechanical activity of the heart. In40 we also briefly demonstrated the feasibility of recovering respiration signals by using a gyroscope sensor for nuclear medicine imaging applications. In this work, we focus on exploring the correspondence between a reference echocardiography/cardiac ultrasound (US) and tri-axial GCG measurements in order to show that GCG is capable for estimating certain myocardial motions and hemodynamic variables. We present an annotation of major fiducial points in the GCG signal based on the timings of cardiophysiological events measured by a pulse wave Doppler. We also compare GCG signals to tissue velocity (TV) and strain curves obtained by TDI and speckle tracking analyses, and show that the timing of the maximal strain is correlated with certain waveform in the GCG signal. Furthermore, we present complementary information on automated heartbeat detection and annotation of the GCG signal that allows for estimating beat-to-beat cardiac time intervals . The accuracies of the annotations and other measurements are determined by statistical analysis.This paper is based on our previous publicationIn the following we describe our experimental set-up and measuring protocol employed for data collection and analysis.Experimental verification of the proposed approach was performed on the data acquired from 9 healthy volunteer subjects with their informed consent. All experiments were supervised in a controlled research environment and were performed in accordance with the Helsinki Declaration. We considered healthy male subjects who had no prior history of cardiovascular disease. The study subjects were asked to lie in the supine position with the upper body slightly tilted in order to facilitate echocardiography. Data was acquired simultaneously from the electrocardiography (ECG), the inertial measurement unit, and from the echocardiography in a time frame of approximately 10–15 minutes. Figure g and ±250 dps, respectively. The accelerometer has an RMS noise of 99 Fs) of 800 Hz. A 4th order Butterworth IIR filter with pass bands 1–20 Hz and 4–45 Hz, respectively, were applied on the gyroscope and accelerometer derived signals, allowing the removal of white noise and signals offset. ECG signals were also de-noised by a fast Fourier transform (FFT) filter and with the frequency bands of 0.5–45 Hz as described in ref. We used a custom-made miniaturized customized joint accelerometer-gyroscope system – inertial measurement unit (IMU) – in order to measure externally heart mechanical motions. Toward this end, a (3 mm × 3 mm × 1 mm) triple-axis, low-power, capacitive digital accelerometer  and an (3 mm × 3 mm × 0.9 mm) ultra-accurate, low power, low noise, 3-axis angular rate sensor  were employed for recovering chest cardiac and respiratory signals. The MEMS sensors were attached to the skin of the chest anterior to the body of sternum using double-sided tape without hair removal in the chest area. The measured acceleration and angular velocity range of the accelerometer and gyroscope were set to ±2The echocardiography examination was conducted by a Vivid E95 scanner with a 1.4–4.6 MHz transducer . A complete echocardiographic study was performed using standard apical views for 3 to 6 cardiac cycles. EchoPAC post-processing software  was employed for off-line echocardiographic analysis of TDI and 3D speckle tracking strain. Conventional echocardiography, electrocardiography, and 3-axis GCG and 3-axis SCG were performed concurrently. For measurement of cardiac time intervals, mitral valve and aortic valve flow velocities were recorded using pulsed-wave (PW) Doppler. For measurement of myocardial velocities, apical 4 chamber TDI images were obtained with an average rate of 106/sec fps. We performed speckle tracking which is an automated functional imaging technique for multidimensional deformation or strain analysis. 3D volume covering the whole left ventricle myocardium was obtained from an apical view averaging 6 cardiac cycles with an average frame rate of 40/sec for 3D speckle tracking strain analysis. The results of 18 myocardial segments were averaged to obtain global strain in longitudinal, circumferential, area, and radial directions. In addition to curves, numerical strain and timing data from each frame was obtained. Figure x, y, and z. Three dimensional GCG is achievable by a tri-axial gyroscope sensor. The axes of rotations are defined in this paper as follows: the x-axis points laterally from left to right, the y-axis points from head to foot, and the z-axis points from back to front. These axes of rotation are illustrated in the Fig. Figure s). During systole, the angular velocity signal corresponding to the x-axis undergoes a fast and strong down-up-down deflection around the ECG R-wave, while a smaller upward deflection is seen around the T-wave. The y-axis consists of a repeating major peak that indicates the heartbeat pulse during systole. This prominent and upward spike is followed by again a minor upward deflection that appears slightly after the reference ECG T-wave. Similarly, the z-axis yields repeating waveforms for the systole and diastole; however, in this paper we will mainly focus on the waveforms corresponding to the x- and y-axes of the GCG, as these signals are typically of better quality.As shown in the Fig. x- and y-axes of the GCG yield monomorphic patterns meaning that these waveforms are similar in shape with different subjects and measurement devices. As an example of this, Fig. y-axis of different sensors, namely Murata SCC1300d02, Bosch BMI 160, Maxim Integrated MAX21000, and the SONY Xperia Z3 compact. Although these sensors have diverse technical specifications in terms of noise level, power consumption, and full scale range, it can be seen that the obtained GCG signals are similar in amplitudes  and in the shapes of the waveforms; in particular the fiducial points described in the following section are visible in all of these signals.The Pulse wave Doppler images were obtained to define opening and closure times of the aortic and mitral valves from the considered 9 healthy subjects. We followed guidelines in ref. Measurements of systolic and diastolic time intervals on the GCG signal requires robust delineation of cardiac fiducial points. Generally, the Q-peak and the R-peak in ECG serve as the reference points for measuring cardiac time intervals in echocardiography. Therefore, in this study we followed the same standard and measured time intervals from the ECG fiducial points to the considered GCG fiducial points. Our hypothesis for this research was that major stationary and repeating waveforms in GCG signal coincide with physiological events in heart. We performed visual inspections, through all study subjects and acquired data, in both PW Doppler images and GCG signals to identify specific GCG waveforms which coincide with particular mechanical cardiac events in each cardiac cycle see Fig.  and nomiy-axis wave pattern is visible. We denote this peak by gyroI (gI). Right after gI, we denote the major maximum peak in the GCG y-axis signal by gyroJ (gJ); this peak occurs slightly after the ECG R-wave. Further in the middle of the cardiac cycle and roughly after the ECG T-wave (around the second heart sound (S2)), a lower magnitude up-down wave  is visible which consists of two reproducible and repeating notches just before and after the ∧ wave peak. This waveform is mostly visible in the signal obtained from the x-axis of the GCG, and we nominate the first notch by gyroK (gK), and the second notch one by gyroL (gL).Around the ECG R-wave and during the systole, a fast downward notch in the gI, gJ, gK, and gL points in every cardiac cycle, the isovolumetric contraction time (IVCT) and the isovolumetric relaxation time (IVRT) could be also estimated. Additionally, other significant systolic time intervals (STI) and indexes of cardiac contractility, including the total electromechanical systole (QS2), the left ventricular ejection time (LVET), and the pre-ejection period (PEP), could be estimated. In our considerations, the QS2 is measured from the ECG Q wave to the moment of gK (AVO), while the LVET is measured as the time interval between the moments of AVO and AVC in the cardiac cycle, which in GCG corresponds to the time interval from gJ to gK. The PEP index can be determined by calculating the time between the ECG Q-wave and the onset of the aortic opening, which corresponds to gJ in GCG. PEP and LVET are both important clinical parameters on myocardial contractility44. Figure With distinguishing of GCG gI − gL correspond to the opening and closing times of the heart valves. More specifically, gI occurs approximately simultaneously with mitral valve closure (MVC), gJ with aortic opening (AO), gK with aortic closure (AC), and gL with mitral valve opening (MVO). In order to assess the validity of the hypothesis we compared the obtained GCG intervals to the reference tissue velocity signals measured by echocardiographic pulse wave interrogations. In all the following statistical analyses, we used Pearson correlation and Bland-Altman evaluation45 with 95% limits of agreement (LoA), corresponding to difference mean ±1.96× standard deviation. A Pearson correlation coefficient (r2) was computed to assess the linear relationships. Positive correlation coefficients and root mean square error (RMSE) between the time intervals were obtained with all cardiac time intervals. Figure We hypothesize that the fiducial points icient r was comp46.In echocardiography myocardial motions and deformations can be measured for example by tissue velocity and strain measurements. For this part of the work, we obtained echocardiographic images from 9 healthy subjects, and measured myocardial longitudinal wall motion and deformation using tissue Doppler imaging (TDI) and three dimensional (3D) speckle tracking, respectively. In TDI images, multiple regions of interest (ROI) were placed in the left ventricle myocardium in apical 4-chamber view in order to measure average myocardial velocity and displacement. As the gyroscope signal is a velocity signal, it is natural to look at the correspondence between the GCG signal and the tissue velocity acquired by the echocardiograph. In this work we consider only correspondence in time, that is, how the timings of the peaks in GCG signal are correlated with the timings of the peak tissue velocities. However, an interesting future research topic is to investigate how the waveforms themselves are correlated and what information can be gained from the magnitude of the GCG signal. Currently, it is not known how the GCG signal attenuates due to the tissue between the heart and the sensor. Accurate estimation of the timing of the maximal tissue velocities, can, however be clinically important, as it enables for example the computation of the myocardial dispersion which is the standard deviation of time to maximum myocardial shortening. Myocardial dispersion reflects the heterogeneity of myocardial systolic contraction and can be used as an indicator for susceptibility to arrhythmias in different heart disease groups such as heart failure, ischemia, and infarctiony-axis signal after the R-peak in ECG and the fiducial point gJ. Another repeating waveform in the y-axis signal is a minor V-shaped dip-rise wave which appears soon after gL. As shown in Fig. systolic peak velocity (SPV) and the diastolic peak velocity (DPV), respectively. As is visible from Fig. Sa) point in TDI, while the timing of DPV coincides approximately with the early diastolic velocity (e′ or Ea) in TDI.We noticed a relatively wide positive polarity waveform  were achieved. Clinically Sa and Ea are important, as Sa is a measure of longitudinal systolic function and is correlated with EF and peak dP/dt, while Ea is a marker of diastolic function.The time intervals from ECG-Q wave to GCG y-axis signal, which we call here angular displacement. Figure y-axis. The average Q-maximal strain and Q-maximal angular displacement were 367 ± 32.2 ms and 371 ± 31.9, respectively. Moreover, Fig. 46.In addition to the tissue velocity, we also assessed the myocardium deformation by measuring global speckle tracking 3D strain, which is the fractional change in length of the myocardium either in radial, longitudinal or circumferential dimension. Strain is a function of position, that is, the integral of velocity, and therefore we compared the strain measurements to the integral of the GCG 15, whereas chest gyrocardiography that comprises a sensor of angular motion indicates rotational precordial movement or vibration on the chest in response to myocardium movements.Thoracic vibrations in three-dimensional space consists of translation and rotation in three orthogonal directions. Translational quantities such as linear velocity and acceleration describe linear motions and are measured by for example an accelerometer sensor, while, as proposed in this study, rotational quantities such as angular displacement, angular velocity, and angular acceleration can be measured by a gyroscope sensor. Chest-accelerometry, also known as seismocardiography, is determined to generate a signal that is indicative of linear thoracic vibrations in response to heart’s contraction and the ejection of blood from the ventricles into the vascular tree48, has shown that gyrocardiography is less sensitive than seismocardiography to intra-subject and inter-subject variability in the morphology in cardiac signals. Figure We mainly considered waveforms characterized by several peaks and valleys, reflecting certain cardiophysiological events of the beating heart, on SCG amplitude of the dorso “ventral component (z-axis) and GCG amplitude of head-to-foot component (y-axis) in order to evaluate linear acceleration and rotational velocity vector trajectories during the heart cycle. Nevertheless, it is likely that other physiological information could be extracted also from the analysis of other GCG-SCG components. Our experience with GCGOur major contributions in this work are the waveform annotation of a cardiac signal measured unobtrusively using a gyroscope, and the use of such signal for the estimation of the timing of maximal tissue velocity and strain of the myocardium measured with echocardiography. Our investigations show that the proposed method, GCG, can provide useful information related to the mechanical performance of the heart.44. LVET is also an important index of contractility, which unlike PEP, is influenced by the heart rate43.Automatic segmentation and delineation of the GCG signals depends on the reliable detection of heartbeats. We developed an automated heart beat detection based on Hilbert transform and provided a primary waveform annotation algorithm for beat-to-beat assessment of cardiac time intervals and estimation of STI related hemodynamic variables in GCG. For further details on the implementation and analysis of the segmentation and waveform annotation, readers can refer to the supplementary material. GCG allows continuous or frequent heart monitoring for the estimation of hemodynamic variables and can be used for heart arrhythmia detection. For example, in ref. 49. Namely, 6-axis motion sensing using joint multi-axial accelerometer and gyroscope sensors, based on incorporated IMUs either in smart devices sensors or in customized biomedical monitoring devices, can yield significant mechanical information – in time and frequency domains – of the heart function not obtainable by ECG alone.Clinical value of SCG- and GCG-based tissue velocity measurement using multi-dimensional motion sensing has been previously addressed in refs 52, or be employed from smart devices. These sensors are not subjected to intervention from electrical monitoring or implantable stimulating signals generated by ECG, pacemakers, and cardioverter defibrillators and therefore may be used for wearable continuous cardiac function monitoring in the future55.Due to the potential advantages of personalized health monitoring systems, a growing number of mobile/wearable devices would benefit from reliable monitoring of the heart. A personal smart monitoring platform can assess the health risks by early detection of the cardiovascular disorders. Recent advances in the development of electromechanical sensors have resurged mechanocardiography techniques for clinical and non-clinical considerations. For instance, MEMS gyroscope and accelerometer can be either embedded into a monitoring patch device for long term usageThe main limitation of this study is that only nine healthy subjects were examined; this effects the statistical power of our outcomes. However, the results are promising, and warrant subsequent measurements and analysis. A smaller problem with the experimental setup was that the movements of the ultrasound probe generated artefacts in the GCG signal. Moreover, GCG and echocardiography signals were synchronized using an external clock, which yields some small random delay between the signals. The TDI and 3D speckle tracking measurements were performed with an average frame rate of 106 ± 21 fps (frames per second) and 40 ± 10 fps, meaning that each frame contains information over 9.5 ms and 25 ms, respectively. It should be noted that in most of the cases considered in this work, the calculated RMSE values fall within the duration of a single frame.A research direction for future is to develop advanced algorithms for automatic annotation of the wearable GCG signal using signal processing and machine learning approaches. Also, the potential of GCG for automated cardiac disease diagnostics will be considered. Sensor fusion algorithms using both SCG and GCG signals, and their clinical applications, will also be investigated in future studies. We should point out that although the measurements were performed concurrently using a 3-axis accelerometer and a 3-axis gyroscope, in this paper we focus on the novel properties of the gyrocardiograph. Nevertheless, we briefly performed primary comparisons on differences and similarities between SCG and GCG.SPV and DPV, are indicative of systolic myocardial velocity and early diastolic velocity  and can potentially provide functional information related to systolic and diastolic activities. We also indicated that the time from ECG onset Q to the maximal TDI strain is correlated to the time interval from ECG onset Q to maximal point of GCG angular displacement. This electromechanical delay may bring new insights into the assessment of myocardial function as its variation, known as myocardial mechanical dispersion, can potentially help in detection of arrhythmias and myocardial infarction46. Therefore, wearable/mobile GCG as a promising mechanical cardiac monitoring tool can be used in quantification of beat-by-beat dynamics of cardiac time intervals and can potentially represent information related to the hemodynamic variables and myocardial contractility.In conclusion, in this paper we have presented a new cardiac monitoring technique called gyrocardiography which is based upon a tri-axial gyroscope sensor and measures angular velocities of the chest as a response to the rotation of the heart. As shown in this paper, a gyroscope can accurately detect very small angular displacements with high temporal resolution, and thereby it is capable of revealing precordial micro-vibrations caused by myocardial motions. Our observations indicated that the morphology of the GCG signal is reproducible with different gyroscopes. Accordingly, we explored the feasibility of GCG waveform annotation on underlying systolic and diastolic repeating patterns and indicated that tri-axial GCG provides reliable fiducial points for cardiac events. Complementary statistical evaluations then revealed that the GCG signal is able to give reliable information on cardiac time interval measurements such as systolic time intervals (STI) and diastolic time intervals (DTI). STIs including left ventricular ejection time and pre-ejection period can be measured by detecting particular indicative mechanical cardiac events, for example, instants of MC, AO, MO, and AC in GCG signal. Moreover, newly-identified GCG points, i.e. Supplementary information


Repair of congenital heart defects involving the right ventricular outflow tract may require the implantation of a right ventricle to pulmonary artery conduit. This conduit is likely to be replaced during childhood. This study compares the operative outcomes of the replacement procedure of Contegra® and homografts in pulmonary position.From 1999 to 2016, 82 children underwent 87 right ventricle to pulmonary artery conduit replacements (60 Contegra® and 27 homografts). Demographics, operative and clinical data were obtained through a retrospective review of the medical records. The two groups were matched for comparison using propensity score matching. All the procedures were performed by the same team of surgeons.p value = 0.758) was observed. There was no difference regarding the blood loss and fluid input. No statistically significant difference was observed between the two groups for the post-operative morbidity. We considered the Pediatric Risk of Mortality (PRISM) score, the day of extubation, the day of withdrawal of inotropic drugs, the length of the intensive care unit stay and the length of hospital stay. The overall mortality is 2.3% but there is no statistically significant difference between the two groups.No statistically significant difference was observed between the two groups when considering the operative data for anesthesia, surgery, cardiopulmonary bypass and aortic clamping durations. A peroperative complication rate of 13.47% and 15.36% in Contegra® and homograft replacement groups respectively . The use of a valved conduit between the right ventricle and the pulmonary artery (RV-PA) for right ventricular outflow tract (RVOT) reconstruction in congenital heart diseases was introduced by Ross and Somerville in 1966  . Among these, three underwent one Contegra® replacement followed by one homograft replacement, one underwent two homograft replacements, and one underwent a homograft replacement followed by a Contegra® replacement. A total of 60 Contegra® and 27 homografts replacements (four aortic homografts and twenty three PH) were performed.This study focuses on the RV-PA conduit replacement procedures, considering all the operations between January 1999 and December 2016 at the “Hôpital Universitaire des Enfants Reine Fabiola”. A total of 87 procedures were conducted on 82 children . The procedures were divided into two groups: Contegra® or homograft replacement. Some were performed multiple times on the same patient (n = 60) and homograft (n = 27) replacements) on a set of covariates , allowing the mean and standard deviations as well as proportions to closer between the two studied groups. We then performed 15 linear or logistic regression, one on each imputed dataset and averaged the 15 p-values [Statistical analyses were performed with the R software  version 3.2.2. We performed 15 multiple imputations, using the “Multivariate Imputation by Chained Equations” (MICE) R package  to reducp-values .The data was retrieved through a retrospective review of the 82 medical records to include preoperative data, medical history, operative reports, anesthesia reports, intensive care unit (ICU) stay reports, pathology reports, computed tomography scans and echocardiography protocols. The two groups were then assessed based on covariates such as: age of explantation, duration of the implantation, weight, gender, the position of the conduit, and the existence of a concomitant procedure during the conduit replacement. In this study, the anatomical position of the conduit concerns conduits implanted for tetralogy of Fallot and pulmonary valve agenesis. The extra-anatomic position concerns truncus arteriosus, double atrio-ventricular discordance, double outlet right ventricle and all the conduits implanted during a Rastelli procedure .For the preoperative results, we analysed anesthesia, surgery, cardiopulmonary bypass and aortic clamping durations, the existence of an operative complication and the fluid input and blood loss. The study defined an operative complication as an unusual and potentially harmful event occurring during the surgical procedure which was reported in the operative report. Those results include re-entry injuries that are defined as injury to cardiac or vascular structures during the sternotomy or during the dissection before cannulation for cardiopulmonary bypass . The fluThe post-operative data, analyzed the Pediatric Risk of Mortality (PRISM) score which is a physiologically based score that can compute expected mortality risk and expected morbidity risk .The same team of surgeons performed all the procedures through median sternotomy followed by the dissection of the cardio sternal and cardio pericardial adherences. The procedures were achieved using cardiopulmonary bypass, with or without hypothermia. Aortic clamping was performed in 17 procedures. All the calcifications and residual tissue were removed when possible. In most cases the conduit was entirely extracted. In several cases, in order to preserve the left main coronary artery, the posterior part of the conduit was left on site. In some cases, the prevalvular part of the conduit was left on site and the new conduit’s proximal anastomosis was performed on it. The aorta and the RV-PA conduct were protected using a Gore-Tex® membrane  or rarely the autologous pericardium. It allows an isolation of the sternum, creating a cleavage plane, which likely makes the re-sternotomy safer.Table In the Contegra® group, the degradation mode of the conduit was a pure stenosis in 27 patients, pure regurgitation in 5 and both in 27. The presence of endocarditis was demonstrated in 7 patients with combined stenosis and regurgitation, and in 3 patients with pure stenosis a thrombus in the conduct was objectified. Four patients reveal the presence of a distal peel (3 in pure stenosis and one both). In the homograft group, there were pure stenosis in 14, pure regurgitation in 2 and both in 11. The 4 aortic homografts have been degraded according to the mode of pure stenosis.p-value (0.05) must be divided by the number of comparisons (n = 8), that is, 0.05/8 = 0.00625, to get the final p-value on which we can draw conclusion. Thereby, any p-value below 0.00625 are considered as significant. CBP: cardiopulmonary bypass; min: minute; ml: milliliters.p value = 0.00625). In the two groups, the main cause of replacement was a stenosis of the conduit associated with a valvar insufficiency. Calcifications were observed in 48% (n = 29) of the explanted Contegra® and in 52% (n = 14) of the explanted homografts. During Contegra® or homograft replacements, an operative complication occurred in 13.47% and 15.36% respectively . The most common complication in the series were re-entry injuries (2 Contegra® and 2 homograft groups), three of which required an emergency conversion to a femoro-femoral cardiopulmonary bypass. Two of these re-entry injuries resulted in a hemothorax requiring further operation to drain the blood and remove the clots. Two air embolisms were also reported in the Contegra® group. We suspected a residual intracardiac shunts that were not preoperatively identified. A postoperative CT-scan determined that both patients required treatment by hyperbaric chamber. Two per-operative ventricular fibrillation episodes (n = 2 Contegra®) were observed requiring three external shocks and the administration of xylocaine for one, and an internal shock for the other. One allergic reaction to protamine (homograft group) was also reported, causing blood pressure elevation and difficult ventilation. One bilateral pneumothorax (Contegra® group) of unknown origin that required per-operative placement of two pleural drains, and one hemorrhage requiring revision for bleeding and transfusion of plasma and platelets were reported.No statistically significant difference was observed between our two groups for the considered operative covariates that were anesthesia, surgery, cardiopulmonary bypass and aortic clamping durations .With respect to blood loss, blood input or other fluid input, there was no statistically significant difference (adjusted n = 6), that is, 0.05/6 = 0.0083, to get the final p-value on which we can draw conclusion. PRISM: Pediatric Risk of Mortality; ICU: intensive care unit; PO: postoperative; d: day; h: hours.A Bonferroni correction must be applied for multiple comparison purposes and the p-value (0.05) must be divided by the number of comparisons .To analyze postoperative morbidity, we considered the day of extubation, the day of withdrawal of inotropic drugs, the length of the ICU stay and the length of hospital stay. As mentioned in Table p-value = 0.301).No death was observed during the post-operative course in the Homograft replacement group. Two deaths (2.37%) occurred in the Contegra® group. The first death occurred in a 19-month-old boy because of a massive air embolism of unknown origin occurred during cardiopulmonary bypass. The patient suffered from pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries, palliated with a Blalock-Taussig shunt at one day of life. His Contegra® was implanted at the age of seven months. The Contegra® had to be replaced during an emergency procedure due to its acute degradation, most likely because of the protrusion of a peel on its distal part responsible for a dilation of the right cavities of the heart. The patient was conducted to a hyperbaric chamber right after the surgery. The MRI performed after 18 h showed a supratentorial cerebral edema with extensive cortical necrosis, injury of the basal ganglia, the mid brain and the pons, and the quasi absence of cerebral flow. He died one day after the surgery. The second death was a six-and-a-half-year-old girl. She suffered from a transposition of the great arteries with ventricular septal defect and pulmonary stenosis. She had first been palliated at the age of four months by a left modified Blalock-Taussig shunt, and at the age of 12 months by a right modified Blalock-Taussig shunt. At the age of six, she underwent a Rastelli procedure with the implantation of a 18 mm Contegra® conduit. During the weeks before the replacement procedure, she developed pneumonia and endocarditis on her Contegra®, was admitted to the ICU and treated by several rounds of antibiotics. The procedure was marked by an episode of ventricular fibrillation reduced by an internal shock of 15 joules. It also required the closure of a Swiss-cheese septum which required an aortic clamping time of 84 min and a cardiopulmonary bypass time of 201 min. The analysis of the removed Contegra® showed thrombosis of the conduit. Her post-operative course was marked by hospital-acquired pneumonia and by the development of a biventricular cardiac failure that was beyond any medical or surgical treatment. She died of a biventricular cardiac failure 31 days after the surgery was performed, 44 days after her admission to the ICU. Notwithstanding, this difference is not statistically significant (adjusted porcine-valved Dacron conduit, are considered easy and safe to replaced [In many CHD cases, both RVOT reconstruction and the Ross procedure require the implantation of a RV-PA valved conduit. Despite advancements, it is likely that in most patients, this conduit will need to be replaced during their childhood, especially since early replacement of the conduit could prevent irreversible structural myocardial changes . The feareplaced  because Most surgeons consider PH as the “gold standard” for RVOT reconstruction, but it is not the “perfect conduit”. Despite providing good hemodynamic results without the need for anticoagulation , the incGiven the aforementioned considerations, the Contegra® conduit was introduced in 1999 for RVOT reconstruction. In Belgium, Contegra® has been available since May 2000 and since then, unsupported Contegra® conduits have been used. Contegra® is a bovine jugular vein conduit with a native triple-leaflet valve stored in diluted and buffered glutaraldehyde. This retains leaflets and conduit wall compliance and likely renders Contegra® non-antigenic . This diLow surgical mortality is reported and death rate is identical between homograft and Contegra® replacements, confirming other reports that proclaim it to be a safe procedure , 27, 42.In conclusion, the “perfect RV-PA conduit” is yet to be found, and both Contegra® or homografts used in pediatric RVOT reconstruction will require explantation and replacement. Multiple RVOT reconstruction with RV-PA conduit replacement can be performed safely with a low surgical morbidity or mortality. We showed that the type of conduit does not influence these results. Therefore, the choice of conduit for RVOT reconstruction should not be influenced by the future surgical risk during the replacement procedure.Limitations of the present report are inherent with the retrospective nature of the study and the small number of patients.