To our knowledge, there has been no large-scale study of FRDA patient DNA samples to determine the frequency of large interruptions in GAA repeat expansions. Therefore, we have investigated a panel of 245 Friedreich ataxia patient and carrier DNA samples using GAA repeat PCR amplification and MboII restriction enzyme digestion. We demonstrate that the vast majority (97.8%) of Friedreich ataxia GAA repeat expansion samples do not contain significant sequence changes that would result in abnormal MboII digestion profiles, indicating that they are primarily pure GAA repeats. These results show for the first time that large interruptions in the GAA repeats are very rare.Friedreich ataxia is a multi-system autosomal recessive inherited disorder primarily caused by homozygous GAA repeat expansion mutations within intron 1 of the frataxin gene. The resulting deficiency of frataxin protein leads to progressive mitochondrial dysfunction, oxidative stress, and cell death, with the main affected sites being the large sensory neurons of the dorsal root ganglia and the dentate nucleus of the cerebellum. The GAA repeat expansions may be pure (GAA) FXN) gene, leading to deficit of the essential mitochondrial protein frataxin. The resulting deficiency of frataxin protein leads to progressive mitochondrial dysfunction, oxidative stress, and cell death, with the main affected sites being the large sensory neurons of the dorsal root ganglia and the dentate nucleus of the cerebellum , with a prediction of 2.3 years earlier onset for every 100 GAA repeats added to GAA1 (Friedreich ataxia (FRDA) is a multi-system autosomal recessive inherited disorder characterized by neurological features of ataxia, dysarthria, weakness, ocular fixation instability, deep sensory loss, and visual and hearing impairment, together with non-neurological features such as hypertrophic cardiomyopathy, diabetes mellitus, kyphoscoliosis, and foot deformities . The mearebellum , 1997. Trebellum . In cont to GAA1 . Thus, t to GAA1 . This su to GAA1 . Earlier to GAA1 .FXN GAA repeats has been possible due to comparatively short repeats (up to approximately 130 repeats), there are reports of interrupted GAA repeat expansion sequences, such as (GAGGAA)5-9 or (GAAGGA)65, and these are associated with either absence of FRDA disease phenotype 9(GAA)20 interrupted 112 GAA repeat has been shown to stably transmit through two generations  and MnlI (GAGG recognition sequence) restriction enzyme digestion to identify specified interruptions within 4 out of 22 FRDA patient samples (MboII (GAAGA recognition sequence) restriction enzyme digestion. Only four FRDA patients were investigated in this study, but one of the four was found to contain an extensive region of GAA repeat interruptions in their larger 1140 GAA repeat allele, which was partially sequenced to be (GAA)21(GGAGAA)5(GGAGGAGAA)70(GAA)n. To expand upon these previous small-number studies, we have now addressed the question, “Do most FRDA patients have pure GAA repeat expansions?” by investigating a large panel of 245 FRDA patient and carrier DNA samples using long-range GAA repeat PCR amplification and MboII restriction enzyme digestion. We find that the vast majority (97.8%) of FRDA patient DNA samples do not contain substantial sequence changes that would result in abnormal MboII digestion profiles, indicating that they are primarily pure GAA repeats. We discuss the implications of this finding with regard to GAA repeat instability and FRDA disease progression.Analysis of the much more frequent large GAA2 alleles (>130 repeats) for the presence or absence of interruptions has not previously been performed to any great extent, primarily because of the technical difficulty in obtaining accurate sequence of an entire long GAA repeat expansion.  samples . SubsequMboII, which has a cleavage sequence of 5′-GAAGA(8/7)-3′. PCR sample (17 μl) was digested in a total reaction volume of 20 μl at 37°C for 1 h. Digested DNA fragments were subjected to heating at 95°C for 10 min followed by slow cooling to room temperature to prevent potential heteroduplex formation, then separated by running on 2% agarose gels [1% Nusieve (Seakem Agarose GTG) and 1% Metaphor agarose]. As the MboII restriction enzyme cuts at the recognition site 5′-GAAGA (8/7)-3′, pure GAA repeats are completely cut by MboII leaving only two fragments from the uncut flanking sequences, 171/170bp upstream (designated hereafter as “170bp”) and 117/118bp downstream (designated hereafter as “120bp”), which do not contain MboII sites. On the other hand, if the GAA repeat expansion contains interrupted GAA sequences that are not cut by MboII, a different pattern of bands would be obtained upon agarose gel electrophoresis: either two bands with sizes that differ from the expected 170 and 120bp or else more than two bands.We obtained 245 peripheral blood genomic DNA samples from FRDA patients (238 samples) and carriers (7 samples) that had previously undergone GAA repeat expansion size determination , then cloned into pCR4.0 using the TOPO TA cloning kit (Invitrogen). For each PCR product, plasmid DNA from two independent colonies was Sanger sequenced by Genewiz using T3 and T7 sequencing primers.Correlation and regression analysis of GAA repeat sizes versus age of onset and subsequent ANOVA statistics were performed using Microsoft Excel data analysis tools (GAA sizes for samples 89–245 were obtained from the EFACTS database).MboII restriction enzyme digestion and agarose gel electrophoresis. This method can detect significant GAA interruptions in either of the two alleles at a resolution of approximately 20bp added to either of the two expected MboII bands of 170 and 120bp or approximately 50bp of internal interruptions 21(GGAGAA)5(GGAGGAGAA)70(GAA)n 5AGAA, lane eight sample:…(GAA)26A(GAA)4G(GAA)2 and lane 10 sample: …(GAA)4GAG(GAA)5. These interruptions were all within the last seven repeats at the 3′ end of the GAA repeat sequence, in a similar location and at a similar frequency to the small 3′ GAA repeat interruptions that were detected in 5 out of 11  FRDA samples as previously reported by We examined the GAA repeat status in 245 FRDA patient and carrier peripheral blood DNA samples by long-range GAA PCR followed by ruptions . As a po70(GAA)n . EighteeR = −0.58, and R2 = 0.34, using a linear model, and an even stronger correlation, R = −0.63, and R2 = 0.40, using a quadratic model . To address potential intergenerational repeat changes, we identified four examples of carrier parents and FRDA-affected offspring within our collection of FRDA patient and carrier DNA samples n interruptions because these will be cut by MboII. Furthermore, care must be taken to exclude possible heteroduplex formation, which may cause difficulties in interpretation of MboII digests by producing an apparent third MboII band that is not real.We recognize that there are some limitations to the pansions , althougpansions . SecondlMboII-detected GAA repeat interruptions may have a less progressive frataxin deficit within their cells and thus a less severe FRDA disease progression, which may suggest a prognosis of milder disease. Due to the unstable nature of pure GAA repeat expansions, individuals with pure GAA repeat expansions are likely to transmit even larger GAA repeats to any offspring. However, this may not be the case for individuals with significant interruptions in their GAA repeat expansions, since a (GAAAGAA)n interrupted 112 GAA repeat has been reported to be stably transmitted through two generations nDM1 repeat, and (CGG)nFMR1 repeat, can make them less prone to expansion. Studies in yeast have shown that such interruptions in (CTG)n repeats reduce hairpin formation during DNA replication and thus inhibit expansion rates (in vitro studies of (CAG)n and (CGG)n repeats have demonstrated inhibitory effects of interruptions on the formation of slipped strand DNA structures, thereby reducing their instability (n repeat expansions with regard to disease pathology has previously been reported for spinocerebellar ataxia type 1 (SCA1) on rates . Other itability . Whateve1 (SCA1) . Interruhenotype . To thisFurther insights into the relevance of interruptions of trinucleotide repeats and associated genetic diseases may be gained by studying suitable mouse models. For example, the comparison of FRDA and Huntington disease (HD) transgenic and knock-in mice also sheds some light on our understanding of the importance of trinucleotide repeat sequence content, somatic instability, and disease phenotype. Both CAG transgenic and CAG knock-in mice can give rise to HD-like phenotypes. However, both of the HD transgenic mice, BACHD and YAC128, contain interrupted repeats , which iWe have shown that major interruptions of GAA repeat expansions are very rare, but when they do occur, they may be of importance to FRDA disease progression, in a similar manner to interruptions in other trinucleotide repeat sequences and their associated genetic diseases. In contrast, we have confirmed that small GAA repeat sequence interruptions occur more frequently at the 3′ end of the GAA repeat sequence, but such small interruptions are not expected to have such a major impact on GAA repeat expansion dynamics. Ultimately, future studies that enable GAA repeat expansion sequence verification at the base pair resolution are needed to allow further in depth conclusions to be made regarding the importance of GAA repeat interruptions and FRDA disease.SA-M, HG, AB, FC, VLC, SC, and MP performed the experiments. SA-M, HG, AB, PG, and MP conceived and designed the study. SA-M, HG, PG, and MP wrote the manuscript. All authors read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Indications for pulmonary valve replacement (PVR) in patients with pulmonary regurgitation (PR) after repaired tetralogy of Fallot (rToF) are debated. We aimed to compare right (RV) and left ventricular (LV) kinetic energy (KE) measured by 4D-flow magnetic resonance imaging (MRI) in patients to controls, to further understand the pathophysiological effects of PR.Fifteen patients with rToF with PR > 20% and 14 controls underwent MRI. Ventricular volumes and KE were quantified from cine MRI and 4D-flow, respectively. Lagrangian coherent structures were used to discriminate KE in the PR. Restrictive RV physiology was defined as end-diastolic forward flow.p < 0.0001. RV diastolic peak KE was higher in rToF  and the difference most pronounced in patients with non-restrictive RV physiology. KE was primarily located in the PR volume at the time of diastolic peak KE, 64 ± 17%.LV systolic peak KE was lower in rToF, 2.8 ± 1.1 mJ, compared to healthy volunteers, 4.8 ± 1.1 mJ, This is the first study showing disturbed KE in patients with rToF and PR, in both the RV and LV. The role of KE as a potential early marker of ventricular dysfunction to guide intervention needs to be addressed in future studies.• Kinetic energy (KE) reflects ventricular performance• KE is a potential marker of ventricular dysfunction in Fallot patients• KE is disturbed in both ventricles in patients with tetralogy of Fallot• KE contributes to the understanding of the pathophysiology of pulmonary regurgitation• Lagrangian coherent structures enable differentiation of ventricular inflowsThe online version of this article (10.1007/s00330-018-5385-3) contains supplementary material, which is available to authorized users. Repair of tetralogy of Fallot (rToF) can result in pulmonary regurgitation (PR) which can cause dilatation of the right ventricle (RV), restrictive RV physiology , decreasFour-dimensional (4D)-flow magnetic resonance imaging (MRI) may provide better understanding and early detection of ventricular dysfunction in rToF with PR , 10 and n = 14, age of surgery was uncertain for one patient). Ten patients had a transannular patch inserted. Median time from correction to study inclusion was 18 years (range 9–46 years). One patient had a stenosis of the left pulmonary branch 10 years after corrective surgery, which was treated with a stent 10 years prior to the inclusion. One patient, corrected at age 29, had a reoperation with a conduit 16 years later, 9 years prior to the inclusion. Patients underwent MRI including 4D phase contrast (PC) flow and performed an exercise test with continuous gas analysis to determine peak oxygen uptake (VO2 peak) described in detail below [2 and/or symptoms and signs of heart failure. Fourteen healthy volunteers, two female, age 30 ± 7 years, were recruited by advertising at the local institution and underwent the same MRI protocol and were used as controls. Inclusion criteria for controls were normal blood pressure (< 140/90 mmHg) and ECG, no cardiovascular medication and no medical history of cardiovascular or other systemic disease.Fifteen patients, five female, referred for cardiovascular MRI were prospectively included in the study. Inclusion criteria were rToF, with PR > 20% (diagnosed on previous MRI or echocardiography) and no pulmonary stenosis. Age at inclusion was 29 ± 12 years (mean ± SD). Seven of the patients had a systemic to pulmonary shunt prior to the corrective surgery. Median age at correction was 14 months, range 3–350 months  cine images covering the entire heart were acquired using a 1.5-T Achieva MRI  or a 1.5-T MAGNETOM Aera MRI . Two-dimensional (2D) PC flow measurements were performed in the ascending aorta and pulmonary artery to measure the effective stroke volume (SV) and PR. Restrictive RV physiology was defined as end-diastolic forward flow in the pulmonary artery , 21. A Phttp://segment.heiberg.se) with an in-house developed module for 4D-flow analysis of KE was used [Segment software  and SV. The delineations were transferred to the 4D-flow data set. KE for each voxel was calculated as LCS were computed in the short-axis orientation at the time of diastolic peak KE in order to find regions of PR and to calculate how much PR contributed to the KE of the RV, Fig. The ratio between systolic/diastolic peaks was calculated to determine if the pattern in the LV and RV differed between patients and controls and if restrictive physiology had an impact on the KE pattern. KE data were linearly interpolated in time to display the average KE over time in patients and controls independent of different heart rates as shown in Fig. KE was analyzed as absolute values but also indexed to planimetrically calculated SV (EDV-ESV) to be able to compare patients with different heart sizes or valvular insufficiencies and to eliminate the possibility of a larger SV, caused by the PR in rToF patients, explaining potential differences. There have been different ways of indexing KE in earlier publications and therefore we report the values in this study using five different indexing methods.2 peak were obtained from the SHIP study [Patients performed a maximal exercise test with continuous gas analysis  on a cycle ergometer . An individualized protocol with a 1-min rest phase, 2-min reference phase on no or low resistance, followed by a ramp with incremental workload until maximal exhaustion was used. Patients were encouraged to continue until respiratory exchange ratio was 1.1 or more, to ensure maximal exertion. Reference values for VOIP study . Twelve-t test and differences before and after PVR using paired t test. Cohen’s kappa was analyzed for the relation of systolic/diastolic peak KE and restrictive RV physiology. Correlations were analyzed using Spearman correlation test. Results with a p value less than 0.05 were considered statistically significant.Statistical analysis was performed using GraphPad . Values are presented as means ± SD. Differences in KE between rToF patients and healthy volunteers were assessed using the Student n = 15, five female, age 29 ± 12 years) and controls  are shown in Table Results of the volumetric measurements in patients .The increase in diastolic KE was most pronounced in patients with non-restrictive RV physiology, Fig. R = 0.54, p = 0.04) and a strong positive correlation between diastolic peak KE and RVESV . KE was primarily located in the PR volume at the time of diastolic peak KE, 64 ± 17 %, n = 14, and there was a moderate positive correlation between the KE located in the PR fraction and the PR volume, R = 0.56, p = 0.04. Diastolic peak KE in the entire RV, on the other hand, did not correlate with PR volume (p = 0.12).There was a moderate positive correlation between systolic peak KE and RVEDV in patients with rToF  in the diastolic peak KE in the RV outside the PR volume in rToF  and the diastolic peak KE in controls .There was no difference . Four of five patients with non-restrictive RV physiology had RV systolic/diastolic KE ratio ≤ 1 and the remaining patient had an RV KE ratio of 1.1, whereas a systolic/diastolic KE ratio > 1 was seen in all 10 patients with restrictive RV (Cohen’s kappa 0.84), Fig. The KE/SV throughout the cardiac cycle in the LV and RV of rToF and controls is shown in Fig. 2 was 30 ± 10 ml/min/kg (n = 13), equivalent to 86 ± 19 % of the predicted value. There was no correlation between peak VO2 and PR volume, , nor were there any correlations between peak VO2 and systolic or diastolic peak KE/SV in either RV  or LV . Furthermore, no correlation was found between peak VO2 and EDV, ESV, SV or EF in either RV  or LV .Mean peak VO2 to 116 ± 18 ml/m2, RVESV from 188 ± 36 ml to 144 ± 35 ml and RVESV/BSA from 97 ± 3 ml/m2 to 73 ± 15 ml/m2 (n = 6). RVEDV decreased from 316 ± 48 ml to 230 ± 43 ml at follow-up after surgery, RVEDV/BSA from 164 ± 18 ml/mPatients after PVR had lower systolic peak KE in both LV and RV, but no difference during diastole, compared to controls, Table All but one patient had decreased peak KE in the RV after PVR, Fig. This is, to our knowledge, the first study that quantifies KE during the entire cardiac cycle in patients with rToF and PR. Our main findings are (1) Patients with rToF and PR with preserved LV global function have decreased LV systolic peak KE compared to controls. (2) RV diastolic peak KE is increased in patients compared to controls as a result of the KE in the PR volume, but RV systolic KE is not different from controls even though flow volumes are much increased. (3) Patients with restrictive RV physiology have less increased KE compared to patients with non-restrictive RV physiology. (4) After surgical PVR systolic KE was more similar to controls in both ventricles. (5) 4D-flow and LCS enable differentiation of flows in patients with valvular regurgitation.The decreased systolic peak KE in the LV in patients is interesting as LV strain has been found to be decreased and regional myocardial velocities altered in rToF patients with preserved LVEF , 27 and The lack of difference in absolute RV systolic peak KE between rToF and controls may seem surprising as the systolic RVSV is higher compared to controls as a result of the PR. KE is determined by mass (volume of blood) and velocity squared. A larger volume passing a fixed RV outflow tract (RVOT) raises KE which explains the functional pressure gradient between the RV and the pulmonary artery seen during increased flows . A possiDiastolic peak KE in the RV was higher in patients than in controls, independent of indexation to SV. Pulmonary regurgitation caused this increase, since the major part of the KE was within the PR volume and the diastolic KE also decreased after PVR.We showed a positive correlation between RV volumes and KE and this is expected as KE is a product of mass, in this case the RV volume, and the squared velocity of the blood. However, KE and volumes are not simply exchangeable as shown by the lack of correlation between diastolic KE and PR volume. The correlation between PR volume and KE was only demonstrated when separating the KE in the inflowing PR volume.In the present study, the degree of PR was similar in patients with restrictive and non-restrictive RV physiology, but patients with restrictive RV physiology had lower diastolic KE and different ratio between systolic/diastolic KE compared to non-restrictive patients. The pathophysiological explanation may be that a restrictive RV with less compliance decreases the velocities of the flow through the tricuspid valve and in the PR and thus decreases the KE even if the PR volume is similar. The reasons for systolic to diastolic KE ratio < 1 in a non-restrictive RV and a healthy LV are different. The non-restrictive compliant RV allows high velocities in the PR volume, leading to high diastolic KE, whereas in the healthy LV the high diastolic KE is caused by ventricular suction of blood from the left atrium.2 and that RV volumes did not correlate with predicted VO2 [2 with a large variation, as expected in this patient group [2 and KE in either LV or RV, but this may be due to the low number of patients. Larger patient cohorts with 4D-flow examination and measurement of peak VO2 are needed to further investigate this possible relationship.A previous study found that the degree of restrictive physiology had the strongest correlation with predicted VOcted VO2 . The difIn this study we adopted a novel approach of using LCS calculated from 4D-flow to differentiate inflow to the RV from the tricuspid valve and the PR. This method can be used in future studies describing the pathophysiology of other valvular regurgitation using KE.All subjects in this study were investigated at rest. Studies have shown that KE accounts for little of the external work in healthy controls at rest, but the proportion increase to 3% in the LV and 24% in the RV during exercise , 32. WhaThe patient population size was rather small, in particular when studying the effect of PVR. Nonetheless, differences between patients and controls were found but future prospective outcome studies are needed to show the clinical impact of these findings.4D-flow MRI show disturbed kinetic energy in patients with rToF and PR not only in the directly affected RV but also in the LV where the global function is seemingly preserved. 4D-flow KE may be key to understanding why LV function is affected in rToF patients even when global function is normal and explain the strong prognostic impact of LV function in these patients. The clinical importance of adding 4D-flow data to an echocardiographic examination and in particular if the information from 4D-flow alters clinical decision-making and outcome will be of interest in future studies.ESM 1(MP4 550 kb)


We present the case of a 32-year-old man who presented with a remote history of chest pain and was diagnosed with non-compaction cardiomyopathy on echocardiography. On presentation, he was relatively asymptomatic with normal cardiac function. Unfortunately, he presented 1 year later with a catastrophic embolic stroke.Left ventricular non-compaction (LVNC) is a myocardial disorder characterised by prominent left ventricular (LV) trabeculae, a thin compacted layer and deep intertrabecular recesses.Two-dimensional echocardiography with colour Doppler is the study of choice for diagnosis and follow-up of LVNC. CMR serves an important role where adequate echocardiographic imaging cannot be obtained.LVNC is associated with high rates of mortality and morbidity in adults, including heart failure, thromboembolic events and tachyarrhythmias. Left ventricular non-compaction (LVNC) is a rare cardiomyopathy and should be considered in the differential diagnosis of patients presenting with unexplained heart failure. In most cases, echocardiography in experienced hands is sufficient to make the diagnosis. Major complications are common, as this case highlights, even in patients where cardiac function is normal. Prevention of embolic complications is an important aspect of treatment in LVNC, and long-term anticoagulation should be considered.A 32-year-old gentleman presented to our institution with non-specific chest pains. He was well otherwise, with no past medical history of note. His maternal uncle had been diagnosed with hypertrophic cardiomyopathy. His presenting ECG was normal.Transthoracic echocardiography demonstrated findings of LVNC with extensive prominent trabeculations in both ventricles and deep intertrabecular recesses . DespiteHe presented over 1 year later with collapse and reduced conscious level. A CT head demonstrated extensive left middle cerebral artery (MCA) territory infarction. On CT intracranial angiography, there was thrombus occupying the M1 and M2 branches of the left MCA. There was normal opacification of the carotid arteries and the vertebrobasilar system with no evidence of dissection flap or stenosis. In addition, his thrombophilia screen and bubble study were negative, and there was no history of illicit drug use. A further CT head 2 days later, following neurological deterioration, demonstrated haemorrhagic transformation within the infarct with associated mass effect , requiriLVNC is a myocardial disorder characterised by prominent trabeculae, inter-trabecular recesses and a left ventricular myocardium with two distinct layers: compacted and non-compacted. Although the classical clinical presentation is with heart failure, arrhythmias and embolic events, presentation is highly variable ranging from an incidental finding in an asymptomatic patient to end-stage heart failure. Biventricular involvement is a rare entity, the prognostic implications of which are unknown. Two-dimensional echocardiography with colour Doppler is the study of choice for diagnosis and follow-up of LVNC. Colour Doppler or contrast echocardiography show evidence of deep, perfused intertrabecular recesses. CMR serves a particularly important role for patients in whom adequate echocardiographic imaging cannot be obtained , 2.In vivo blood clots within the non-compacted layer have been documented in patients with embolic events (In LVNC, mural thrombi may develop within the inter-trabecular recesses where blood flow is sluggish, which can cause systemic embolisation. c events . During c events . Thus, pc events . Some inThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.Permission has been obtained from the patient’s wife.S G and R S conceived the manuscript. S G wrote the first draft, which was reviewed by R S.


Comparisons were performed by the Fisher or ANOVA tests. Bonferroni post hoc, Spearman correlation, and multiple correspondence analyses were also performed. Edema was observed in 8 (9.8%) patients; 2 (5.4%) of G1, 4 (12.1%) of G2, and 2 (16.7%) of G3. It was observed at the basal inferolateral segment in 7 (87.5%) cases. LGE was observed in 48 (58.5%) patients; 16 (43.2%) of G1, 21 (63.6%) of G2, and 11 (91.7%) of G3 (p < 0.05). It was observed in the basal inferior/inferolateral/anterolateral segments in 35 (72.9%) patients and in the apical anterior/inferior/lateral and apex segments in 21 (43.7%), with midwall , subendocardial , subepicardial , transmural , and RV  distribution. Subendocardial lesions were observed only in patients with LVEF < 35%. There was no involvement of the mid-inferolateral/anterolateral segments with an LVEF > 35% (p < 0.05). Deteriorations of the LV and RV systolic functions were positively correlated  without evidence of LGE in the RV. Edema can be found in patients with chagasic cardiomyopathy in the chronic stage. In later stages of cardiac dilation with low LVEF, the LGE pattern involves subendocardium and mid locations. Deteriorations of RV and LV are positively correlated without evidence of fibrosis in the RV.The persistence of inflammatory processes in the myocardium in varying degrees of chronic Chagas heart disease has been poorly investigated. We hypothesized that edema could occur in patients with chronic chagasic cardiomyopathy and corresponds to the persistence of inflammatory processes in the myocardium. Eighty-two Chagas disease (CD) seropositive patients  without ischemic heart disease or conditions that cause myocardial fibrosis and dilation were considered. Late gadolinium enhancement (LGE) and T2-weighted magnetic resonance imaging of edema were obtained and represented using a 17-segment model. Patients were divided into three clinical groups according to the left ventricular (LV) ejection fraction (EF) as G1 (EF > 60%;  Trypanosoma cruzi infection, is a pathology of crucial interest in public health. The vectors, bug members of the subfamily Triatominae, are hematophagous insects distributed mainly from the southern United States to South America [Chagasic heart disease, caused by  America . It is e America . In the  America . Additio America . In Colo America .T. cruzi, the asymptomatic phase can last for decades until unknown triggers initiate cardiac involvement in >90% of the cases [After infection with he cases , which ihe cases . This ishe cases –10. In fhe cases .Recently, cardiac magnetic resonance (CMR) has been considered a sensitive technique to detect myocardial damage in Chagas heart disease , 12–14; n=37), G2 , and G3 . Sociodemographic data, clinical history, and comorbidities were obtained from patients' medical records. The inclusion criteria were patients over 18 years old, positive for Chagas disease according to the CDC criteria, epidemiological background, and two positive laboratory tests . Each patient signed a consent form to be part of the study.This study was performed with 82 patients in different clinical phases of Chagas heart disease. Patients were divided into groups according to the left ventricular (LV) ejection fraction (EF) as G1 . Additionally, a quantitative functional evaluation was carried out. Structural measures  and functional measures  were obtained from each patient. Tissue characterization evaluated the presence of myocardial edema by means of T2 sequences with fat suppression and the presence of LGE with T1 IR acquisitions in 2D and 3D. Additionally, images of LGE were obtained specifying the location and degree of transmurality. The intravenous contrast material used was Gadobutrol (0.1 mmol/kg), a gadolinium-based MRI contrast agent.The interpretation of the resonances was carried out by specialists in radiology and diagnostic images of the participating institutions. A second reading of the study was made by an expert in advanced cardiac imaging with experience in cardiovascular magnetic resonance analysis; the specialists were blinded with respect to the previous analysis, in order to estimate the reproducibility of the imaging variables obtained in the study.Comparisons of normally distributed continuous variables between groups were performed by the one-way analysis of variance (ANOVA) with the Bonferroni post hoc test for multiple comparisons. The nonparametric test for discrete variables and nonnormal continuous variables was the Kruskal–Wallis test by ranks. Normality was determined by the Shapiro–Wilk test. The Fisher exact test was used for proportion comparisons between the groups. A confidence level of 95% was used to considered test results statistically significant.Multiple correspondence analysis (MCA), a multivariate data analysis, was employed to construct relationships among categorical variables associated with the presence and location of LGE in the different LVEF groups. Chi-squared tests were performed to verify the association between categorical variables. All statistical analyses were performed using the R language .n=45), class II , and class III .p < 0.05). It was observed in the basal inferior/inferolateral/anterolateral segments in 35 (72.9%) patients and in the apical anterior/inferior/lateral and apex segments in 21 (43.7%) patients, with midwall , subendocardial , subepicardial , transmural , and RV  distribution. The distribution of LGE in a 17-segment model (AHA) is shown in p < 0.05) (p < 0.05). There was no involvement of the midwall and subepicardial segments with an LVEF >35% (p < 0.05) (p < 0.01), LV telediastolic volume index (p < 0.01), LV telesystolic volume (p < 0.01), LV telesystolic volume index (p < 0.01), LV mass (p < 0.01), LV mass index (p < 0.01), VD telesystolic volume (p < 0.01), and VD telesystolic volume index (p < 0.01) when compared to the other groups. There were no differences in the VD telediastolic volumes and VD telediastolic indexes between the groups. This predominant distribution at the inferolateral wall of the LV and a heterogeneous distribution inside the myocardium is in concordance with prior studies [LGE was observed in 48 (58.5%) patients; 16 (43.2%) of G1, 21 (63.6%) of G2, and 11 91.7%) of G3 ( < 0.05) . Those p < 0.05) . G3 pati% of G3 , LV telediastolic volume index (rs=−0.77), LV telesystolic volume (rs=−0.90), LV telesystolic volume index (rs=−0.91), LV mass (rs=−0.71), and LV mass index (rs=−0.73). In addition, LVEF showed a high positive correlation with RVEF (rs=−0.69) as shown in We found that patients with LGE had a trend toward worse NYHA functional class compared to patients without LGE, although LGE was found in 25 (52.1%) patients with NYHA functional class I and 22 (45.8%) patients with NYHA functional class II, and it was found in a patient with NYHA functional class III. LVEF and CMR-derived LV volumes showed high negative correlation with echocardiographic measurements for LV telediastolic volume (p < 0.05). Prominent inflammation, fibrosis, and vasculitis in the right chambers were shown in experimental models of mice infected with T. cruzi, even during the acute infection phase [Although usually associated with reduced LVEF, we found that RVEF was significantly lower in G3 patients. This finding is in accordance with recent studies which suggest that RV systolic dysfunction in Chagas disease depends mainly on LV increased afterload , 29. Furon phase . In humaon phase , 32.p < 0.05). Greater LV telesystolic volume and LV telesystolic volume index were found in those patients (p < 0.05). Edema was observed in 8 (9.8%) patients, 2 (5.4%) of G1, 4 (12.1%) of G2, and 2 (16.7%) of G3. It was observed mainly at the basal inferolateral segment in 7 (87.5%) cases. Edema distribution is represented in a 17-segment model in The presence of edema in the chronic phase of the disease was previously related with severe impairment of myocardial status  and may In Our findings indicate that the concept of indeterminate form of Chagas disease, although valid for the collective prognostic evaluation of this group of patients, should be updated in the analysis of individual cases, considering the findings obtained by the application of more accurate diagnostic methods, such as CMR , 33–35. The aim of this study was to characterize CMR findings caused by Chagas at different stages of disease severity in Chagas-seropositive patients and solve the hypothesis that edema could occur in patients with chronic chagasic cardiomyopathy and corresponds to the persistence of the inflammatory process in the myocardium. We found that edema can be found in patients with chagasic cardiomyopathy in the chronic stage. In later stages of cardiac dilation with low LVEF, the LGE pattern involves subendocardium and mid locations. Deteriorations of RV and LV are positively correlated without evidence of fibrosis in the RV.


Patients with uremia have high cardiovascular disease morbidity and mortality despite having normal left ventricular ejection fraction (LVEF). Longitudinal strain (LS) can be associated with subtle changes in LV systolic function. The aim of this study was to use two-dimensional speckle-tracking echocardiography (2DSTE) to assess subclinical LV myocardial dysfunction and to explore strain-changing regularities in uremic patients with LVEF ≥ 55%.The study population included 40 uremic patients and 40 healthy volunteers. 2DSTE was performed on all participants to assess peak LS in the basal, mid and apical LV  and the respective time to peak LS .BLS, MLS, and ALS were significantly decreased in the uremic group relative to healthy controls and LS increased going in a basal to apical direction in both groups. T-BLS, T-MLS and T-ALS was significantly increased in the uremic group compared with the control group. In uremic patients, T-BLS, but not T-MLS or T-ALS, was significantly delayed relative to the control group. Bivariate analysis of creatinine (Cr) or urea nitrogen and strain parameters revealed a correlation only between ALS and Cr.2DSTE can identify LV myocardial abnormalities in uremic patients with preserved LVEF at early stage, as well as some changing regularities of LS and T-LS in the left ventricle. Chronic kidney disease (CKD) is an important public health problem that is characterized by poor health outcomes and high health care costs . Uremia Between March 2017 and December 2017, 40 clinically stable uremic outpatients undergoing regular hemodialysis (three times per week) at the Shanghai East Hospital nephrology clinic were consecutively enrolled. Patients having arrhythmia, primary hypertension, previous myocardial infarction, moderate or large hydropericardium, or LV systolic dysfunction with LVEF < 55% were excluded. The underlying causes of uremia among the study subjects were: chronic glomerulonephritis (16 cases), congenital renal malformation (4 cases), diabetes mellitus (7 cases), chronic interstitial nephritis (5 cases), polycystic kidney (4 cases), gouty nephropathy (2 cases) and purpura nephritis (2 cases). In addition, 40 age- and sex-matched healthy volunteers were enrolled as controls. All control subjects met the following inclusion criteria: no history of cardiac symptoms, hypertension or diabetes, normal physical examination, electrocardiogram, chest radiography, renal function and echocardiography results and no use of medication. Written and informed consent was obtained from all study participants. The study was approved by the Shanghai East Hospital ethics committee.The biochemical indices of uremic outpatients included blood creatinine (Cr) and urea nitrogen (Un) levels, which were evaluated at the hospital laboratory on the same day as the sample collection. Reference levels of Cr and Un were 58–110 µmol/L and 3.20–7.10 mmol/L, respectively, in accordance with standards used by the biochemistry laboratory of Shanghai East Hospital.All participants underwent an echocardiogram using a commercially available echo system  with a dedicated software package . Baseline transthoracic echocardiograms were performed with a frame rate of 40–60 Hz. Patients or controls with insufficient two-dimensional (2D) image quality for subsequent analyses were excluded. All image acquisition was performed with the ECG placed at the left lateral decubitus position. All echocardiographic studies were performed according to ASE-recommended guidelines  by an exStandard two-dimensional echocardiography was performed to obtain conventional parameters in the parasternal long axis, namely, the left atrial diameter (LAD), LV septal wall thickness (LVST), LV posterior wall thickness (LVPT), LV diameter at the end of diastole (LVEDD), and the LV diameter at the end of systole (LVESD). Fractional shortening (FS) was then calculated using the formula: [(LVEDD − LVESD)/LVEDD] × 100. LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV) and LVEF were calculated from the apical four-chamber and two-chamber views using Simpson’s biplane method . The earThree standard apical views  were obtained over 4 cardiac cycles while the subject held his/her breath Fig. . TemporaAmong the uremic and control groups, 5 subjects were randomly selected to test intra- and inter-observer variability in the 2DSTE analysis. The 2DSTE data for these subjects were reanalyzed 2 weeks after the first analysis by the same observer (Yun Dong) and by a second independent observer (Yuqin Ma). Both observers were blinded to the previous measurements.All analyses were performed using SPSS version 22 software . Shapiro–Wilk test was used to assess the distribution of continuous variables. Results were expressed as mean ± standard deviation (SD) for normally distributed variables and median (interquartile range) for non-normally distributed variables. Comparisons between continuous variables were performed using Independent-Samples T test, Mann–Whitney U test, One Way Anova test or Kruskal–Wallis test as appropriate. Correlations between selected variables were verified by Pearson correlation coefficients  and Spearman coefficients . Intra-class correlation (ICC) of intra- and inter-observer variability in strain parameters were calculated. A P-value < 0.05 was considered significant for all described analyses.Among the study subjects, 9 ERSD patients and 7 controls were excluded due to poor images that did not allow visualization of least three LV segments by 2DE. A total of 31 patients and 33 controls were included in the final statistical analysis. The possibility of acquiring high-quality images was 77.5 and 82.5% for the uremic and control group, respectively.Conventional echocardiography parameters for the two groups are compared in Table 2.1.The 2DSTE analyses for the two groups are shown in Table 2.2.2.3.Intra-group analyses of T-BLS, T-MLS and T-ALS are shown in Table 2.4.Relationships between 2DSTE parameters and biochemical indexes are shown in Table Intra-group analyses of BLS, MLS and ALS are shown in Table 3.Intra- and inter-observer variability are shown in Table Many previous studies emphasized that the leading cause of death for uremic patients is CAD, including heart failure, myocardial infarction, and sudden cardiac death . Thus, eThe major findings of our study were: (a) BLS, MLS, and ALS was significantly decreased in patient’s group compared with the control group, and LS increased from basal to apical in both groups. (b) T-BLS, T-MLS and T-ALS were significantly prolonged in the uremic group compared with the control group. In uremic patients, T-BLS showed a greater delay than did T-MLS and T-ALS, which were absent in the control group. (c) Bivariate analysis indicated that there was no correlation between strain parameters and Cr or Un except for ALS and Cr, which showed a negative correlation.Longitudinal fibers are located mostly in the endo-epicardium, which is more sensitive to ischemia and pressure loading. LS mainly represents the function of subendocardial longitudinal myocardial fibers , 26. TheThere were certain limitations to our study. First, our sample size was relatively small and conducted at a single center. Second, the patients were not followed over the long term to document the occurrence of cardiovascular events such as severe arrhythmias or ischemic events. Therefore, a larger study with long-term follow up of the study subject group is required to support our findings. Prospective clinical trials are also needed to establish whether our findings have therapeutic or prognostic implications and whether 2DSTE could be used to provide a better understanding of the physiopathology and treatment of uremic cardiomyopathy with normal LVEF.The findings in our study clearly demonstrate that 2DSTE can identify left ventricular myocardial abnormalities in uremic patients with preserved LVEF during the early disease stage, but we also found some changing regularity of LS and TLS in the left ventricle. These parameters may provide an opportunity to identify uremic patients who are at risk for future cardiovascular events. Large prospective, multicenter studies are needed to investigate these possibilities.


This study aimed to assess subacute post-intervention Rubidium-82 (82Rb-PET perfusion imaging was performed at median 36 hours [IQR: 22 to 50] after the treatment. The extent of hypoperfusion and absolute blood flow (mL·min·g) were estimated on a global and a 17-segment model with dedicated software. At 3-months follow-up patients completed the CMR functional and late gadolinium enhancement imaging.STEMI patients undergoing percutaneous coronary intervention were included prospectively. Rest-only P < .005. Extent of hypoperfusion correlated with final infarct size, r = 0.58, P < .001, while blood flow correlated with ejection fraction, r = 0.41, P < .05. In linear mixed models, higher subacute absolute blood flow  was associated with greater wall motion. Segmental extent of subacute hypoperfusion  was associated with the degree of late gadolinium enhancement at 3-months.42 patients were included, but only 35 had follow-up CMR and constituted the study population. Absolute blood flow was significantly lower in the infarct-related territory compared to remote myocardium, 82Rb-PET is feasible following STEMI and seems predictive of myocardial function and infarct size at 3-months.Subacute rest-only The online version of this article (doi:10.1007/s12350-017-0993-x) contains supplementary material, which is available to authorized users. The time aspect combined with the possibility of proper patient monitoring during the examination becomes increasingly important with the decreasing hospitalization time and the widespread use of early transfer (same day) to local hospitals that may not have the same imaging facilities. We have previously reported about the feasibility of 82Rb-PET in assessing the infarct size subacutely after STEMI compared to SPECT and CMR.11The assessment of left ventricular function and final infarct size (FIS) in the chronic phase after an ST-elevation myocardial infarction (STEMI) is clinically important because these parameters impact patient management and risk stratification.This prospective cohort study aims to uncover whether PET derived measurements of resting blood flow and extent of severe hypoperfusion in the subacute phase of STEMI can predict final infarct size, LVEF, and regional wall motion as measured by CMR at 3-months follow-up.4 − V6 or leads II, III, and aVR, or >0.2 mV in lead V1 − V3. Exclusion criteria were cardiogenic shock, previous MI, stent thrombosis, unconsciousness, or previous coronary artery bypass grafting. All patients were pretreated with standard therapy, including oxygen, sublingual nitroglycerin, aspirin (300 mg), prasugrel (60 mg), and heparin  in the prehospital setting. The infarct-related vessel was identified by coronary angiography, and pPCI was performed according to international guidelines. Patients were treated lifelong with 75 mg aspirin and 10 mg prasugrel daily for 12 months.Patients with index STEMI were prospectively included in the study Figure . Other rStandard echocardiography was performed according to guidelines, routinely at discharge. Blood was sampled for creatine-kinase MB and Troponin T immediately before PCI and four additional times at fixed time-points post-PCI.At 3-months follow-up, patients were interviewed to exclude any admission for restenosis/angina, and in addition, patient journals were audited.The independent local ethics committee approved this study, protocol no: H-4-2010-054. All patients included received verbal and written information, and written consent was obtained from all the patients before inclusion in compliance with the Declaration of Helsinki.82Rb i.v.  and underwent 7 minutes of 3D list mode dynamic data acquisition. PET and CT images were manually inspected for any misalignment and corrected if necessary before reconstruction of attenuation-corrected images. Images were reconstructed into 21 frames  with attenuation, scatter, and decay corrections using 3D iterative ordered-subsets expectation maximization, Gaussian filtering with 10 mm full width at half maximum, including time-of-flight and point-spread-function. Examination time was approximately 15 minutes.Rest PET MPI was performed the subsequent day after pPCI and when patients were clinically stable. The protocol has been described previously.Cedars QPS/QGS® software  was used to process and analyze semi-quantitative and quantitative data in a semi-automated manner. Two experienced observers assessed the accuracy of slice-alignments in the ventricular planes and intervened if necessary (blinded to CMR data). Disagreements were solved by consensus. Tracer uptake was normalized to maximal uptake (index 100).extent of severe hypoperfusion in the left ventricle was determined by an automated algorithm with a threshold of 2.5 standard deviations (SD) below normal counts in each pixel and estimated as percent of the LV volume and per AHA-17 segment model.11Absolute rest myocardial blood flow (ml·min·g) was calculated by applying Lortie’s one compartment modelMyocardial perfusion was quantified using two methods: extent of hypoperfusion and absolute myocardial blood flow. Quantitation of the Follow-up imaging was performed 3 months after pPCI on a 1.5 T scanner  with the use of a 6-channel body array coil. Functional assessment of the LV was performed using an ECG-triggered balanced steady-state free-precession cine sequence covering the entire LV . Final infarct size (FIS) was quantified 10 minutes after administration of Gadolinium-based contrast . An ECG-triggered enhancement inversion-recovery was used . In short-axis images of the LV, the inversion time was adjusted in each slice from base to apex in order to null the signal from the normal myocardium.On short-axis cine images endo- and epicardial contours were manually drawn on End-diastolic and End-systolic frames. Papillary muscles were incorporated into the LV lumen volume. LV volumes, wall thickening in percent, and wall motion in millimeters were subsequently obtained automatically from the software.Wall thickening was calculated by expressing the end-systolic increase for each AHA-16 segment as a percentage of its end-diastolic wall thickness ((end-systolic − end-diastolic) × 100/ end-diastolic). Each AHA-16 segment was categorized as normal, hypokinetic or hyperkinetic based on a normal database of wall thickening.42 FIS was assessed on the late gadolinium enhancement images after manual endo- and epicardial contour tracking. FIS was defined as hyper-intensive myocardium . FIS was calculated as percent of the LV volume and percent transmurality per AHA-16 segment. The analyses were performed by two experienced observers that were blinded to PET data using CVIContinuous normally distributed variables are summarized as mean±SD and non-normally distributed continuous variables as median  and categorical variables as frequencies or percent (%). Generalized Estimating Equations’ test was used when comparing three variables. The Mann-Whitey test was used for comparisons between two independent groups. Correlation between any two modalities was examined with Spearman’s rank correlation. Correlations less than 0.39 were interpreted as “fair,” values between 0.40 and 0.59 as “moderate,” and values above as “strong”.1682Rb-PET for follow-up cardiac function and morphology three different sets of predictors corresponding to models of increasing complexity were considered. Model 1 contains only PET derivatives as explanatory variables; model 2, in addition, included AHA-17 segments, infarct-related artery segments, and vascular territory. These variables were included to adjust for differences in regional tracer uptake due to physiological and pathophysiological circumstancesR2 (variance explained) was estimated according to Nakagawa et alIn order to assess the predictive ability of subacute 82Rb-PET MPI and follow-up CMR constituted the study population. Baseline demographics and medical history for patients enrolled are summarized in Table A total of 42 Patients were recruited for the study, but seven were lost to follow-up CMR Figure . The 35 P < .005 for difference).Rest PET MPI was performed at a median of 36 hours  after pPCI. The median myocardial area with severe hypoperfusion was 20.0% of the LV  in the subacute phase. Absolute median global blood flow, blood flow in the infarct-related artery territory (IRA), and blood flow in the non-IRA territory were 0.94 , 0.71  and 1.0  mL·min·g, respectively. Blood flow at IRA territory was significantly lower than the global blood flow and the blood flow at non-IRA territory  had late gadolinium enhancement . LGE, wall thickening, and wall motion stratified by wall function categories are listed in Table As presented in Table The extent of hypoperfusion and myocardial blood flow stratified by wall function categories is summarized in Table 82Rb-PET for follow-up cardiac function and morphology three different prediction models of increasing complexity were considered. Results are listed in Table R2) compared to the simple model which only includes the PET derivatives as predictors (model 1).R2, but at the expense of higher complexity. The estimates of model 2 are reported below.In order to assess the predictive ability of subacute β = 4.6, confidence interval , P < .001, R2 = 0.67); such that for every 0.1 mL·min·g increase of blood flow, there was a 0.46 mm increase in the wall motion during systole. The extent of severe hypoperfusion was best in predicting LGE transmurality, ; such that for every 1% increase of extent of severe hypoperfusion, there was 0.43% increase in LGE transmurality per segment.PET derived variables on a segment-to-segment basis were all significant predictors of CMR parameters. Absolute blood flow showed the best model fit for predicting wall motion at follow-up,  according to follow-up LVEF tertiles and compared patients in the lower third tertile  with the upper two tertiles . This was done in order to put the PET measurements at the subacute phase in the context of an important and valuable clinical parameter, LVEF. Median LVEF was 48.0%  in Group 1 compared to 60%  in Group 2 (P = .001). Baseline characteristics for the two groups are shown in Table P = .02). Furthermore, global blood flow and blood flow in the IRA were significantly lower in Group 1 compared to Group 2, see Figure We stratified the cohort  derived from [CMR-assessed FIS has previously been shown to be a strong predictor of subsequent cardiac eventsPreviously, research groups have demonstrated the benefits of myocardial perfusion imaging in post-infarction patients regarding functional recovery, LVEF, and cardiovascular death.99mTc- sestamibi on SPECT was not significantly correlated to discharge LVEF (determined by electron beam CT), but became so after remodeling had progressed at 6-weeks  and 1-year .99mTc- sestamibi SPECT imaging was performed on average 7 ± 2 days after admission, whereas, our PET imaging was performed earlier at a median of 36 hours after primary PCI. This could be one explanation for the difference in correlation coefficient between ours and the Mayo Clinic study. Ndrepepa et al reported similar moderate correlation as ours between initial perfusion defect size and LVEF at follow-up examined in 626 patients with MI .99m Tc-sestamibi uptake and LVEF due to stunning. The extent of 82Rb uptake affected by stunning remains unclear. 82Rb is dependent on both the blood flow rate and the metabolic state of the myocardium.82Rb.A Mayo Clinic study demonstrated that discharge infarct size measured with 13N-ammonia PET imaging.82Rb-uptake already at the subacute state. Whether this is due to decreased extraction of the tracer during reactive hyperemia and/or the metabolic state of the myocardium as a ramification of the ischemia/reperfusion injury remains uncertain. We find that rest-only PET perfusion imaging in the subacute phase after MI seems sufficient to predict future cardiac contractility. However, it is well-known that the myocardial flow reserve adds more information regarding the microcirculatory status than rest-only imaging. We can only speculate if this would also be the case in our population. However, since stress testing is contraindicated in the subacute phase of an MI, this could not be tested in our study.A study comparable to ours, confirm that areas with reduced wall motion were associated with decreased stress blood flow as well as reserve blood flow capacity as assessed 24 months after index MI with 82Rb-PET examination has not been optimized for this indication. One example is our assessment of extent of hypoperfusion using a cut-off value of 2.5 SD, this value is derived from SPECT examinations of perfusion, and we have recently shown that this value is probably not optimal.Our results could indicate that a single non-stress examination lasting less than 15 minutes performed during initial admission after an STEMI could add prognostic information to the cardiologist that could potentially individualize risk-management of follow-up surveillance. However, the Another PET imaging method to predict regional and global LV function recovery is fluorodeoxyglucose (FDG). FDG-PET showed good sensitivity and specificity in predicting improvement in regional function after revascularization in patients with chronic coronary artery disease.82Rb-PET imaging was able to differentiate between patients with high and low LVEF. Cuculi et al found no difference between resting and hyperemia flow with an invasive measuring technique at pPCI. This was probably due to microcirculatory jeopardization and therefore the inability to obtain hyperemia. But importantly, they found a significantly lower coronary flow reserve the following day in patients with lower LVEF compared to patients with preserved LVEF.Although the LVEF of group 1 (48%) was not substantially reduced and would be considered near normal, the Of potential limitation is the lack of follow-up angiography to insure patent IRA. A silent reocclusion of the IRA after the reperfusion would lead to a deteriorating wall motion function. However, no patients were admitted to the hospital for AMI in the follow-up period, and no patients reported crescendo angina at the 3-months follow-up. Furthermore, the sample size is relatively small, and all participants were presented to a single center. Hence, confounders such as demographics and treatment can influence the results.82Rb-PET is uncertain, and since it measures flow at a single time point, the condition of the microcirculation is uncertain as well.Potential mismatch between CMR and PET could be due to misalignment of segments. However, the standard use of AHA-16 segments should minimize this limitation. Finally, the optimal timing of 82Rb-PET imaging is feasible and can provide fast assessment of the absolute blood flow at the infarct territory and the extent of hypoperfusion following STEMI. These parameters seem predictive of myocardial function and infarct size at follow-up, factors that are of clinical importance for prognosis and morbidity.82Rb-PET imaging and warrants further research in larger study populations.The management of patients after infarction could thus potentially be enhanced with the knowledge provided by cardiac 82Rb-PET MPI in the early phase after STEMI and enable assessment of absolute blood flow to predict follow-up LV morphology and function in a time-efficient manner.Our findings could expand the role of Supplementary material 1 (PPTX 1535 kb)Below is the link to the electronic supplementary material.


At the European Society of Cardiology (ESC) congress of this year 2018, held in Munich from August 25th to 29th, 4594 abstracts were presented. Of those, 423 (10.8%) belonged to an imaging category. Experts in echocardiography (VD), cardiovascular magnetic resonance (CMR) (CBD), nuclear imaging (OG), and cardiac computed tomography (CT) (PMH) have selected the abstracts in their areas of expertise that were of most interest to them and are summarized in this bird’s eye view from this ESC meeting. These abstracts were integrated by one of the Editors of the Journal (JB). P = 0.004) and troponin T  compared to patients with preserved microvascular coronary function. Despite similar LVEF, patients with coronary microvascular dysfunction showed more impaired left ventricular (LV) systolic function as assessed with tissue Doppler velocity (s′)  and speckle-tracking global longitudinal strain (GLS)  compared with their counterparts. In addition, patients with coronary microvascular dysfunction showed more impaired right ventricular longitudinal strain  and lower reactive hyperemia index as a measure of systemic endothelial function. These results suggest that coronary microvascular dysfunction may be an important pathophysiological mechanism of heart failure with preserved LVEF and may set the basis to develop effective therapies that target this mechanism.Coronary microvascular dysfunction as mechanism underlying the pathophysiology of heart failure with preserved left ventricular ejection fraction (LVEF) was evaluated in the prospective, multicenter PROMIS-HFpEF  trial.Cardiac amyloidosis is characterized by diffuse LV hypertrophy and on speckle tracking analysis, the LV GLS is characterized by a typical apical sparing . This LV GLS pattern is associated with poor outcomes.A novel method that integrates blood pressure measurements and LV GLS provides noninvasive LV pressure-strain loops and permits calculation of global and segmental myocardial work in various cardiac diseases. Edwards et alThree-dimensional (3D) transesophageal echocardiography (TEE) is key in the evaluation of patients referred for transcatheter aortic valve replacement, particularly when the anatomy of the aortic valve is bicuspid. In 104 patients with bicuspid aortic valve stenosis, who were evaluated for transcatheter aortic valve replacement but who were eventually treated with surgical aortic valve replacement, Dr Wang2 (upper quintile) had the highest age- and sex-adjusted risk profile (hazard ratio [HR] 1.9 compared with patients within the lowest quintile [LA volume index < 22 mL/m2]). The analysis based on deciles of LA volume index showed that the increase in mortality risk began with the LA volume index decile of 29-31 mL/m2 .8Finally, the use of machine learning in echocardiography provides important insights. From the national echocardiographic database of Australia (NEDA), a vendor-agnostic cloud-based database containing echocardiographic data from ten Australian laboratories, Murphy et alCartlidge et alMachine learning principles  are raising increasing attention as innovative approaches to explore and learn complex patterns within imaging data and improve human interpretation of large data clusters. Juarez-Orozco et alP = 0.024). The authors conclude that focal FDG uptake is an early sign of disease-related myocardial damage in patients with Anderson-Fabry disease and is associated with impaired LV longitudinal function. Moreover, their findings support the notion that inflammation plays an important role in glycosphingolipids storage disorders.Hybrid 18F-fluorodeoxyglucose (FDG) PET and magnetic resonance imaging (MRI) permit differentiation between myocardial scar from fibrosis associated with inflammation. Spinelli et alKeller et al2/m2) included in the PRIMID-AS (PRognostic Importance of MIcrovascular Dysfunction in Aortic Stenosis) study. Cardiovascular magnetic resonance (CMR) imaging was performed at baseline and 12-month follow-up. The authors observed a significant increase in indexed LV end-diastolic volume  and indexed LA volume , reduction in LVEF  and impairment in LV diastolic function  despite no change in the indexed aortic valve area. In addition, there was a significant reduction in rest and stress myocardial blood flows and increases in myocardial fibrosis both on native T1 mapping and late gadolinium enhancement (LGE) imaging  who did not receive early intravenous metoprolol showed the highest cumulative event rates compared with the patients who received metoprolol or had more preserved LV systolic function. These results underscore the role of feature-tracking CMR for detailed risk stratification of patients with ST-segment elevation myocardial infarction.Feature-tracking CMR is a novel technique that permits assessment of myocardial deformation on cine CMR images. Using this methodology, Podlesnikar et alP < 0.001). The study demonstrated that a noninvasive CFR assessment by phase-contrast cine MRI could represent a novel risk stratification tool in patients with diabetes mellitus.Phase-contrast cine MRI of the coronary sinus is a noninvasive method to quantify CFR which has been associated with prognosis in patients with suspected CAD. In 163 patients with diabetes mellitus, Kato et alP = 0.004). Importantly, the rates of invasive coronary angiography and coronary revascularization were similar at 5 years in both arms.The 5-year follow-up results of the Scottish Computed Tomography of the Heart (SCOT-HEART) trial were presented at this ESC congress in Munich.P < 0.001 for all-cause mortality and HR 5.62, P < 0.001 for cardiac mortality). Therefore, perivascular fat attenuation index reflects coronary inflammation and could guide preventive therapies in primary prevention and intensify secondary prevention in patients with CAD.In the EPICardial Adipose Tissue in HEART Diseases (EPICHEART) study,Another pioneering study describing coronary CTA radiomics to identify novel imaging biomarkers of plaque vulnerability was presented by Kolossvary et alP < 0.001). This reduction in radiation dose was not associated with the increase in the number of nondiagnostic coronary CTA . This large international radiation dose survey demonstrates considerable reduction of radiation exposure in coronary CTA during the last decade and underlines the importance of training and adaptation of contemporary cardiac scan protocols.As coronary CTA is becoming a widely available imaging technique and one of the first-line tests used in patients with suspected CAD, the radiation dose exposure is highly relevant. Hausleiter et al. presented the results of the Prospective Multicenter Registry on RadiaTion Dose Estimates of Cardiac CT AngIOgraphy iN Daily Practice (PROTECTION-VI) study that evaluated the radiation dose and the utilization of dose-saving strategies for cardiac CTA.


Deoxyhemoglobin increases blood magnetic susceptibility, which can be measured using an emerging cardiovascular magnetic resonance (CMR) technique, Quantitative Susceptibility Mapping (QSM) – a concept previously demonstrated in healthy subjects using a breath-hold 2D imaging approach (2DBHQSM). This study tested utility of a novel 3D free-breathing QSM approach (3DNAVQSM) in normative controls, and validated 3DNAVQSM for non-invasive ΔSaO2 quantification in patients undergoing invasive cardiac catheterization (cath).Differential blood oxygenation between left (LV) and right ventricles  testing compared 2DBHQSM (ECG-triggered 2D gradient echo acquired at end-expiration) and 3DNAVQSM . Clinical testing was subsequently performed in patients being considered for cath, including 3DNAVQSM comparison to cine-CMR quantified LV function (n = 39), and invasive-cath quantified ΔSaO2 (n = 15). QSM was acquired using 3 T scanners; analysis was blinded to comparator tests .Initial control  were not significantly different between 3DNAVQSM and 2DBHQSM . Acquisition times were 30% lower with 3DNAVQSM , paralleling a trend towards lower LV mis-registration on 3DNAVQSM (p = 0.14). Among cardiac patients  3DNAVQSM was successful in 87% (34/39) and yielded higher ΔSaO2 (24.9 ± 6.1%) than in controls (p < 0.001). QSM-calculated ΔSaO2 was higher among patients with LV dysfunction as measured on cine-CMR based on left ventricular ejection fraction  or stroke volume . Cath measurements (n = 15) obtained within a mean interval of 4 ± 3 days from CMR demonstrated 3DNAVQSM to yield high correlation , small bias (− 0.1%), and good limits of agreement (±8.6%) with invasively measured ΔSaO2.3DNAVQSM provides a novel means of assessing cardiac performance. Differential susceptibility between the LV and RV is increased in patients with cine-CMR evidence of LV systolic dysfunction; QSM-quantified ΔSaO2 yields high correlation and good agreement with the reference of invasively-quantified ΔSaO2.3D Increased ΔSaO2 has been shown to predict adverse prognosis in patients with heart failure with and without pulmonary hypertension [Differential blood oxygenation between the left and right heart  to 2D breath held QSM (2DBHQSM) in controls, as well as to the reference of ΔSaO2 measured in patients undergoing invasive cardiac catheterization.Quantitative susceptibility mapping (QSM) is an emerging cardiovascular magnetic resonance (CMR) technique that enables quantification of diamagnetic and paramagnetic materials –23. IronNAVQSM was first compared to 2DBHQSM among healthy subjects without clinically reported cardiovascular conditions or associated risk factors to test the relative performance in a cohort able to undergo prolonged imaging inclusive of both pulse sequences. Next, a second group of healthy subjects were scanned and rescanned to test the reproducibility of 3DNAVQSM ΔSaO2 measurement. The second group of healthy subjects was asked to get off and then get back on the table between the two scans. All healthy subjects were without self-reported cardiovascular disease or atherosclerosis risk factors.3DNAVQSM was then performed among clinical patients who were being considered for or had undergone invasive catheterization to quantify blood oxygen saturation. Catheterization was performed by experienced physicians using standard techniques; intracardiac blood samples were obtained under baseline conditions  and used to calculate ΔSaO2 between the left and right heart. To test the effect of gadolinium in ΔSaO2 measurement, QSM were obtained in 3 healthy subjects and in 4 patients both pre-contrast and ~ 30 min post-contrast administration.After initial testing, 3DThis study was performed at Weill Cornell Medicine . All participants (controls and patients) provided written informed consent for research participation. This protocol was performed with the approval from the WCM Institutional Review Board.NAVQSM and 2DBHQSM imaging parameters were identical between healthy subjects and patients: 1stTE/ΔTE/#TE/TR/BW = 2.3 ms/3.6 ms/5/20 ms/111.1 kHz, acquisition matrix = 192 × 144, slice thickness = 5 mm, views per heartbeat = 10, parallel imaging factor = 2. Full 3D flow compensation was implemented for both 2DBHQSM and 3DNAVQSM to minimize the phase generated by intra-chamber blood flow [NAVQSM scan time, 75% partial Fourier acquisition was applied in the phase and slice encoding direction. Typical resolution is 1.5 × 1.5x5mm3, 40cm2 FOV, and 20 slices per scan. Furthermore, 2DBHQSM used electrocardiographic (ECG) gating and breath-holding, and 3DNAVQSM used ECG and respiratory gating to ensure the acquisition of data at a consistent cardiac and respiratory phase. QSM was performed using non-contrast CMR in healthy subjects, and at the end of clinical exams in patients, which was approximately ~ 30 min post-gadolinium  infusion. As stated above, in 3 healthy subjects and 4 patients, QSM was acquired both pre- and post-contrast.CMR was performed using commercial 3 T scanners . 3Dood flow . To shorBHQSM employed a conventional ECG-triggered multi-echo gradient echo sequence, for which data was acquired during end-expiration (~ 12 s per breath-hold). 3DNAVQSM employed a tailored ECG-triggered navigator gated multi-echo gradient echo sequence, for which data was acquired during free breathing: a cross pair diaphragmatic navigator was used to track respiratory motion [2Dy motion , 32. A 2y motion . In PAWSo, bandwidth = 781 Hz/Px, resolution: 1.5 × 1.5x6mm3, and SENSE acceleration R = 2, which was acquired in contiguous long and short axis images, the latter of which were segmented to quantify LV end-diastolic and end-systolic chamber volumes for calculation of LV and right ventricular (RV) ejection fraction (EF) as well as stroke volume.Ancillary imaging was performed to test QSM in relation to conventional cardiac functional/ remodeling indices. Cine-CMR was performed using a conventional balanced steady state free precession (bSSFP) pulse sequence with typical parameters: TE = 1.4 ms, TR = 3.8 ms, FA = 60QSM maps were reconstructed by first obtaining a total field map  with the contributions of fat chemical shift removed. This was done using both graph-cut based phase unwrapping  and IDEAw is the signal to noise (SNR) weighting, f is the total field, d is the dipole kernel, * is the convolution operator, P is the preconditioner, λ is the regularization parameter, MG is a binary edge mask constructed by retaining the highest 70% of gradients of the T2*w image obtained by taking the square root of the sum of squares gradient recalled echo (GRE) images across echoes), and ∇ is the gradient operator [P is a binary mask that is 1 inside the region of interest (ROI) and a larger value, Poutside, outside of the ROI (see below). The final QSM map, χ, is then χ = Py∗. The last two terms constrain the susceptibility variation within the RV and the LV blood pools, where λRV and λLV are the regularization parameters, MRV and MLV are the mask for RV and LV obtained through manual segmentation on the GRE images. Poutside = 20, λ = 1/1000, and λRV = λLV = 1/20 were empirically determined in an initial study in healthy subjects via visual inspection of the corresponding QSM, and then fixed for subsequent subjects.The first two terms are the data fidelity term and structure consistency regularization term, respectively, where operator , P is a i in the Gauss-Newton solver, the noise weighting, w, in fat voxels for the next iteration i + 1 was recalculated as ρi = wi|f − d  *Pyi| is the voxel-by-voxel data term residual for the i th iteration, and σi is the standard deviation of ρi over all voxels.To account for potential field errors from water/fat separation, an iterative reweighted least squares fitting method, MERIT , was imp∆χ) was converted to blood oxygenation difference (ΔSaO2) using an established formula [The differential susceptibility between RV and LV blood pools ( formula :2\documχdeoxyheme is the molar susceptibility of deoxyheme such that μmol/ml), where Hct is the hematocrit, Hct was assumed to be 47% in men and 42% in women. These values were obtained by taking the average of the range in men and in women observed in a prior study [Hct data was obtained from peripheral blood samples. Note that the current approach only measures the susceptibility difference between RV and LV blood pools (therefore only measures the oxygen saturation difference between the RV and LV blood pools), bypassing the need to reference the blood susceptibility to a susceptibility reference , which may or may not replicate in-vivo conditions. Post-processing was performed using MATLAB .Where moglobin . \documeor study . For patImage quality (of GRE images) was assessed using two different approaches. Image quality for individual short axis slices (in-plane data) was scored semi-quantitatively based on visually assessed motion artifact/endocardial blurring . Scoring was performed by consensus of three experienced physicians . Through plane image quality was measured quantitatively based on the magnitude of slice misregistration (from both in-plane and through-plane motion), which was measured as the standard deviation of the second derivative along heart surface curves that were obtained from two perpendicular reformatted long-axis images that depict the heart-lung interface : a highe2 and the invasively quantified ΔSaO2, and to test the reproducibility in scans with and without contrast. Two-sided p < 0.05 was deemed indicative of statistical significance. Statistical analyses were performed using MATLAB and Prism 7 .Continuous variables were compared between groups using Student’s t-tests (expressed as mean ± standard deviation). 2D and 3D image quality scores were compared using a two-tailed Wilcoxon paired-sample signed rank test. Pearson correlation coefficients, Deming linear regression , and theNAVQSM and 2DBHQSM were acquired in a cohort of 10 healthy subjects . Whereas in-plane image quality  was higher for 2DBHQSM compared to 3DNAVQSM , through plane image quality tended to be higher (lower slice misregistration) for 3DNAVQSM compared to 2DBHQSM .3DNAVQSM successfully generated interpretable QSM in all 10 healthy subjects, whereas 2DBHQSM was successful in only 6/10 (60%) of cases. Figure NAVQSM despite non-interpretable 2DBHQSM (1A), as well an interpretable QSM dataset concordantly acquired by 2DBHQSM and 3DNAVQSM (1B).3DBHQSM was uninterpretable, failure was due to slice misregistration between sequential LV short axis datasets. Consistent with this, quantitative slice misregistration was over 2-fold higher in cases for which 2DBHQSM failed (n = 4) compared to cases (n = 6) in which 2DBHQSM yielded diagnostic results . There was no significant difference in slice misregistration between 3DNAVQSM and 2DBHQSM in exams for which both sequences were successful .In all cases for which 2DNAVQSM to yield a 30% reduction compared to 2DBHQSM  attributable to the interval time between each breath-hold. Navigator efficiency for 3DNAVQSM was 54 ± 12%. Reduced scan time yielded by 3DNAVQSM remained significant even among controls in whom both pulse sequences produced diagnostic results and acquisitions were reduced by an average of 37% , with navigator efficiency for 3DNAVQSM 56 ± 16%.Regarding data acquisition time, results demonstrated 3DNAVQSM and 2DBHQSM acquired in controls in whom the latter pulse sequence was successful , corresponding to ΔSaO2 of 17.5 ± 3.1% and 14.7 ± 2.0%, respectively. Of note, the RV/LV susceptibility difference (and ΔSaO2) calculated using 3DNAVQSM was not significantly different when compared between controls with and without diagnostic results yielded by 2DBHQSM .Regarding QSM results, mean RV/LV susceptibility difference was not significantly different between 3DNAVQSM  was high, as evidenced by small mean differences (− 0.4%) and reasonable limits of agreement (±2.2%) between data acquired during two separate scans .Reproducibility of 3Dreement ±.2% betweNAVQSM was acquired in 39 patients whose population characteristics are shown in Table 1. In this group, QSM data was successfully obtained in 87% (34/39) of cases. In 5 cases, 3DNAVQSM yielded non-diagnostic results  – all of which had substantial motion artifact. In the remainder of patients (n = 34), RV/LV susceptibility difference calculated using 3DNAVQSM was substantial (298 ± 72 ppb), corresponding to a ΔSaO2 of 24.9 ± 6.1% (p < 0.001 vs. controls). Image acquisition time in the overall clinical cohort was 6.9 ± 2.8 min; increased acquisition time tended to be longer among patients compared to controls  due to greater respiratory variability and lower navigator efficiency in patients (36 ± 12% vs. 54 ± 12%).3D2 on QSM was observed among patients with LV dysfunction (EF < 50%) as quantified by cine-CMR . Similarly, patients in the bottom median of cine-CMR quantified LV stroke volume had greater ΔSaO2 on QSM .Among the overall clinical cohort in whom QSM was successful n = 34), results varied in relation to LV systolic dysfunction as quantified using cine-CMR. As shown in Fig. 4, result2 and increased magnitude of difference in context of LV dysfunction. As shown in Fig. 2 ; corresponding to small bias (− 0.1%) and reasonable limits of agreement (±8.6%) between the two tests  and non-invasive QSM .In a subgroup of 15 patients who had successful QSM, invasive cardiac catheterization (cath) was available as a reference standard for heart chamber oxygenation: all patients underwent catheterization for evaluation of known/suspected heart failure – 47% had LV systolic dysfunction and 53% had primary pulmonary hypertension. Mean interval between tests  was 4 ± 3 days range 0–12 days). Figure  days. FiNAVQSM was obtained successfully in all 7 subjects who were scanned both before and after contrast administration. As shown in Fig. 2 measured from pre- and post-contrast QSM matched very well , with a small bias (− 0.7%), small limits of agreement (±1.9%), and a small mean absolute difference (0.9%).3DNAVQSM had a greater success for interpretable results than did 2DBHQSM (100% vs. 60%) and did so within shorter scan time. Second, 3DNAVQSM performed robustly in a subsequent cohort of 39 patients with established cardiovascular disease, among whom results demonstrated differential LV/RV susceptibility in 87% (34/39) of cases: magnitude of ΔSaO2 differed in relation to LV systolic dysfunction as quantified on cine-CMR, as evidenced by greater ΔSaO2 on QSM among patients with impaired LVEF (< 50%) compared to those with preserved LVEF, and similar results when QSM results were compared in relation to decreased LV function as stratified based on stroke volume. Third, among a subgroup of patients undergoing invasive catheterization, 3DNAVQSM yielded good correlation with invasively quantified ΔSaO2, corresponding to reasonably small bias and limits of agreement  between approaches.This is the first study to test the free breathing 3D cardiac QSM for non-invasive measurement of blood oxygenation, inclusive of validation data provided by cine-CMR quantified cardiac remodeling and invasively quantified oxygen saturation in cardiac patients. Key findings are as follows: first, among a normative test cohort, 3DWhile our data validate cardiac QSM for differential chamber oxygenation, it is important to recognize that prior research has applied different CMR approaches for this purpose. Most previous approaches are based on measurement of blood CMR relaxation times  , 13, 42.2 measured from 3DNAVQSM (17.5 ± 3.1%) was in agreement with a prior study that reported ΔSaO2 in healthy subjects undergoing invasive cardiac catheterization [2 as measured in controls were also lower than that in patients with cardiovascular disease , consistent with expected physiological differences between the two groups. Among our subgroup of patients with cath validation (n = 15), QSM derived ΔSaO2 demonstrated a linear relationship with invasive measurements, and bias between the two oxygenation measurement approaches was small. While our data cannot be interpreted in context of an exact partition value with which to guide clinical decision making, it should be noted that an array of studies have demonstrated prognosis to vary in relation to magnitude of differential oxygen saturations between the left and right heart [2 as a non-invasive risk stratification tool, such that clinically stable patients with normal values would be screened out as low risk, whereas those with elevated QSM derived ΔSaO2 are referred for confirmatory invasive testing.Our QSM results regarding differential LV and RV blood oxygen saturation are consistent with values reported in prior literature as well as expected differences between subjects with and without cardiovascular disease. Regarding control data, ΔSaOrization , in whicAVQSM 17. ± 3.1% w2 measurements agree well between pre- and post-contrast.Note that, in this work, QSM was performed during non-contrast imaging in healthy subjects, and at the end of contrast-enhanced exams (~ 30 min post gadolinium infusion) in patients. Whereas gadolinium changes blood susceptibility, prior data has shown gadolinium to be near completely cleared from myocardium, and to be well mixed in the intravascular space at our imaging time point , 53. AccBHQSM approach generates data by imaging LV (short axis) slices individually via sequential breath-holds in order to reconstruct a 3D field map. When one or more of these breath-holds is acquired at a different respiratory position than the others, the resulting field map will not be a true 3D volume, and the QSM map will contain artifacts as the reconstruction model assumes a continuous 3D dataset as input. The susceptibility inversion problem is inherently 3D, given that susceptibility changes within one region of a given structure (e.g. RV blood pool) affects the field in the surrounding areas in all three  spatial directions: this is because the field is a 3D convolution of the underlying 3D susceptibility distribution with the dipole kernel. The 3DNAVQSM approach has no inherent mis-registration limitation, and the success of 3DNAVQSM acquisition depends on navigator accuracy in motion tracking. These aspects of QSM reconstruction may explain our seemingly discordant finding regarding GRE image quality and diagnostic performance of the two QSM pulse sequences tested in our study: even though GRE images from the 2DBHQSM sequence were assigned higher image scores than images from the 3DNAVQSM sequence, 2DBHQSM failed to generate interpretable QSM more often than did 3DNAVQSM and this failure was primarily attributable to slice mis-registration.One key technical innovation in our current study concerns use of navigator technology for free breathing 3D QSM. The conventional cardiac 2DNAVQSM sequence is long (~ 4–7 min) compared to other routine clinical sequences. One potential approach to shorten scan time is to increase parallel acceleration factor, use compressed sensing [NAVQSM approach is that the respiratory motion is tracked by a diaphragmatic navigator, which is known to occasionally fail [There are several limitations of our study. First, scan time of 3D sensing , 55, and sensing  or echo  sensing . Non-Car sensing  and mult sensing  are alsolly fail . More adlly fail , 61–63. Heart rate could have impacted our QSM results. This has been shown to be the case for oxygenation methods such as BOLD, which relies on the magnitude of the CMR signal. On the other hand, QSM, which relies on the phase of the CMR signal, is expected to be relatively insensitive to heart rate because the contributions to the phase (field) induced by the difference in LV and RV magnetic susceptibility (oxygenation) are not affected by heart rate. Further research is warranted to specifically assess physiologic factors impacting QSM, as well as to validate this pulse sequence in a larger clinical cohort including patients undergoing catheterization for different indications.In conclusion, we provide validation of free breathing 3D cardiac QSM as an index of cine-CMR evidenced LV dysfunction and differential LV/RV oxygen saturation as measured by invasive catheterization. Future research is necessary to test accelerated free-breathing QSM strategies, refine cardiac QSM for myocardial tissue characterization, and validate QSM-derived blood oxygenation for non-invasive stratification of heart failure symptoms and prognostic outcomes.