Conclusion: Breath acetone discriminated HFrEF from other cardiac pathology using a consumer sensor, but was not cardiac specific.Background: Multi-omics delivers more biological insight than targeted investigations. We applied multi-omics to patients with heart failure with reduced ejection fraction (HFrEF). Methods: 46 patients with HFrEF and 20 controls underwent metabolomic profiling, including liquid/gas chromatography mass spectrometry (LC-MS/GC-MS) and solid-phase microextraction (SPME) volatilomics in plasma and urine. HFrEF was defined using left ventricular global longitudinal strain, ejection fraction and NTproBNP. A consumer breath acetone (BrACE) sensor validated results in n = 73. Results: 28 metabolites were identified by GCMS, 35 by LCMS and 4 volatiles by SPME in plasma and urine. Alanine, aspartate and glutamate, citric acid cycle, arginine biosynthesis, glyoxylate and dicarboxylate metabolism were altered in HFrEF. Plasma acetone correlated with NT-proBNP , 2-oxovaleric and cis-aconitic acid, involved with ketone metabolism and mitochondrial energetics. BrACE > 1.5 ppm discriminated HF from other cardiac pathology (AUC 0.8, 95% CI 0.61 to 0.92,  Heart failure is a common heterogeneous condition which carries significant morbidity and mortality. Despite numerous advances in heart failure management, new diagnostic tools and methods of patient stratification are needed to meet the growing demands that heart failure poses on healthcare providers. New tools are required to diagnose heart failure and stratify patients for treatment strategies. Metabolomics is a well-established analytical method, which involves the broad identification and quantitation of hundreds to thousands of metabolites in a single analysis. Metabolomics applied to heart failure has demonstrated its diagnostic superiority to brain natriuretic peptide (BNP) in patients with both reduced and preserved ejection fraction . CellulaMetabolomics can be applied to multiple biological tissues including plasma, urine and even breath, the latter known as volatilomics. Metabolomic profiling of volatile organic compounds (VOCs) in breath is beginning to show promise as a diagnostic tool for heart failure ,8,9. ForA commonly used VOC sensing technique is gas chromatography-mass spectrometry (GC-MS). This technique is sensitive, allowing the identification of individual components of gas mixtures, however, is not necessarily suitable for use in clinical environments given its speed and requirement for pre-processing and storage of samples . Liquid We investigated the utility of metabolomics, multi-omics and deep phenotyping in the interrogation of biological processes occurring in patients with heart failure with reduced ejection fraction (HFrEF). We then translated those findings to investigate the potential utility of a low-cost breath acetone (BrACE) sensor for predicting the presence of HF in both an inpatient and outpatient setting. In addition, we evaluated these methods in identifying novel biomarkers for heart failure and ventricular arrhythmia.The NanoHF study (A Novel Nanosensor array for Heart Failure diagnosis) was approved by the Northern B Health and Disability Ethics Committee (16/NTB/115) (#16/680) and Waitematā District Health Board’s IRB (#RM13458). Patients were identified from an echocardiography database, > 18 years of age, able to provide written informed consent and had previously documented signs and symptoms of heart failure with an ejection fraction between 20 and 45% on echocardiography. Exclusion criteria included diabetes mellitus , chronic renal impairment (eGFR < 50 mL/min), chronic lung disease , and/or hospital admission within 3 months of enrolment related to exacerbation of heart failure. This was because these conditions have been associated with higher levels of serum acetone when compared to controls. Heart failure was defined as a clinical syndrome accompanied by biochemical  or mechanical  < 18%) abnormalities. Enrolment was enriched for patients with devices . Controls were self-reported volunteers who also underwent ECG and echocardiography.The primary objective was to evaluate the ability of a novel breath sensor, optimised to detect acetone, and volatilomics to discriminate VOC patterns of heart failure. The secondary purpose was to explore the biology and validate a metabolomic panel for heart failure.g for 5 min, plasma was stored at −80 °C before being shipped on dry ice to core lab facilities for testing. NT-proBNP was measured using a Siemens Dimension Vista assay.Blood was collected using EDTA tubes. After centrifugation at 3000× dl-alanine-2,3,3,3-d4).Plasma and urine samples underwent thawing, extraction and methyl chloroformate derivatisation, as described previously . Gas ChrA targeted metabolomics approach was used to analyse plasma samples from HFrEF patients and controls. The sample preparation and analysis procedures were performed according to the AbsoluteIDQ p400 kit  using a Thermo Q-Exactive Orbitrap LC-MS. This kit allows the measurement of 400 metabolites by UPLC-MS/MS (ultra-high performance liquid chromatography-tandem mass spectrometry) and FIA-MS . The data analysis and calculation of the metabolite concentrations analysed by FIA were automated using MetIDQ software .200 µL plasma and urine were used for solid-phase microextraction (SPME) volatilomics with a divinylbenzene/carboxen/polydimethylsiloxane fibre assembly. Fused silica Rxi-5Sil MS Columns were used in an Agilent 5975C Series GC/MSD using methods similar to those previously described to identify 73 VOCs . The orit-test for continuous parametric variables, a Mann-Whitney U test for nonparametric and Chi-square test for categorical variables. Receiver-operating characteristic curve (ROC) analysis was used to assess the performance of diagnostic biomarkers by c-statistic. All tests were two-tailed and p < 0.05 was deemed statistically significant, except where tests for multiplicity were applied. Medcalc software version 16.8.4 was used to analyse the data. Machine learning to a validated 4 metabolite panel (1), using logistic regression (LR), random forest, decision tree and support vector machine with a 67:33 training/validation random split with tenfold cross-validation. An interactive network was generated to compare the metadata of patients using a Javascript D3 Force layout using a Pearson correlation matrix.Metaboanalyst was used for pathway and multivariate analysis which was adjusted for multiplicity to reduce the false discovery rate (FDR) . UnivariThree hundred sixty-two patients were screened for inclusion/exclusion criteria. Sixty-six participants  were enrolled in the study, with written informed consent. Baseline characteristics are outlined in 28 metabolites across all diagnostic definitions of heart failure were identified by GCMS which met FDR . NumerouUsing a previously validated panel of metabolites   and LR, t-test, p < 0.05) which have previously been associated with heart failure. These included pentane, 2-butanone, and 2-pentanone.Only one volatile, acetone, reached significance by the stringent FDR used . Howeverp = 0.046). However, in a sample of breathless inpatients (n = 12) with noncardiac pathology, BrACE was 3.2 +/−2.7 ppm (mean/SD) , reflecting increases in ketone body production due to physiological stress  differences in HF patients versus controls in the clinical validation . BrACE had an AUC of 0.8, 95% CI 0.61 to 0.92 for discriminating heart failure in 12 (41%) cardiac outpatients with compensated heart failure . BrACE wl stress .https://projects.interacta.io/theranostics/ (28 January 2021). Plasma acetone correlated with NT-proBNP , triacylglycerol (55:9), 2-oxovaleric and cis-aconitic acid, involved with ketone metabolism and mitochondrial energetics.Metabolites from the citric acid cycle dominated the pathway analysis, with other pathways identified including arginine, alanine, aspartate and glutamate biosynthesis, as well as glyoxylate and dicarboxylate metabolism. Networks showed multiple hubs, including GLS with a high degree of betweenness centrality In this study, we took a multi-omics approach using urinary and plasma metabolomics, volatilomics, biomarkers and DNA sequencing to deeply phenotype patients with HFrEF. Our main objectives were to evaluate the volatilome of patients with heart failure, using plasma and urine as a surrogate for breath, and then validate our results using a widely available breath acetone sensor. We also used untargeted and targeted metabolomics to validate a 4 metabolite panel previously shown to be diagnostic for HFrEF .Acetone was first identified as a potential biomarker in the breath of heart failure patients in 1995 by Kupari et al. . Breath In our study we had intended to validate BrACE using a SWN sensor array, capable of discriminating VOC patterns similar to mass spectrometry; however, the sensor was not ready for clinical use. A previous study by Samara et al, at the Cleveland Clinic, used SIFT-MS  and discriminant analysis, a form of machine learning, to identify a breath fingerprint for heart failure . This inMetabolomics has provided a wealth of information about not only the mechanisms underlying heart failure but also suggested therapies. Ketone bodies, such as acetoacetate and beta-hydroxybutyrate (βOH), are one of the many energy substrates for the heart, inclusive of glucose, branched-chain amino acids and free fatty acids. It is believed that ketone body formation from the liver is an early adaptive response to heart failure. Though debate still exists around whether this is a positive or negative adaptive mechanism a recent knockout model would suggest the former . DeletioIn our study, untargeted GC-MS/LCMS metabolomics revealed several pathways altered in heart failure, with mitochondrial metabolism at the forefront. Although standardisation has been an issue with metabolomics, we have shown a 4-panel metabolite profile, using an LCMS kit, produces a reproducible result, equivalent to the diagnostic capacity of NTproBNP . LCMS idThis study was limited by its small sample size. Moreover, results that were not prespecified can only be considered exploratory. Due to the small sample size controls were not age, gender and race matched with heart failure patients. The GC-MS analysis used an in-house non-quantitative method, which may not be reproducible elsewhere. However, the p400 LCMS kit did provide quantitation on a commonly available, well-validated mass spectrometry platform which has also previously been used in heart failure . Althoug


Atrial fibrillation, the most common cardiac arrhythmia, results in substantial morbidity and mortality related to its increased risks of stroke, heart failure, and impaired cognitive function. The incidence and prevalence of atrial fibrillation in the general population is rising, making atrial fibrillation treatment and management of its risk factors highly relevant clinical targets. One well-studied risk factor for the development of atrial fibrillation is diabetes mellitus. Inhibitors of sodium-glucose cotransporter 2 (SGLT2), common medications used to treat diabetes mellitus, have been observed to decrease the incidence of atrial fibrillation. This review discusses the SGLT2 and its role in glucose homeostasis, molecules inhibiting the transporter, possible physiological mechanisms responsible for the decreased incident atrial fibrillation in patients treated with SGLT2 inhibitors and proposes mechanistic studies to further our understanding of the biological processes involved. Atrial fibrillation (AF) and atrial flutter (AFL) are the most common cardiac arrhythmias afflicting an estimated 59.7 million individuals worldwide in 2019 , 4 and aCurrent pharmacotherapies targeting ion channels to treat AF have their own arrhythmogenic potentials , 11 and In this review, we provide a brief background on SGLT2, its role in glucose homeostasis, molecules inhibiting the transporter, potential mechanistic basis for the apparent protective effects on AF by the inhibitors, and prospective studies to further elucidate responsible mechanisms.+-coupled glucose transporter in S1 segments and a high-affinity Na+-coupled glucose transporter located in S3 segments [+/glucose cotransporter that mediated saturable Na+-dependent and phlorizin-sensitive transport of D-glucose and labeled it SGLT2 to distinguish it from the high-affinity isoform SGLT1. SGLT2 expressed in the S1 segment of the nephron is responsible for approximately 90% of glucose reabsorption with the remainder done by SGLT1 in the S3 segment [The original finding that the glucose filtered and reabsorbed in human kidneys is sensitive to competitive inhibition by a naturally occurring compound called phlorizin  promptedsegments . Kanai esegments  characte segment , 19. The segment  of whichPhlorizin, the prototypical SGLT1/SGLT2 dual inhibitor, while effective in lowering glucose levels in animal and human studies, is not an antidiabetic drug candidate given its poor pharmacodynamic and pharmacokinetic properties , 22. Nonhad a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care [The FDA’s regulatory guidance of 2008 recommended outcome trials to rule out increased cardiovascular risk for all glucose-lowering therapies undergoing evaluation. Surprisingly, in the EMPA-REG OUTCOME trial, patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared to placebo, ard care . This unard care . A multiard care , 30–40 hard care  or heartard care . That thard care –47 with ard care , 49. Anaard care . These rSGLT2 is reportedly located almost exclusively in the epithelium of the renal proximal tubular segment with no detectable expression in the human heart –53. Khem2 increase in body mass index (BMI) was evident in the Women’s Health Study [2 by year 5 no longer had a significantly increased risk of subsequent AF in adjusted analyses in that study. This is substantiated by the observation in the LEGACY study that progressive weight loss has a dose-dependent effect on long-term freedom from AF in obese individuals with symptomatic AF [The association of AF with obesity was recognized in the long-term prospective Framingham Heart Study . A 4.7% th Study . Interesmatic AF . In thismatic AF  and thatmatic AF . The losmatic AF . Dual-enmatic AF  to demonmatic AF .The mechanistic basis for the association of obesity with AF is unclear. Obesity increases epicardial adipose tissue (EAT) mass overlying the posterior left atrium, atrioventricular groove, and infiltrating the atria –64. PhysAtrial fibrillation and congestive heart failure (HF) often coexist, with each condition predisposing to the other . They shEmpagliflozin treatment of individuals with diabetes and established cardiovascular disease produced a rapid and significant improvement in diastolic function . A subseIn patients with cardiac disease, tissue Doppler assessment of ventricular relaxation can be used to assess the effect of left ventricular relaxation in mitral E velocity, and the E/e’ ratio can be applied for the prediction of left ventricular filling pressures , 104 andThe mechanism underlying the acute improvement in left ventricular function by SGLT2 inhibitors is unclear. The effect of empagliflozin is thought to result from osmotic diuresis with electrolyte-free water excretion leading to immediate cardiac preload reduction, suggested by reduced early mitral inflow velocity E . A matheper se does not affect the rate of new-onset AF [The relationship between type 2 diabetes and new-onset AF is well documented . A meta-onset AF .Similarly, on a population level, elevated blood pressure is a risk factor for incident AF. A 20-mmHg increase in systolic blood pressure is associated with 21% higher risk of AF . Intensi+-binding site of the NHE [+ concentration. This is expected to activate the reverse mode of the Na+/Ca++ exchanger to increase intracellular Ca++, cause Ca++ overload, induce atrial electrical remodeling, and predispose to AF. Inhibition of the NHE in such a situation would be expected to interrupt this sequence of events and inhibit AF [As discussed earlier, SGLT2 is located almost exclusively in the epithelium of the renal proximal tubular segment with no detectable expression in the human heart –53. Howe the NHE , suggest the NHE , 132. Ithibit AF . Howeverhibit AF  reportedhibit AF  observedhibit AF . Thus, tShao et al.  have posThe post hoc analysis of the DECLARE-TIMI 58 trial indicating decreased incidence of AF in high-risk patients with type 2 diabetes treated with dapagliflozin  is hypotSGLT2 inhibitors elicit pleotropic effects. It is critical to identify the principal driver of the drug-mediated reduction in incident AF. Delineation of the beneficial structural and functional changes in various organ systems relevant to AF pathogenesis as highlighted in this review will facilitate subsequent investigations of the molecular basis for the beneficial effects of the drugs on AF.Comparative proteomic analysis of EAT samples biopsied before and after drug treatment may yield insights to specific effects on pathways related to inflammation, fibrosis, apoptosis, arrhythmogenesis, etc. Inflammatory cytokines such as TNF-α, IL-1, IL-6 directly modulate the function of cardiac ion channels to promote arrhythmia . For insStretch of the pulmonary veins triggers arrhythmia as discussed earlier. Elevated left atrial pressure resulting from left ventricular diastolic dysfunction is transmitted to the pulmonary veins given the anatomical continuity between the two. This leads to increased pulmonary vein volume and dilated vein orifices  and is pMechanistic studies with SGLT2 inhibitors may be supported by analysis of circulating biomarkers or fibrosis including type I procollagen C-terminal propeptide (a marker of collagen type 1 synthesis), type III collagen N-terminal propeptide (a marker of collagen type 3 synthesis), , 146 andThe post hoc analysis of the DECLARE-TIMI 58 trial demonstrated a reduction in AF incidence in diabetes mellitus patients treated with SGLT2 inhibitors. The mechanism for this reduction in AF is unknown. Possible mechanisms for the SGLT2 inhibitor-induced reduction in incident AF include reduction in epicardial fat inhibiting pathological atrial remodeling and rapid improvement in left ventricular diastolic function ameliorating hemodynamic stress on the atrium and pulmonary veins. Off-target interactions by the drugs potentially mitigating cardiomyocyte ionic imbalance and ameliorating oxidative stress-induced mitochondrial dysfunction are ancillary mechanisms worth exploring as well. Given the modest reductions in hemoglobin A1c and blood pressure in patients treated with SGLT2 inhibitors, these are unlikely to be predominant mechanisms by which SGLT2 inhibitors reduce AF. Biochemical, functional, and structural studies as highlighted in this review will further help elucidate the mechanistic bases for the observed beneficial effects of SGLT2 inhibitors on incident AF.


Loeffler-endocarditis (LE) is considered a chronic restrictive cardiomyopathy and manifestation of eosinophilic myocarditis characterized by eosinophilic infiltration. LE is a rare underdiagnosed disease and associated with high morbidity and mortality.We report a case of a 46-year-old man suffering from LE associated with thromboembolic events without peripheral eosinophilia. The patient presented with typical clinical signs of acute onset of limb ischaemia, predominantly on the right limb, indicating immediate iliacal thrombectomy and due to a severe compartment syndrome additional fasciotomy. Total occlusion also of left popliteal artery suggesting an impaired chronic and aggravated impaired perfusion indicated also urgent left sided revascularization. Subsequent echocardiography revealed severe left ventricular dysfunction with a striking amount of spontaneous echo-contrast, noticeable in the left ventricular cavity. Furthermore the initial CT scan demonstrated asymptomatic left kidney- and brain infarctions. Diagnostic workup including endomyocardial biopsy (EMB) of the left ventricle, uncovered an underlying LE without peripheral eosinophilia.This case demonstrates and highlights the findings, treatment and outcome of a patient with LE and associated thrombo-embolic events without peripheral eosinophilia and emphazises the importance of awareness for LE in patients presenting with an acute cardiac decompensation and thrombo-embolic events. EMB should be performed early in unstable patients unsuitable for cardiovascular magnetic resonance imaging.The online version contains supplementary material available at 10.1186/s12872-022-02911-3. Endocarditis parietalis fibroplastica or Loeffler-endocarditis (LE) is a rare, underdiagnosed idiopathic systemic disease, first described in 1936 –5. In paA 46 years old, previously healthy man presented with typical clinical signs of acute onset of limb ischemia , predominantly on the right limb. An emergency contrast enhanced computed tomography (CT) scan of the complete aorta to thighs was performed, based on the initial suspicion of an aortic dissection. An aortic dissection however was ruled out. Main findings were a complete occlusion of the distal right common-, the right external- and internal iliac artery and common femoral artery. Furthermore, an occlusion of the left profound femoral artery and mild arteriosclerosis was found, the occluded vessel segments however were characterized by hypodense thrombotic material Fig. . The CT After the patient had gone through a SARS CoV2 infection he was finally discharged from hospital free of symptoms 8 weeks after admission. Last follow-up echocardiography revealed an unchanged LV dysfunction with an estimated ejection fraction of 34%, associated moderate LV hypertrophy and decreasing spontaneous echo contrast. Heart failure medication in combination with anticoagulation and continued immunosuppressive therapy including prednisolone and azathioprine was continued. The patient was equipted with a LifeVest® as wearable cardioverter defibrillator to protect patients at risk of sudden cardiac death.To our knowledge, this is the first report of multiple thrombo-embolic events in a patient with LE without peripheral eosinophilia. It provides new information on the natural history of this rare but clinically relevant disease.In LE cardiac involvement with migration of eosinophils into the myocardium follows a stepwise pattern from subclinical acute necrosis of the myocardium , thromboNoninvasive multimodality imaging, including transthoracic- and transesophageal echocardiography as the mainstay of diagnostic imaging and surveillance for LE could, in our case, not provide classic findings as LV wall thickness, valvulopathy or LV thrombus , 10, 18.A beneficial effect of immunosuppressive therapy with prednisone and azathioprine with significant improvement of LV function and decrease of LV dimensions was first shown in a randomized placebo-controlled study by Frustaci et al. in 2009 . In the The goal of recommended medical therapy in LE, including heart failure management and anticoagulation if presence of an intracardiac thrombus, is a decrease of eosinophil-mediated end-organ damage and prevent adverse thrombotic events , 16, 28.Decision for premature implantable cardioverter defibrillator system remain challenging in patients with impaired LV function (ejection fraction ≤ 35%), but should be avoided in patients with inflammatory cardiomyopathy as LV function may improve significantly with guideline-based heart failure therapy . Close sIn conclusion, LE without evidence of peripheral eosinophilia and absence of intracardiac thrombus formation, as demonstrated in this unique patient report, can be associated with life-threatening systemic thrombo-embolic events. Our case highlights the importance of considering LE as an important differential diagnosis in the setting of an acute cardiac syndrome in combination with thrombo-embolic events and helps to identify characteristic features found in patients with LE.early multimodality imaging including transesophageal echocardiography and if possible CMR imaging to explore not only the presence of an LV thrombus but also possible spontaneous echo-contrast to consider immediate anticoagulation aiming to prevent thrombo-embolic eventsEMB should be performed early in patients with severely impaired LV dysfunction of unknown etiologyImmunosuppressive therapy should be initiated promptly in a patient with proven LEFor strategic recommendation based on the experience in our particular case, we suggest in a patient suspicious for LE the following take-home messages:Additional file 1: Video 1. Transesophageal echocardiography showing severe systolic LV dysfunction and a striking amount of spontaneous echo contrast but no evidence of LV thrombus in a 3-chamber view (video clip).


An optimal threshold of 5.0% was obtained for LGE with 87% sensitivity and 48% specificity; the positive likelihood ratio (LR) was 1.67, and the negative LR was 0.27. Edema was 12.8% (9.4–18.1%) at the acute phase, 7.3% (5.5–8.8%) at follow-up, and 6.7% (5.6–8.6%) in controls, the acute phase being higher than both follow-up and controls (both p < 0.001), while follow-up and controls did not differ (p = 0.900). An optimal threshold of 9.5% was obtained for edema with a sensitivity of 76% and a specificity of 88%; the positive LR was 6.33, and the negative LR was 0.27. LGE and edema thresholds are useful in cases of suspected mild myocarditis.In this study, we aimed to quantify LGE and edema at short-tau inversion recovery sequences on cardiac magnetic resonance (CMR) in patients with myocarditis. We retrospectively evaluated CMR examinations performed during the acute phase and at follow-up. Forty-seven patients were eligible for retrospective LGE assessment, and, among them, twenty-five patients were eligible for edema evaluation. Both groups were paired with age- and sex-matched controls. The median left ventricle LGE was 6.4% (interquartile range 5.0–9.2%) at the acute phase, 4.4% (3.3–7.2%) at follow-up, and 4.3% (3.0–5.3%) in controls, the acute phase being higher than both follow-up and controls ( Myocarditis is an inflammatory disease of the myocardium, defined by histological and immunohistochemical criteria ,2,3. ItsThe reference standard for the diagnosis of myocarditis is an endomyocardial biopsy. However, it is rarely performed due to its risks, which makes it inadvisable in patients with mild, low-risk disease ,3,12. InCMR diagnosis of myocarditis is currently based on the Lake Louise criteria , which sLake Louise criteria have, so far, been assessed only visually, meaning edema and LGE are not quantified in clinical practice. Indeed, while qualitative differences can be appreciated between myocarditis patients and healthy individuals, no quantitative variation has been determined, and no diagnostic thresholds for quantitative scoring are currently available.Thus, the aim of our study was to analyze and quantify edema and LGE in myocarditis patients both at the acute phase and follow-up as well as in controls, in order to establish quantitative thresholds for such parameters, under the hypothesis of significantly higher values of those biomarkers in myocarditis patients. This would allow for a more accurate diagnostic interpretation, particularly for uncertain cases.The local Ethics Committee approved this retrospective study . This study was partially supported by Ricerca Corrente funding from the Italian Ministry of Health to IRCCS Policlinico San Donato. This research received no specific grant from any public funding agency or the commercial or non-profit sectors. Due to the retrospective nature of this study, specific, informed consent was waived. All CMR examinations included in this study were performed at our institution between September 2008 and March 2017. Patients were selected for clinical suspicion of myocarditis, represented by the presence of cardiac signs or symptoms (such as hypotension or syncope), biomarkers (troponin elevation), changes in electrocardiographic pattern  radiologist’s report.Inclusion criteria for edema in myocarditis patients were the presence of one CMR examination at the acute phase and one at follow-up, both comprising turbo inversion recovery magnitude sequences. We also included CMRs of age- and sex-matched controls, who were to have a CMR examination that was deemed negative by an expert radiologist’s report.Before September 2014, CMR was performed with a 1.5-T unit  with 40-mT/m gradient power and a 4-channel surface phased-array coil; after September 2014, CMR was performed with another 1.5-T unit , with 45-mT/m gradient power and an 18-channel surface phased-array coil. Coils were placed over the thorax of patients in the supine position. Prospective gating was always applied to the electrocardiographic signal.On both machines, for LGE evaluation, short-axis sequences were acquired 5–15 min after injecting 0.1–0.15 mmol/kg of gadobutrol . While the echo time (TE) was 3.33 ms, the repetition time (TR) was adapted to the heart rate, the inversion time was chosen from 260 to 330 ms to better differentiate the myocardium, and the flip angle was 25°. For the evaluation of myocardial edema, T2-weighted short-axis short-tau inversion recovery (STIR) sequences, with patient-dependent TR and TE, an inversion time of 150 ms, and a flip angle of 180° were used. Cine sequences were bright-blood steady-state free precession sequences, with a TE of 1.40 ms, TR of 48.30 ms, and a flip angle of 60°. STIR sequences were always run before administering contrast, while cine sequences were run after contrast administration. An 8-mm slice thickness was always chosen.For image analysis, the QMass post-processing tool  was used. Cine sequences were manually bordered to obtain left ventricle functional data such as end-diastolic volume index, end-systolic volume index, stroke volume, and ejection fraction. Short-axis turbo inversion recovery magnitude sequences were also manually bordered; a threshold of 2 standard deviations (SD) was used to identify edema. Short-axis LGE sequences were manually bordered, and a 6-SD threshold was used to identify enhanced areas. Image analysis for edema was performed twice by one reader and once by a different reader. An example of automatic LGE and edema quantification can be viewed in After data collection and analysis, a diagnostic algorithm for myocarditis was hypothesized for patients with LGE and edema data. The LGE and edema of patients were assessed, and when the two parameters were concordant , the diagnosis of myocarditis was either finalized or excluded. When the LGE and edema were discordant, a visual assessment was performed to discern whether the two phenomena were anatomically related. If there was at least one area where edema and LGE were concomitantly present, the criterion was deemed positive; otherwise, it was regarded as negative because an aberrant quantification of one of the two parameters could have been due to faults in automatic tissue characterization. The criterion was tested by each reader with their edema data.Data were reported as median with their interquartile range (IQR). Differences were investigated for significance with non-parametric tests, either with the Wilcoxon test when paired or the Mann-Whitney U test when independent. ROC analysis was performed for edema and LGE data comparing the acute phase to controls to set thresholds and evaluate their sensitivity and specificity. A diagnosis of myocarditis, based on a clinical suspicion of myocarditis represented by the presence of cardiac signs or symptoms or rise of cardiac biomarkers in the absence of other cardiac pathologies, and a CMR examination, positive according to the Lake Louise criteria, was used as ground truth for ROC analysis. Thresholds maximizing sensitivity and specificity  were chosen. Positive and negative likelihood ratios were calculated. The reproducibility of the diagnostic criterion was assessed through Bland-Altman analysis and reported as bias and its coefficient of repeatability (CoR). Concordance of the diagnostic criteria was assessed through Cohen’s κ.p-value < 0.05, the null hypothesis was rejected.Statistical analysis was performed using SPSS v.17.0 . Whenever a statistical test yielded a From a total of 96 patients with suspected myocarditis and a CMR examination performed between September 2008 and March 2017 retrieved from our database, 47 were eligible for the LGE study, of which 25 were eligible for the edema study according to the inclusion and exclusion criteria, as shown in p = 0.868). Four patient acquisitions were performed on Magnetom Sonata, 41 were performed on Magnetom Aera, and controls were paired accordingly.Results for LGE are shown in No significant differences were found in the end-diastolic volume index, end-systolic volume index, stroke volume, and ejection fraction among acute phase patients, follow-up patients, and controls.p < 0.001) as well as between the acute phase and controls (p < 0.001), while the difference between follow-up and controls was not significant (p = 0.139).The left ventricle LGE percentages were 6.4% (IQR 5.0–9.2%) at the acute phase, 4.4% (IQR 3.3–7.2%) at follow-up, and 4.3% (IQR 3.0–5.3%) in controls. Significant differences could be found between the acute phase and follow-up .Edema data is shown in No significant differences were found within the end-diastolic volume index, end-systolic volume index, stroke volume, and ejection fraction among acute phase patients, follow-up patients, and controls.p < 0.001 for both), while the difference between follow-up and controls was not significant (p = 0.900).Left ventricle edema percentages were 12.8% (IQR 9.4–18.1%) at the acute phase, 7.3% (IQR 5.5–8.8%) at follow-up, and 6.7% (IQR 5.6–8.6%) in controls. Significant differences were found between the acute phase and follow-up or controls , while inter-reader Cohen’s κ was 0.766 (p < 0.001).The application of the proposed diagnostic criteria showed 24 true positives, 22 true negatives, 4 false positives, and 4 false negatives, leading to a sensitivity of 92% and a specificity of 85%, with a positive likelihood ratio of 6.00 and a negative likelihood ratio of 0.09. Intra-reader Cohen’s κ was 1.000  but low specificity (48%). Indeed, minimal LGE appears most commonly as a thin, subepicardial line, easily mistaken for adipose tissue, that the software cannot assess with sufficient accuracy, resulting in a falsely negative assessment . This meRegarding edema analysis, there were no significant differences between the left ventricular functional parameters of patients and controls, which is consistent with the age-matching we performed. The left ventricular ejection fraction of patients was well within the normality range, meaning that patients had mild disease without severe impairment of cardiac function. This was expected since such patients were at low risk, with no hemodynamic compromise or heart failure.The significant differences in edema observed between the acute phase and follow-up or controls may prove that edema, representing acute inflammation, is higher during the onset and initial stages of myocarditis, while it tends to reduce at follow-up. The ROC curve obtained from edema data of acute-phase patients and controls has a good area under the curve, resulting in an acceptable value of sensitivity (76%) and a high value of specificity (88%). The positive likelihood ratio for (6.33) edema suggests that it could be used to finalize a diagnosis of myocarditis, with a high increase in disease probability when edema tests positive. The negative likelihood ratio for edema (0.27) suggests that it would yield an adequate performance when excluding myocarditis, equal to that of LGE. Therefore, myocardial edema could be used as a quantitative biomarker to be added to visual assessment. Moreover, for quantification of edema, it is notable that the percentage of myocardial volume attributable to edema in controls (median 6.7%) was not significantly different from that of low-risk myocarditis at follow-up (median 7.3%). This finding can be explained by the fact that inflammation is expected to recede in the time intercurrent between the acute phase and follow-up and null at follow-up. The presence of some degree of edema detected in the controls is likely due to signal inhomogeneities or artifacts , which aThe proposed quantitative diagnostic criterion for myocarditis provides both high sensitivity (92%) and high specificity (85%), with good positive and negative likelihood ratios (6.00 and 0.09 respectively), therefore, bearing a higher sensitivity than a visual assessment of edema and LGE as a part of Lake Louise Criteria , with only a slightly lower specificity . TherefoOur study had some limitations, the first being its retrospective nature. Moreover, it was monocentric, meaning the results are in relation to the magnetic resonance units used on our population and to the chosen sequences, technical parameters, and the type and dosage of contrast material. In addition, our subjects were studied using two different 1.5-T magnetic resonance units and coils. Further studies should be conducted to confirm our results, especially in terms of diagnostic thresholds.In conclusion, the results of our study show that quantitative thresholds for LGE and edema can be defined for helping in ruling in and ruling out myocarditis to be primarily used when visual assessment is inconclusive.


Here we describe our technique and results of beating heart pulmonary thromboendarterectomy (PTE) with cardiopulmonary bypass (CPB) in four patients for treatment of chronic thromboembolic pulmonary hypertension (CTEPH).Retrospective analysis of data from patients who underwent PTE for CTEPH between January 2019 and September 2020. Patients were followed up with clinical assessment, 2D echocardiography, and computed tomography pulmonary angiogram.vs. 16 mm), and improved postoperative oxygen saturations (88.5% vs. 99%). In follow-up (ranging between 2-15 months), all patients reported improvement in quality of life and were in New York Heart Association class I.Four patients were operated for CTEPH using our technique. Moderate tricuspid regurgitation (TR) and severe TR were found in two patients each. Severe right ventricular (RV) dysfunction was found in all cases. Thrombi were classified as Jamieson type II in three cases and type I in one case. Postoperative median direct manometric pulmonary artery (PA) pressures decreased (from 46.5 mmHg to 23.5 mmHg), median CPB time was 126 minutes, and median temperature was 33.35 °C. Mechanical ventilation was for a median of 19.5 hours. There was one re-exploration. Median intensive care unit stay was 7.5 days. There was no mortality. Postoperative 2D echocardiography revealed decrease in median PA systolic pressures (from 85 mmHg to 33 mmHg), improvement in RV function by tricuspid annular plane systolic excursion (median 14 mm With our described simple modifications, advances in perfusion, and blood conservation technologies, one can avoid the need for deep hypothermic circulatory arrest during PTE. In this technique, a bloodless field is essential, and deep hypothermic circulatory arrest (DHCA) has been the preferred method to extract the pulmonary thrombus beyond the sublobar levels. However, DHCA is not devoid of its adverse effects which mainly include neurologic deficits,3, renal dysfunction,5, and bleeding. In pursuit to control the troublesome back bleeding from the bronchial vessels and collaterals without the use of DHCA, several methods have been described to achieve complete thromboendarterectomy. Here, we describe our technique and modifications needed for PTE on beating heart cardiopulmonary bypass (CPB) with mild hypothermia on four patients.Pulmonary thromboendarterectomy (PTE) is the definitive surgical treatment for chronic thromboembolic pulmonary hypertension (CTEPH)As this was a retrospective case series, ethical clearance was waived off. Retrospective data of patients who underwent beating heart PTE from January 2019 to September 2020 at the Department of Cardiothoracic and Vascular Surgery, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences , were collected, and the operative records were reviewed. This study included four patients. Written and informed consent was taken. The patients were followed up with clinical assessment, investigations like transthoracic 2D echocardiography (2D echo) and computed tomography pulmonary angiogram (CTPA) were performed, and the data was collected.Inclusion criteria were patients reporting to/referred to our department with: (a) New York Heart Association Functional Classification (NYHA) class III & IV symptoms, (b) thrombus in main, lobar, or segmental pulmonary arteries (PA) as seen in CTPA, (c) no debilitating comorbidities, and (d) 2D echo evidence of right ventricular (RV) dysfunction. All patients with acute pulmonary embolism did not fit to undergo CPB, and those for emergency pulmonary embolectomy were excluded.2), CPB time, location of thrombus as described by Jamieson’s classification as well as University of California San Diego (UCSD) surgical classification, postoperative course, and any postoperative complications were studied.Demographic variables, pulmonary artery pressure (PAP) , RV dysfunction as measured by tricuspid annular plane systolic excursion (TAPSE) on 2D echo, central venous pressure (CVP), oxygen saturation (SpO2 were measured before and after PTE.Pulmonary artery systolic pressure (PASP) was measured by pre- and postoperative echocardiogram. PAP was measured intraoperatively before and after PTE by direct needle manometry of main pulmonary artery (MPA). CVP and SpOAnesthesia was induced by intravenous administration of morphine, fentanyl, and vecuronium and maintained with intravenously administered propofol and inhalation of isoflurane. Monitoring was done by a radial artery line, central venous line, electrocardiography, nasopharyngeal and rectal thermometer, and transesophageal echocardiography. The heart rate was regulated to 60-70 beats per minute by boluses of beta blocker metoprolol.2. A high-pressure external sucker attached to the cell saver is used to connect an olive tip sucker, which is used as a dissector. The α-stat strategy of pH management is employed.Standard CPB circuit with St. Thomas II cardioplegia on standby and a cell saver  is established. An aortic cannula and two straight venous cannulae for bicaval cannulation of appropriate size are used. Four pump suction lines are readied for a free cardiotomy sucker, vent sucker of the right superior pulmonary vein (RSPV), right ventricle, and either of the PAs  and 2. ATwo DeBakey vascular forceps (23 cm length), two ventricular septal defect retractors (23 cm length), one olive tip sucker connected to cell saver, a mastoid retractor with rubber inserts on blade tips, and a vascular clamp (straight or angled) are required .The operation is performed via a median sternotomy. After an inverted T pericardiotomy and attachment to the wound edges, direct pressure manometry by puncturing MPA is done. The superior vena cava (SVC) is looped and mobilized by cautery dissection. Mobilization of the branch PA is done intrapericardially, and none of the pleurae are opened. The aorta is looped with a vessel loop for better visualization  and 2.CPB is established by cannulating the ascending aorta and both caval veins after achieving an activated clotting time of > 480 seconds with heparinization (300 U/kg).A straight cannula in the SVC is guided high, near to the convergence of the innominate vein via the right atrial appendage, and snared. This method of cannulation further helps in proximal mobilization of the SVC. The inferior vena cava is cannulated and snared. An antegrade aortic root cardioplegia needle is inserted should the need for DHCA arise.A vent catheter is introduced into the RSPV. The left pulmonary artery (LPA) is then dissected beyond the origin of the upper lobe artery with careful preservation of the left phrenic nerve. A small arteriotomy is made in the right pulmonary artery (RPA) just right to the aorta, and a vent catheter is introduced into it and snared. Ventilation is then stopped.With the surgeon standing on the right side of the patient, an incision is then made in the MPA and is extended into the LPA beyond the origin of the upper lobe artery. Stay sutures are taken and the arteriotomy is exposed. A sump sucker is introduced into the right ventricle via the pulmonary valve and snared through the MPA wall. If bleeding from the RPA obscure the field of view, a vascular clamp may be applied upstream to the RPA vent.Any fresh or loose clots are removed for visualization of the chronic thrombus. Thromboendoarterectomy then commences with creation of the correct plane in the media. The correct plane appears as a smooth pearly white structure which is amenable to peeling with controlled traction, countertraction, and a sweeping motion of the olive tipped sucker . The freMeanwhile, the blood collected from the cell saver is then transferred to the cardiotomy reservoir. In the endarterectomy of the sublobar branches, traction and dissection of the thrombus evert the media, and this may risk perforation of the PA. One should gently extract the thrombus which should come out spontaneously with its tapered tail .After the endarterectomy, gentle positive pressure ventilation is initiated by the anesthetist to check for breach of PA wall which appears as air bubbles in the operating field. Brisk bright red back bleeding is an indirect sign of clearance from the endarterectomized segment.For final confirmation, an endoscope  is inserted into the LPA and clearance is confirmed in each segment with the olive tipped sucker clearing the bronchial back bleed. The thrombus extracted is examined in toto to confirm complete PTE in all segments.The RPA clamp is removed, and the incision is then extended from the vent insertion site to the right lower lobe branch just after the takeoff of the middle lobe artery. Visualization of the RPA tree is partially obscured due to the SVC running above it. Here, the modified mastoid retractor is applied between the SVC and aorta for better visualization of the pulmonary arterial tree. Alternatively, the SVC can also be retracted to the left for better viewing of the descending lobar branches. The dissection is carried out and the steps are analogous to the left as described.Upon completion, the pulmonary arteriotomies are closed in two layers with 5-0 polypropylene sutures. The patient is then weaned off CPB; direct PA pressure manometry is done, and chest is closed after heparinization reversal and hemostasis.A total of four patients were operated for CTEPH from January 2019 to September 2020. Patient preoperative data is presented in . As per the UCSD surgical classification, the thrombi were classified as class I in all cases with one case having complete occlusion of the LPA (IC left)  . Post PTIC left) . The medIC left) .Patients postoperatively received mechanical ventilation for a median of 9.5 hours . There w2 also showed improvement (88.5% vs. 99%). Postoperatively, over a follow-up ranging between 2-15 months, all patients reported improvement in their quality of life and were in NYHA class I . Improvement in RV function was derived by TAPSE on 2D echo (median: 14 mm vs. 16 mm) . Median  class I . There w. From its evolution of embolectomy to the current standard thromboendarterectomy, it cannot be over emphasized that complete clearance of the organized thrombus in the correct plane is vital for good outcomes. Utley et al. emphasized that circulatory arrest was absolutely essential for distal segmental vessel thromboendarterectomy because of the increased bronchial circulation.PTE is the definitive treatment of CTEPH-6. However, different strategies to avoid the side effects of DHCA, to obtain a relatively bloodless field, and to decrease operating time have been described.The use of DHCA and the adverse effects have been extensively described in literature for the conduct of PTE.In our procedure, we use four pump suckers and one external sucker connected to cell saver which helps us in obtaining a bloodless field. DHCA and its potential complications are thus avoided. Balloon catheter occlusion of the descending aorta to obtain a bloodless field as described by Hagl with the abovementioned setup was not needed,10. As the procedure is conducted on beating heart with CPB support, we negate the need of complex cannulation of the aortic arch vessels for selective antegrade cerebral perfusion for PTE-13. Our method of PTE differs from the method described by Mikus et al. in the fact that we use extensive venting of the left atrium via the RSPV, the right ventricle, the contralateral PA, and do not arrest the heart. We, however, follow a strategy of blood conservation similar to the described by the author by using a negative suction dissector connected to a cell saver. We also differ from the technique described by Bisoi et al. because we vent the RSPV and do not transect the SVC.In our modifications for performing PTE on beating heart with CPB, we avoid division of the great vessels without compromising clearance, thereby minimizing vascular traumaIn our series, the hospital stay was prolonged because we are located in a remote area with poor patient compliance on follow-up. Our low-cost modifications for the conduct of PTE in this resource poor region are unique because of the use of mild hypothermia, the avoidance of cardioplegic arrest, avoidance of transection of the great vessels, and the ability to obtain a relatively bloodless field using external negative suction. The thorough checking of clearance the endarterectomized field by an endoscope also ensures that we can address remaining thrombus burden in the same setting.This study has its limitations. First, it was a retrospective analysis covering a 20-month period. Second, small sample size is a limiting factor to gain significant results. However, we believe this study may provide some useful information for the surgical management of CTEPH patientsThe definitive treatment of chronic pulmonary hypertension is the complete evacuation of the thrombus load in the pulmonary vascular tree. Thromboendarterectomy under DHCA has been the most commonly technique employed to omit bronchial back bleed. Advances in perfusion, blood conservation, and our described modifications can make it possible to avoid circulatory arrest. However, the superiority of our technique cannot be established in view of the small number of cases.


It decreases heart rate with minimal effect on blood pressure or inotropy, making it an attractive agent with an overall low side effect profile. The use of ivabradine in the pediatric population is limited, with current approvals only for dilated cardiomyopathy patients.2/dose every 8 hours on postoperative day (POD) 7. She continued with hemodynamically compromising periods of EAT, prompting discontinuation of sotalol and initiation of an amiodarone infusion at 7 mcg/kg/min on POD 10. She continued to have breakthrough EAT requiring as-needed amiodarone boluses, and enteral propranolol at 1 mg/kg/day divided every 6 hours was started on POD 11, which lowered baseline heart rates from the 130–150 bpm range to 110–120 bpm range. The amiodarone infusion was subsequently reduced to 3.5 mcg/kg/min on POD 12 for continued maintenance dosing. By POD 15, she was noted to have profound hypoxic and bradycardic events during ventilator weaning trials. Although acute hypoxemia appeared to be the proximate cause of episodic heart rate decreases, propranolol lowered her baseline heart rate such that further bradycardia was poorly tolerated from a hemodynamic perspective. As such, propranolol was discontinued.Our patient was born at 37 6/7 weeks’ gestation with hypoplastic left heart syndrome  and severe tricuspid valve regurgitation owing to incomplete coaptation of the tricuspid valve leaflets. Her birth weight was 3.3 kg. She underwent stage 1 palliation with Norwood procedure and Sano shunt at 4 days of life. She developed multifocal EAT within the first days of life and was initially loaded with digoxin 16 mcg/kg the day prior to Norwood-Sano. No pacing wires were placed at the time of her Norwood procedure. Postoperatively, she was continued on parenteral digoxin 3 mcg/kg twice daily. She had breakthrough runs of EAT with rates up to 220 beats per minute (bpm), resulting in hemodynamic instability , promptiAt POD 18 she developed refractory EAT, which did not respond to 10 (1 mg/kg) boluses of amiodarone, nor to an increase in amiodarone infusion to 7.5 mcg/kg/min. An esmolol infusion was not tolerated owing to hypotension. She became hemodynamically unstable, with mean arterial pressures as low as 20 mm Hg during EAT. In response, a procainamide bolus at 15 mg/kg was given, with resultant conversion to normal sinus rhythm; a procainamide infusion was started at 40 mcg/kg/min; and amiodarone was discontinued. The procainamide drip was titrated to serum procainamide concentrations of 10–12 mg/mL and N-acetyl procainamide (NAPA) concentrations of 10–13 mg/mL. Serial electrocardiograms were followed and QRS and QTc duration remained <20% prolonged compared to her baseline. While on the procainamide drip, she had initial rhythm control, and intermittent bouts of EAT were addressed with adjustments to the procainamide infusion and trials of esmolol infusion. However, as before, esmolol use was limited owing to associated hypotension with escalation of the medication. Frequent electrocardiograms were obtained throughout this time to monitor the QTc interval, given overlap in use of several antiarrhythmics with no significant QTc prolongation. She had a period of clinical stability on this regimen, but on POD 37 had recurrence of EAT, requiring initiation of an esmolol infusion up to 250 mcg/kg/min.Owing to the severity of her tricuspid valve regurgitation with resultant severe right atrial dilatation as a likely contributing mechanism for her incessant EAT in conjunction with worsening heart failure, it was recommended she undergo tricuspid valve repair . This waDespite improvement in her arrhythmia management, with chest closure her overall care became complicated by challenging hemodynamics owing to AV valve regurgitation and elevated filling pressures. She developed chylous ascites, resultant fluid and electrolyte derangements, protein loss, coagulopathy, hypogammaglobulinemia, and occlusion of the superior vena cava. Transient episodes of breakthrough atrial ectopy in the form of isolated premature atrial contractions and runs of EAT occurred. The ivabradine alone could not control the atrial arrhythmias with the added hemodynamic stress. Procainamide and esmolol were reinitiated in an attempt to gain better control of EAT . The pat,,f current owing to sodium and potassium ions entering the cell in response to hyperpolarization. This controls the automatic slow diastolic depolarization of the cells in the sinoatrial node and thus controls heart rate. Inhibition of HCN by ivabradine results in a decreased rate of the slow diastolic depolarization phase and lowers heart rate.Ivabradine, an inhibitor of the HCN channels, is currently approved for use in adult patients with heart failure and also used in chronic stable angina, inappropriate sinus tachycardia, and postural orthostatic tachycardia syndrome.,,,,Given its ability to slow heart rate, the use of ivabradine has been reported in various tachydysrhythmias, specifically those due to enhanced automaticity, with promising results. Several case reports and series have shown ivabradine to be beneficial in the management of atrial tachycardia in adolescent and adult patients.,EAT, a form of supraventricular tachycardia due to automaticity, can be seen both in pediatric patients with structurally normal hearts and in those with other forms of CHD. Arrhythmias including EAT following surgery for CHD are a concern in the postoperative period, as they can exacerbate an already delicate hemodynamic state with the potential to worsen cardiac output. Risk factors for the development of EAT in the postoperative period following surgery for CHD include lower weight, single-ventricle physiology, longer cardiopulmonary bypass time, The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) category, delayed sternal closure, age at surgery, use of milrinone, low serum potassium levels, and atrial trauma.,Given the automatic nature of EAT, some authors have reported use of ivabradine for this dysrhythmia in patients with structurally normal hearts.Physicians should be aware of chronotropic insufficiency as a result of ivabradine. As infants typically rely on heart rate augmentation to increase their cardiac output owing to limited ability to augment stroke volume, chronotropic insufficiency potentially contributes to insufficient cardiac output in the setting of stress. This was seen in our case; however, this effect of ivabradine can be well managed with atrial pacing to maintain sufficient overall cardiac output. Many postoperative CHD patients have atrial and/or ventricular pacing wires in place, making this a feasible management strategy in this population. We would not advocate for initiation of ivabradine in the patient population of infants under 6 months of age with congenital heart disease without capability for atrial pacing as a backup. Should an infant prove to have acceptable heart rate with no clinical evidence of decreased output on steady-state dosing, ivabradine may be considered for use in the outpatient setting in this patient population.•Ectopic atrial tachycardia is an automatic tachycardia that can be incessant in nature and seen in postoperative pediatric patients. Owing to the tenuous hemodynamic state in the postoperative period, ectopic atrial tachycardia may have more significant hemodynamic consequences.•Currently, ivabradine is only approved for use in pediatric patients with dilated cardiomyopathy, but numerous studies have shown potential benefit in various forms of automatic tachycardias.•Ivabradine is the only hyperpolarization-activated cyclic nucleotide-gated (HCN) channel inhibitor currently approved for use in the United States and acts to decrease heart rate with minimal effect on blood pressure or inotropy.•In neonates, especially with complex congenital heart disease, heart rate increases are vital to augmentation of cardiac output, and thus bradycardia or chronotropic insufficiency can result in clinically significant change in cardiac output.•As ivabradine acts to decrease heart rate, the clinician must be mindful of the potential for clinically significant decrease in cardiac output with use in a pediatric patient, owing to the effect of bradycardia on cardiac output.Ivabradine has been shown to be useful in arrhythmias due to automaticity. Postoperative infants and children after surgery for CHD are at increased risk for the development of arrhythmia, specifically automatic arrhythmias such as EAT. The currently used antiarrhythmic agents in these situations have numerous adverse effects that can further complicate the clinical scenario, worsening overall hemodynamics. The use of ivabradine to slow the heart rate and control automatic tachycardias with minimal side effects other than bradycardia may prove to be a useful therapeutic modality for these types of patients. The challenge of resultant chronotropic insufficiency can be reasonably mitigated with the use of pacing wires, which are often placed after surgery in these patients.


Acute myocardial infarction may be associated with new-onset arrhythmias. Patients with myocardial infarction may manifest serious arrhythmias such as ventricular tachyarrhythmias or atrial fibrillation. Frequent, prolonged electrocardiogram (ECG) monitoring can prevent devastating outcomes caused by these arrhythmias.We aimed to investigate the incidence of arrhythmias in patients following myocardial infarction using a patch-type device—AT-Patch .This study is a nonrandomized, single-center, prospective cohort study. We evaluated 71 patients who had had a myocardial infarction and had been admitted to our hospital. The ATP-C120 device was attached to the patient for 11 days and analyzed by 2 cardiologists for new-onset arrhythmic events.P=.04). However, different dosages of β-blockers did not make a significant difference.One participant was concordantly diagnosed with atrial fibrillation. The cardiologists diagnosed atrial premature beats in 65 (92%) and 60 (85%) of 71 participants, and ventricular premature beats in 38 (54%) and 44 (62%) participants, respectively. Interestingly, 40 (56%) patients showed less than 2 minutes of sustained paroxysmal atrial tachycardia confirmed by both cardiologists. Among participants with atrial tachycardia, the use of β-blockers was significantly lower compared with patients without tachycardia (70% vs 90%, Wearable ECG monitoring patch devices are easy to apply and can correlate symptoms and ECG rhythm disturbances in patients following myocardial infarction. Further study is necessary regarding clinical implications and appropriate therapies for arrhythmias detected early after myocardial infarction to prevent adverse outcomes. Acute myocardial infarction is a common cardiac emergency associated with high potential for mortality and a substantial risk of complications . The majHowever, conventional ECG monitoring devices such as multilead portable ECG monitoring or Holter monitoring devices are not useful for continuous monitoring of ECG signals for longer than 24 hours, particularly after discharge from the hospital . In addiTo compensate for these drawbacks, a new generation of ECG monitoring devices with advanced technologies have been developed . The ZioA wearable ECG monitoring patch device can detect ECG rhythm disturbances in patients with postmyocardial infarction. In this study, we investigated the incidence of arrhythmias in patients with postmyocardial infarction using another new wearable patch-type device—AT-Patch .This study is a nonrandomized, single-center, prospective cohort study. We evaluated patients who had been admitted to our hospital for myocardial infarction and discharged after treatment. Eligible patients had a history of acute myocardial infarction and provided written informed consent to participate. Exclusion criteria were as follows: (1) previously diagnosed with atrial fibrillation, (2) implanted pacemaker, cardioverter-defibrillator, or any electrical devices, and (3) skin problems such as allergic contact dermatitis. Our prospective study enrolled 73 adults aged 55 years or older from April 2020 to November 2020. Among them, 2 participants dropped out due to loss of the device before data acquisition.ATP-C120 is a single-lead ECG monitoring device that can continuously monitor the ECG signals for as long as 14 days (11 days if the device is connected to a smartphone via Bluetooth) when attached to the skin over the area of the heart . The devWhen the device is attached to the patient, several predefined methods are used to prevent the occurrence of noise or signal loss. First, the skin is cleansed and disinfected using a 70% ethanol solution. Skin hair is removed if necessary. Subsequently, the protective film is removed from the patient-side surface of the device. The device is placed at the left third intercostal space, tilted inward 45 degrees. A continuous ECG signal is recorded to a memory card for 11 days. Subsequently, the device is linked to a computer and the data are downloaded and analyzed by a specific program (AT-report) provided by ATsens.1c or HbA1c) and the 12-lead ECG results before the attachment of the ATP-C120 device were obtained. We detached the device after 11 (SD 5) days and recorded the date and time. Two independent cardiologists analyzed the recorded data for arrhythmic detection.According to institutional Good Clinical Practice for medical devices, we attached the experimental ATP-C120 device to participating patients. We obtained demographic data, as well as past and present medical and drug administration history, and conducted physical examinations . In addition, laboratory parameters  was performed for categorical variables. Statistical analyses were performed using R .Data are presented as numbers and frequencies for categorical variables and as mean (SD) for continuous variables. The incidence of atrial fibrillation followed by myocardial infarction is described as proportions and 95% CIs. A 2-sided The study was reviewed and approved by the Institutional Review Board of Seoul National University Bundang Hospital (B-2003/603-002).A total of 71 patients who had a history of acute myocardial infarction were included in the analyses. The baseline characteristics are shown in The incidence of arrhythmias as detected by ATP-C120 and confirmed by 2 cardiologists (C1 and C2) is shown in In P=.56). The LVEF  and the size of left atrium or left atrial volume index  were not significant contributors to atrial tachycardia. However, among medications, the use of β-blockers made a significant difference   . Further; P=.04) .Lastly, reported adverse events associated with the ATP-C120 patch are described in In this study, we analyzed 71 patients’ ECG signals after myocardial infarction for 11 days. Several studies reported that myocardial infarction may be associated with new-onset arrhythmias. In particular, some fatal arrhythmic events such as ventricular tachyarrhythmia often occur during or immediately after acute myocardial infarction ,3. ProloIn this study, potentially fatal arrhythmias such as ventricular tachyarrhythmias or atrial fibrillation, which can produce devastating events, were scarcely detected. However, a moderate number of participants with postmyocardial infarction had nonsustained atrial tachycardia events. Several studies reported that nonsustained atrial tachycardia and paroxysmal atrial fibrillation share similar electrical stimulating pathways . Other sβ-Blocker therapy after myocardial infarction is necessary for survival . TherefoThis study was a comprehensive analysis of the incidence of postmyocardial infarction arrhythmias. One major limitation of our study was the small number of patients. Therefore, only a few clinically important arrhythmic events were recorded. However, this does not indicate that prolonged monitoring after myocardial infarction only shows trivial arrhythmic episodes. This study showed that there was an interestingly high incidence of supraventricular arrhythmic events. This infers the need for further investigation regarding the progression to atrial fibrillation and fatal complications after arrhythmic episodes.A wearable ECG monitoring patch device is easy to apply and can detect ECG rhythm disturbances in patients with postmyocardial infarction. Further study is necessary regarding clinical implications and therapeutic approaches for early detected arrhythmias after myocardial infarction to prevent adverse outcomes among patients.


Coronary cardiovascular magnetic resonance angiography (CCMRA) of congenital heart disease (CHD) in pediatric patients requires accurate planning, adequate sequence parameter adjustments, lengthy scanning sessions, and significant involvement from highly trained personnel. Anesthesia and intubation are commonplace to minimize movements and control respiration in younger subjects. To address the above concerns and provide a single-click imaging solution, we applied our free-running framework for fully self-gated (SG) free-breathing 5D whole-heart CCMRA to CHD patients after ferumoxytol injection. We tested the hypothesis that spatial and motion resolution suffice to visualize coronary artery ostia in a cohort of CHD subjects, both for intubated and free-breathing acquisitions.3 isotropic spatial resolution was performed in seven minutes on a 1.5T CMR scanner. Eleven patients were anesthetized and intubated, while seven were breathing freely without anesthesia. All patients were slowly injected with ferumoxytol (4 mg/kg) over 15 minutes. Cardiac and respiratory motion-resolved 5D images were reconstructed with a fully SG approach. To evaluate the performance of motion resolution, visibility of coronary artery origins was assessed. Intubated and free-breathing patient sub-groups were compared for image quality using coronary artery length and conspicuity as well as lung-liver interface sharpness.In 18 pediatric CHD patients, non-electrocardiogram (ECG) triggered 5D free-running gradient echo CCMRA with whole-heart 1 mmData collection using the free-running framework was successful in all patients in less than 8 min; scan planning was very simple without the need for parameter adjustments, while no ECG lead placement and triggering was required. From the resulting SG 5D motion-resolved reconstructed images, coronary artery origins could be retrospectively extracted in 90% of the cases. These general findings applied to both intubated and free-breathing pediatric patients (no difference in terms of lung-liver interface sharpness), while image quality and coronary conspicuity between both cohorts was very similar.A simple-to-use push-button framework for 5D whole-heart CCMRA was successfully employed in pediatric CHD patients with ferumoxytol injection. This approach, working without any external gating and for a wide range of heart rates and body sizes provided excellent definition of cardiac anatomy for both intubated and free-breathing patients.The online version contains supplementary material available at 10.1186/s12968-022-00871-3. Coronary cardiovascular magnetic resonance angiography (CCMRA) is employed in pediatric patients with congenital heart disease (CHD), where the accurate assessment of anatomic structures and coronary vessels constitutes a fundamental requirement for interventional planning. Conventional clinical practice includes first-pass magnetic resonance angiography and 2D cardiac cine acquisitions, which typically require lengthy scanning sessions with repeated breath-holding, under anesthesia and respiratory intubation at times . A speci2) and high temporal resolution (15–30 phases per cardiac cycle). The goal of this work was to translate and exploit the efficiency and simplicity of the free-running framework to provide an automated push-button solution for whole-heart CCMRA in pediatric patients that does not require any breath-holding, navigation, external gating, or triggering device. Similar to previous studies including the aforementioned MUSIC technique [Recently, the free-running framework  was deveechnique , 9, 10. echnique , 12 provFIT, Siemens Healthineers, Erlangen, Germany). The study was approved by the Institutional Review Board and written informed consent was obtained from the legal guardians prior to CMR scanning. The proposed free-running sequence, further described below, was added to an existing clinical protocol wherein each patient received a 4 mg/kg dose of ferumoxytol , injected slowly over 15 min, with monitoring performed every 5 min during injection and 30 min afterwards. Eleven patients were under respiratory intubation and general anesthesia during the exam , while in the remaining 7 patients, data were collected during free-breathing and without anesthesia . A previously reported prototype free-running  sequence [The study was performed in 18 pediatric cardiac patients  at the Children’s Hospital of Philadelphia  on a whole-body 1.5T clinical MR scanner  and interface sharpness (S) of the RCA, LM + LAD, and LCx were measured on the reformatted images, the coronaries being rather small in diameter and subject to a large amplitude of displacement during the cardiac and respiratory motion. Cases where the coronary origin was not visible were excluded from further analysis. The visible coronaries were then divided into Group 1 (patients under respiratory intubation) and Group 2 (free-breathing), and vessel sharpness and length were statistically compared between the two groups using t-tests.For all 18 subjects, one systolic and one diastolic end-expiratory 3D cine frame were manually selected from the reconstructed 5D datasets that included 52–96 3D images in total depending on the heart rate. In the 36 resulting 3D images  had to be excluded from further analysis due to the interferences induced by the free-running GRE acquisition Table . In AddiR1 = 5.9 ± 1.1) to that at end-inspiration , with images in R1 showing the sharpest interface in 15/18 cases, and those in R4 the most blurred interface in 12/18 cases. More detailed results are presented in Fig. Group 1  and Group 2 , no significant difference was found at any of the 4 resolved respiratory levels   and LG1,diast = 7.7 ± 2.9 cm vs LG2,diast = 5.0 ± 1.7 cm (p = 0.041). Detailed length and sharpness values are presented in Table Examples of reformatted coronary arteries extracted from end-expiratory systolic and diastolic bins from three different subjects are shown in Fig. A previously reported fully SG free-running framework for cardiac and respiratory motion-resolved 5D imaging of the whole heart was tailored for—and successfully applied to—a cohort of pediatric CHD patients injected with ferumoxytol contrast agent. Apart from exchanging the bSSFP module with GRE and removing fat suppressions and ramp-up pulses, no further adjustments were made, and the proposed imaging technique provided effective cardiac and respiratory motion-resolution, strong blood signal, and overall good definition of the cardiac anatomy with high contrast between the blood-pool and the myocardium. It is noteworthy that a high detail visibility of anatomical structures such as the coronary arteries was obtained in a cohort of CHD pediatric patients, where CMR imaging is often more challenging, and where small structures, high heart rates, and complex anatomy often occur. Moreover, the proposed framework proved to work in a simple “push-button” manner even for a wide range of body sizes, heart rates, clinical questions, and both with or without anesthesia and intubation.3 and 13 mm3 for 4D ROCK MUSIC vs. 0.93 to 1.13 mm3 for 5D free-running), they allow the FOV volume to encompass the whole heart (4D ROCK MUSIC: 480 × 280 × 140 mm3 vs. 5D free-running: 192 × 192 × 192 mm3 when at 13 mm3 resolution), and they operate at similar acquisition durations (4–6 min for the 4D ROCK MUSIC vs. 7–8 min for 5D free-running).Successful attempts to provide an efficient, comprehensive, and easy-to-use approach to ferumoxytol-enhanced motion-resolved whole-heart imaging in pediatric patients have been reported by Han et al. with the 4D MUSIC technique and its further development to 4D ROCK MUSIC , 5, 7. IDespite these similarities, the temporal resolution obtained with the free-running framework has been improved. While the previously published ROCK-MUSIC approach included 9 cardiac phases that are defined prior to the data acquisition, resulting in an average temporal resolution of over 60 ms in a cohort of pediatric patients with a 106 ± 12 bpm heart rate , the proThe radial trajectory used in this study leads to an isotropic FOV. Unlike Cartesian sampling, the individual readout, phase-encode, and slice-encode dimensions cannot readily be tailored to the patient but given the two-fold oversampling of radial readouts in all directions, wrap-around artifacts are far less of a concern compared to Cartesian and therefore the field-of-view does not need to be adjusted for each patient, potentially reducing scan planning, and improving overall efficiency.The free-running framework includes the reconstruction of the fifth dimension (in addition to x–y–z-cardiac dimensions), resolving 4 different motion states of the respiratory cycle for each cardiac phase. While this provides us with the opportunity to visualize 3D cine images at different respiratory levels, this also affords another advantage: instead of discarding data that were acquired outside of a small gating window at end-expiration (leading to a respiratory gating efficiency of about 40% for the 4D ROCK MUSIC approach), all the acquired data contribute information to the final image reconstruction of free-running datasets, increasing the efficiency to 100%. This also implies that scanning time doesn’t need to be manually and prospectively adjusted to the specific patient. Further, unpredictable respiratory patterns can be flexibly accommodated by the retrospective approach to motion resolution. In fact, neither respiratory patterns nor heart rate have a direct influence on scanning time that always remains constant for our proposed approach. This means that this protocol may more easily be integrated into a clinical routine exam. Finally, the reconstruction of different respiratory motion states provides a yet to be exploited opportunity for co-registration using motion fields . This coThe use of ferumoxytol as a CMR contrast agent provides a significant T1-shortening effect in the blood pool that may particularly benefit GRE sequences, which enables imaging with high spatial and high temporal resolution as demonstrated by the current study. Still, a number of limitations must also be considered. Slow infusion of ferumoxytol is necessary to avoid potential anaphylactic reactions which in turn prolongs patient preparation. Additionally, unlike gadolinium, ferumoxytol remains primarily intravascular and may therefore not be easily used for perfusion and delayed enhancement imaging. Considering these limitations, the free-running framework may offer additional advantages in that it provides a comprehensive evaluation of the structure and anatomy of the heart in a predictable scan time creating a potential trade-off between preparation time and actual time in the scanner. Furthermore, while the current study used ferumoxytol, previous studies have demonstrated free-running CCMRA with native contrast and therefore, the current results with ferumoxytol motivate further study of free-running CCMRA in a pediatric population without the use of contrast agents. Conversely, in the current study, strong flow dephasing artifacts were present as demonstrated by Additional file In the current study, half of all subjects had significantly corrupted ECG traces as confirmed by both visual inspection of the raw signals as well as the impact on subsequent reconstructions. This result underscores the utility of the cardiac SG approach which worked well in all patients. At higher field strengths, an alternative to ECG may become even more important. Still, an additional hardware-based gating device that is unaffected by gradient switching such as pulse oximetry or pilot tone  may alsoTo our knowledge, an uninterrupted, motion-resolved, ferumoxytol-enhanced free-breathing CCMRA without tracheal intubation, anesthesia and controlled ventilation has not been reported in a pediatric CHD cohort. While comparing the free-breathing group to their intubated counterpart, most of the quantitative measurements performed on the reconstructed 5D images did not show significant differences, neither in terms of respiratory motion-resolution at the lung-liver interface, nor for the computed length and sharpness of coronary arteries. The only exceptions were represented by the higher percentage of visible coronary ostia (93% in Group 1 vs 86% in Group 2) and the longer RCA measured in patients scanned under controlled ventilation conditions. Even if these results could be confounded by a relatively small number of patients, the large range of age and spectrum of CHD present in the examined cohort, together with a potential age bias in terms of patient selection for free-breathing scanning , these results may still suggest that the more regular and controlled respiratory pattern of intubated patients may be advantageous in younger pediatric subjects. Additionally, all patients were visually monitored throughout the scan and no instances of significant bulk patient motion were observed in the free-breathing cohort. This was further confirmed by inspecting the SI projections which showed periodic cardiac and respiratory motion without the expected jumps or drifts in signal intensity that typically accompany bulk movement. As a result, we observed high quality images in even our very young free-breathing patients .Additional file 2. 5D image with variable temporal resolution. Transverse, coronal, and sagittal planes from 5D motion-resolved images displayed along the cardiac dimension. Images are reconstructed from the same dataset (Patient 16) with 8 different temporal resolutions, ranging from 15 ms (30 bins) to 150 ms (3 bins).Additional file 3. Electrocardiogram (ECG)-gated vs self-gated (SG) reconstruction. 5D motion-resolved images from the same dataset. Binning and reconstruction were performed first with the electrocardiogram (ECG) triggers (top row) and then with the SG cardiac signal (bottom row).Additional file 4. ECG-gated vs SG reconstruction. 5D motion-resolved images from the same dataset. Binning and reconstruction were performed first with the ECG triggers (top image) and then with the SG cardiac signal (bottom image).Additional file 5. 5D motion-resolved image. Cardiac and respiratory motion is visualized in a two-year-old (patient 15) under free-breathing conditions.Additional file 6. 3D fly-through images from all free-breathing subjects. Cardiac anatomy is well demonstrated in all subjects under free-breathing conditions.


While chronic thromboembolic pulmonary hypertension (CTEPH) results from macroscopic and microscopic obstruction of the pulmonary vascular bed, the function of the right ventricle (RV) and increased RV afterload are the main determinants of its symptoms and prognosis. In this review, we assess RV function in patients diagnosed with CTEPH with a focus on the contributions of RV afterload and dysfunction to the pathogenesis of this disease. We will also discuss changes in RV function and geometry in response to treatment, including medical therapy, pulmonary endarterectomy, and balloon pulmonary angioplasty. Chronic thromboembolic pulmonary hypertension (CTEPH) is diagnosed in patients presenting with precapillary pulmonary hypertension (PH) with an increased mean pulmonary artery pressure (mPAP) > 20 mmHg at rest, a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) > 2 WU ,4.The persistence of fibro-thrombotic material in the pulmonary vascular bed results in increased PVR and right ventricle (RV) afterload . As the Current regimens are used to treat CTEPH by targeting the occlusions at various levels . For exaIn this manuscript, we will review the pathophysiology of RV dysfunction in CTEPH, with a particular emphasis on points of clinical relevance and the impact of specific medical and surgical treatments.The pathophysiological mechanisms underlying CTEPH are complex and include both macroscopic and microscopic changes to the pulmonary vascular bed together with pathophysiologic RV responses to the resulting increased afterload . The perSome researchers have suggested that differences in these hemodynamic responses might be used to differentiate between CTEPH, characterized by a proximal macroscopic obstruction and pulmonary arterial hypertension (PAH), in which obstruction is limited to the distal pulmonary vessels with a diameter of less than 1 mm. This point remains controversial. Results from previous studies revealed that an early pulse wave reflection in CTEPH was the result of increased stiffness of the proximal PA . This anOther researchers suggested that patients with CTEPH might exhibit higher PA pulse pressures compared to those diagnosed with PAH and thus potentially associated withreduced PVC . HoweverMicrovasculopathy has been detected in both the occluded and non-occluded lung areas in patients with CTEPH . VariousThe RV adapts to progressive increases in afterload via different mechanisms in order to maintain a sufficient cardiac output (CO) at rest and during exercise ,28. The When the mechanisms leading to adaptation are ultimately exhausted and the RV has no further capacity to adapt, the RV enters into a phase of maladaptive remodeling with volumetric adaptation . This phExercise results in a dramatic increase in RV work because of the need to increase CO to meet the oxygen requirements of active muscles . TherefoThe cellular and tissue responses and mechanisms underlying the transition from compensated RV remodeling to RV failure are complex and not fully understood . ActivatWhile the RV may evolve from an adaptative to a maladaptive phenotype, this change may not be irreversible. A severely dysfunctional RV may improve dramatically in response to significant afterload reduction. This is the underlying rationale for the treatment of CTEPH with PEA, BPA, and potentially lung transplantation. However, it is not clear whether RV function will be fully restored after these treatments, nor do we fully understand what mechanisms might be precluding a complete RV functional repair.RV dysfunction is an important factor contributing to the symptoms and decreased exercise capacity in patients diagnosed with PH. However, the symptoms due to RV dysfunction that emerge in patients who develop CTEPH after an acute pulmonary embolism (APE) are highly variable and follow a non-linear trajectory. A wide range of PVR and RV dysfunction may be encountered in patients with the same level of pulmonary vascular obstruction and hemodynamic disturbance. Thus, the nature and relevance of the patient symptoms may change greatly, from nearly asymptomatic CTEPD to the most severe and decompensated presentations of CTEPH. This high variation in hemodynamic presentation precludes direct clinical comparison between patients with CTEPH and those with PAH, as the latter present most frequently with high pulmonary pressures and high levels of PVR. 2) with invasive hemodynamic measurements taken during exercise, the cardiac index (CI) was identified as an independent predictor of impaired VO2 and abnormal functional capacity [Several studies have assessed and correlated RV function with symptoms in patients with CTEPH. Among these, persistently increased RV afterload after PEA has been linked to symptoms, including correlations between symptoms and mPAP/CO ratio during exercise  and betwcapacity . Similarcapacity . Taken tcapacity ,63.RV dysfunction triggered by increased afterload is also the major determinant of prognosis in CTEPH. Results from a large multicenter prospective study of 679 patients revealed that the prognosis of CTEPH patients was positively and independently associated with the New York Heart Association (NYHA) functional class, surgery , and RV afterload . In patiRHC remains the “gold standard” for the diagnosis of PH. This method results in accurate measurements of critical pressures, including those measured in the PA (mPAP) and the RA (RAP). Moreover, RHC provides critical information on cardiac function via the direct measurement of CO with either the thermodilution or Fick methods . AssessmEchocardiography remains an important tool that can be used to screen patients for CTEPH after APE in cases with persistent symptoms . The sys2) and the inferior vena cava (>21 mm) with decreased inspiratory collapse and hepatic venous reflux [Echocardiography is also in wide use as a means to assess RV function . Signs oa cava >2 mm with s reflux . Speckles reflux .Echocardiography may also be used for a follow-up of CTEPH patients. Results of a recent study revealed the comparatively high sensitivity (68%) and specificity (67%) of transthoracic echocardiography (TTE) for determining the intermediate or high probability of PH and detecting residual PH after PEA .Cardiac MRI (cMRI) is a useful alternative to echocardiography for the identification and monitoring of patients with PH and to assess RV function . This mePEA is the recommended treatment for patients with CTEPH that is amenable to surgical treatment ,2. PEA cInterestingly, the extent of RV reverse remodeling does not depend on preoperative RV function or geometry. Results from a retrospective study that included 17 patients who had undergone PEA revealed a significant improvement in hemodynamics at day 2 . ResultsTR both before and after PEA has also been examined . ResultsPEA not only results in improved RV function and RV volumes, it also alleviates RV septal bowing in left heart chambers, increases LV volumes, and improves LV function. Interventricular dyssynchrony may be normalized, thus further increasing the CO . Contractility assessed by GLS and the global circumferential strain were also improved after PEA and correlated with contractility measurements determined by more invasive procedures . FinallyA non-invasive assessment of RV function with TAPSE, RV-S, and RV-MPI documents the incomplete restoration of RV function one year after PEA despite normalization of RV geometry and after a transient depression observed in the early postoperative period . RV wallIncomplete restoration of RV function and RV mass has been linked to evidence of residual PH after PEA . Up to oOther explanations that have been proposed to explain the incomplete restoration of RV function after PEA involve the development of myocardial fibrosis and thus intrinsic decreased contractility. Similarly, RVSV also improved after PEA, albeit without a complete restoration to levels exhibited by healthy subjects . MoreoveBalloon pulmonary angioplasty (BPA) is an established modality used to treat CTEPH patients ,2. BPA iResults from multiple studies have revealed improvements in hemodynamics together with improvements in both cardiac function and RV afterload via increases in CO and decreases in mPAP and PVR ,111,113.While PEA remains the treatment of choice for CTEPH with a proximal disease, approximately 40% of the patients are considered inoperable secondary to inaccessible vascular obstruction or significant comorbidities . RiociguAdministration of riociguat resulted in improved RV function, reversal of RV hypertrophy, improved vascular remodeling, and decreased myocardial fibrosis in various animal models of PH ,119,120.Results from a human clinical study revealed that the administration of riociguat results in improved pulmonary hemodynamics associated with improvements in mPAP, CO, CI, and PVR. The changes observed in PVR correlated with increased exercise capacity  and remaRV function is an important marker of prognosis in patients diagnosed with CTEPH. The physiopathology of RV dysfunction in this potentially severe disease is complex and involves a multifactorial increase in RV afterload that may be assessed non-invasively by echocardiography and cMRI. Invasive procedures, such as PEA and BPA, may be used to normalize hemodynamics and RV geometry in patients with this disease. However, the observed decrease in afterload does not systematically translate into a normalization of RV function. Persistent RV dysfunction may be linked to ongoing RV overload due to residual obstruction or microvasculopathy. Persistent dysfunction may also be due to diminished levels of intrinsic RV contractility potentially associated with irreversible myocardial fibrosis. Administration of the sGC-activating drug, riociguat, results in improved RV function and may contribute to the ongoing amelioration of RV function after surgery or other interventional treatments.