Aim: Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite synthesized in host organisms from specific food constituents, such as choline, carnitine and betaine. During the last decade, elevated TMAO levels have been proposed as biomarkers to estimate the risk of cardiometabolic diseases. However, there is still no consensus about the role of TMAO in the pathogenesis of cardiovascular disease since regular consumption of TMAO-rich seafood  is considered to be beneficial for the primary prevention of cardiovascular events. Therefore, the aim of this study was to investigate the effects of long-term TMAO administration on mitochondrial energy metabolism in an experimental model of right ventricle heart failure.Methods: TMAO was administered to rats at a dose of 120 mg/kg in their drinking water for 10 weeks. Then, a single subcutaneous injection of monocrotaline (MCT) (60 mg/kg) was administered to induce right ventricular dysfunction, and treatment with TMAO was continued . After 4 weeks, right ventricle functionality was assessed by echocardiography, mitochondrial function and heart failure-related gene and protein expression was determined.Results: Compared to the control treatment, the administration of TMAO (120 mg/kg) for 14 weeks increased the TMAO concentration in cardiac tissues up to 14 times. MCT treatment led to impaired mitochondrial function and decreased right ventricular functional parameters. Although TMAO treatment itself decreased mitochondrial fatty acid oxidation-dependent respiration, no effect on cardiac functionality was observed. Long-term TMAO administration prevented MCT-impaired mitochondrial energy metabolism by preserving fatty acid oxidation and subsequently decreasing pyruvate metabolism. In the experimental model of right ventricle heart failure, the impact of TMAO on energy metabolism resulted in a tendency to restore right ventricular function, as indicated by echocardiographic parameters and normalized organ-to-body weight indexes. Similarly, the expression of a marker of heart failure severity, brain natriuretic peptide, was substantially increased in the MCT group but tended to be restored to control levels in the TMAO+MCT group.Conclusion: Elevated TMAO levels preserve mitochondrial energy metabolism and cardiac functionality in an experimental model of right ventricular heart failure, suggesting that under specific conditions TMAO promotes metabolic preconditioning-like effects. Impaired energy metabolism is one of the cornerstones of heart failure pathophysiology  was identified as a metabolite, which is both microbiota- and diet-derived, and associated with the incidence of adverse cardiovascular outcomes  weighing 280–380 grams (6–8 weeks old) were obtained from the Laboratory Animal Centre, University of Tartu  and housed under standard conditions  for 2 weeks prior to the start of the experiment. The animals were fed a standard R70 diet  with unlimited access to food and drinking water. All the experimental procedures were performed in accordance with the guidelines reported in the EU Directive 2010/63/EU and in accordance with local laws and policies, and all of the procedures were approved by the Latvian Animal Protection Ethical Committee of the Food and Veterinary Service, Riga, Latvia . These studies are reported in accordance with the ARRIVE guidelines , TMAO (n = 10), MCT  (n = 10) and TMAO+MCT (n = 10). One animal in the control group and 2 animals in the other groups died during the experiment due to reasons not related to the experimental protocol and treatment. The samples from these rats were excluded from further analysis; therefore, the final animal count was nine rats in the control group and eight rats in the other groups. The animals in the TMAO group and TMAO+MCT group received TMAO  at a dose of 120 mg/kg in their drinking water daily for 10 weeks. To induce pulmonary hypertension and right ventricular remodeling and dysfunction, a single subcutaneous injection of monocrotaline (MCT)  at a dose of 60 mg/kg was administered to the animals in the MCT and TMAO+MCT groups. TMAO treatment was continued in both groups that previously received TMAO until the end of the experiment. The rats were weighed twice a week to monitor their general health condition. Since the time from MCT injection to right ventricular failure onset differs markedly  to record ECG from the II lead. Then, the rat was placed on the left side, and a four-chamber view was recorded from the apical point of view using a Philips  S12-4 sector array transducer. Right ventricular (RV) end-diastolic area (RV-EDA) and RV end-systolic area (RV-ESA) were recorded. ECG was used to determine the exact time of RV systole and diastole. Furthermore, RV-EDA and RV-ESA were used to calculate RV fractional area change (RVFAC). The rat was again placed in a decubitus position, and functional parameters of the left ventricle were recorded at the papillary muscle level using a Philips  linear L15-7io transducer.After the echocardiographic assessment of ventricular anatomy and functioning, invasive direct right ventricular pressure measurement was performed. The anesthetized rat was intubated using a 16-G intravenous catheter and mechanically ventilated with 2% isoflurane dissolved in 100% oxygen at a tidal volume of 1.5 ml/100 g. The abdominal cavity was opened, and the diaphragm was incised to expose the pleural cavity. The ribs on both sides of the chest were cut to access the heart. An 18-G needle was connected to a pressure transducer  and inserted into the cavity of the right ventricle through the apex of the heart. The right ventricular pressure was measured until a stable pressure reading was obtained.To calculate the organ-to-body weight indexes, the heart and lungs were excised and weighed. Then, the right ventricle (excluding the septum) was separated from the heart and weighed.To obtain plasma, the blood samples were centrifuged at 1,000 g and 4° for 10 min and then stored at −80°C until further analysis. The levels of triglycerides and total cholesterol in plasma were measured using commercially available kits from Instrumentation Laboratory . The level of free fatty acids (NEFA) was measured using a commercially available kit from Wako Chemicals . All measurements were carried out according to the manufacturer's instructions.Determination of the TMAO concentrations in the plasma and heart homogenate samples was performed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) using the positive ion electrospray mode as previously described . The samples were then vortexed and centrifuged at 15,000 g for 20 min. The supernatant was transferred to UPLC vials and used for UPLC/MS/MS analysis. MassLynx 4.1. software with a QuanLynx 4.1. module  was used for data acquisition and processing.A Rat BNP 45 ELISA Kit  was used to test the levels of makers of congestive heart failure in right ventricular tissue extracts. Extract preparation and analysis were carried out according to the manufacturer's instructions.Total RNA was isolated from right ventricular tissues using TRI reagent  according to the manufacturer's recommended protocol. First-strand cDNA synthesis was performed using the High-Capacity cDNA Reverse Transcription Kit  following the manufacturer's instructions. The qPCR mix consisted of SYBR® Green Master Mix , synthesized cDNA, and forward and reverse primers specific for VCP, BNP, αMHC, and βMHC. These genes were chosen to characterize heart failure severity and cardiac hypertrophy. The reaction was carried out in an Applied Biosystems Prism 7500 instrument according to the protocol provided by the manufacturer. The relative expression levels of each of the genes of interest were calculated with the ΔΔCt method and were normalized to the expression level of the VCP gene. The primer sequences used for the qPCR analysis are available in 2, 20 mM taurine, 10 mM KH2PO4, 20 mM HEPES, pH 7.1, 0.1% BSA essentially free of fatty acids) at 37°C using an Oxygraph-2k . Mitochondrial functionality measurements were performed using a previously described respirometry protocol . If the data were not normally distributed, the Kruskal-Wallis test followed by Dunn's multiple comparison test was used. The results were considered statistically significant if the p-value was < 0.05.The statistical analysis of the data was performed using GraphPad Prism  software. All the data are represented as the mean ± standard error of the mean (SEM). Data distribution was determined using Shapiro-Wilk's normality test. The statistical significance of the experimental results was verified by one-way ANOVA followed by Dunnett's multiple comparison test  following an unpaired Administration of TMAO at a dose of 120 mg/kg in the drinking water for 14 weeks resulted in a 6-fold increase in the TMAO plasma concentrations (up to 100 μM) in both the TMAO and TMAO+MCT groups . The anaThe echocardiographic assessment did not reveal any significant differences in cardiac function between the control and TMAO groups. Administration of TMAO at a dose of 120 mg/kg in the drinking water for 14 weeks did not affect direct right ventricular (RV) pressure, RV systolic and diastolic area or RV fractional area change  as well To evaluate MCT-induced cardiac and pulmonary remodeling, the organ mass indexes were calculated. There was no difference in the whole heart-to-body weight index or in the left ventricle-to-body weight index between the experimental groups . Long-te/β-MHC expression ratio , indicating partial complex I dysfunction  and no further metabolization was needed by gut bacteria. However, the possible interindividual variability caused by alterations in gut microbiota composition should be considered if TMAO precursors  were administered during the experiment, since various bacterial genera are able to metabolize different precursors to synthesize TMA  in rats did not affect cardiac functionality (Ufnal et al., Previously, increased plasma TMAO levels in experimental models of heart failure led to worsening of cardiac parameters, suggesting that TMAO is a detrimental factor in cardiovascular disease pathophysiology. It has been shown that administration of TMAO and its precursor, choline, exacerbates left ventricle remodeling and cardiac function loss (Organ et al., in vitro (Sun et al., in vivo (Li et al., The protective role of TMAO was previously explained by its ability to reduce endoplasmic reticulum stress (Makhija et al., In conclusion, our study presents evidence that chronic TMAO administration protects cardiac functionality by preserving mitochondrial energy metabolism in an experimental model of monocrotaline-induced right ventricle heart failure, where TMAO acts as a preconditioning factor. In addition, our results provide a novel insight on the theory, that the role of TMAO in the pathogenesis of cardiometabolic diseases is not limited to either detrimental or protective effects, suggesting that it might actually be dual and depend on specific conditions.The original contributions presented in the study are included in the article/The animal study was reviewed and approved by Latvian Animal Protection Ethical Committee of the Food and Veterinary Service, Riga, Latvia; Food and Veterinary Service Ethical approval Nr. 105.MV, RV, MD, and MM-K performed planning of the study. MV, RV, SK, HC, and MM-K conducted experiments. MV, RV, SK, and MM-K performed data analysis. ES performed bio-analytical assays and data analysis. MV wrote the manuscript with input from RV, MD, and MM-K. All authors have read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Purpose: This study aimed to prospectively evaluate the early effects of radiation on cardiac structure and function following neoadjuvant chemoradiation for distal esophageal cancer.Methods and Materials: Patients with non-metastatic esophageal cancer who were suitable for tri-modality therapy with concurrent chemoradiotherapy followed by esophagectomy were enrolled. Cardiac magnetic resonance imaging (CMR) was obtained at baseline and 3–5 months following completion of chemoradiation. Standardized myocardial segmentation was used to identify regions on post-treatment CMR with new T2 signal or late gadolinium enhancement (LGE). Pre and post-treatment cardiac function was assessed with quantitative end points including left ventricle end-systolic volume (LSESV). Serum biomarkers of cardiac damage including troponin I, CRP, and BNP were collected at baseline and time of follow-up CMR.Results: A total of 11 patients were enrolled from 2016 to 2018. Patients had clinical stage T2 (18%) and T3 (82%) disease with clinical N0 (27%) and N1 (73%) nodal stage. All patients completed baseline CMR and completed chemoradiotherapy. One patient did not complete follow-up CMR or serum biomarkers and was excluded from the analysis. The median time from completion of chemoradiation to follow-up CMR was 3.9 months. Three out of 10 patients (30%) developed new structural findings of myocardial fibrosis and/or reversible ischemia involving the basal and mid-inferior and inferoseptal walls. In these three patients, the LVESV was significantly increased from baseline following radiation. There were no differences in other quantitative end points or serum biomarkers between the patients with myocardial damage and those without.Conclusions: Our study is the first to our knowledge to prospectively demonstrate radiation associated structural and functional heart damage as early as 3 months following neoadjuvant chemoradiation for distal esophageal cancer. Given the early onset of this subclinical heart damage, strategies should be developed to identify patients at risk for future clinically significant heart toxicity. Increasing numbers of patients with esophageal cancer are being treated with combined modality therapy including chemotherapy and radiation. Due to improvements in outcomes, cancer survivorship has increased and there is a growing focus on long-term treatment-related toxicity. The association of increasing exposure to ionizing radiation with long-term cardiac toxicity is well-established in breast cancer , 2, lympAlthough neoadjuvant chemoradiation offers a significant survival advantage in patients with resectable esophageal cancer, large volumes of normal tissues are frequently irradiated to cover sites of tumor spread, potential lymph node involvement, and target motion . CardiacCardiac imaging can play an important role in pretreatment risk assessment, early detection of cardiac injury, and identification of cardiac complications in patients receiving potentially cardiotoxic cancer treatment. Numerous previous reports and meta-analyses have concluded that stress cardiac magnetic resonance imaging (CMR) is a sensitive and specific method of detecting coronary arterial disease, myocardial fibrosis, and cardiac function –15. StreAmerican Society of Clinical Oncology (ASCO) cancer survivorship guidelines suggest follow-up cardiac imaging 6–12 months after completion of cancer therapy in patients considered to be at elevated risk for heart failure . SimilarIn addition to imaging evaluation of left ventricular ejection fraction (LVEF) and myocardial damage, there has also been considerable interest in biomarkers to identify early cardiac injury such as elevated troponins, B-type natriuretic peptides (BNP), N-terminal T-pro-BNP (NT-proBNP) and C-reactive protein (CRP) –20. CollWhile the long-term effects of radiation on the heart have been well-characterized, there is a paucity of data on acute cardiac toxicities. Early identification of cardiotoxicity could lead to better preventative strategies and improved radiation therapy delivery techniques to mitigate clinically significant cardiac toxicity following thoracic radiotherapy. We therefore sought to prospectively collect baseline and acute post-treatment cardiac imaging and biomarkers to correlate early structural and functional changes with clinically significant cardiac outcomes, as well as to identify dosimetric predictors of cardiac toxicity.This prospective, IRB-approved study enrolled patients seen at the MedStar Georgetown University Hospital who had non-metastatic esophageal cancer and were suitable candidates for tri-modality therapy with concurrent chemoradiotherapy followed by esophagectomy from 2016 to 2018. Patients were required to be at least 18 years old and have histologically proven diagnosis of adenocarcinoma or squamous cell carcinoma of the esophagus or gastroesophogeal (GE) junction. Patients could not have any evidence of metastatic disease, have received prior thoracic radiotherapy or underwent esophagectomy. Eastern Cooperative Group (ECOG) performance status had to be 0–1 with a predicted life expectancy >3 months. Patients could not have a prior history of unstable angina, uncompensated congestive heart failure (CHF), uncontrolled hypertension , severe mitral or aortic stenosis, advanced atrioventricular (AV) node block without pacemaker, electronically active implants, other non-MR compatible implants, contraindications to gadolinium contrast or acute systemic illness.Magnetic resonance imaging was performed with a 1.5 Tesla MR system using a torso and spine coil in conjunction with electrocardiographic gating. Cardiac MRIs were obtained at baseline and 3–5 months following completion of chemoradiation. The imaging protocol consisted of scout images to identify cardiac axes, black blood double inversion-recovery imaging of the thorax in the axial planes, cine 2D steady-state free precession imaging in standard long-axis planes, and stacked short-axis planes to cover the entire left ventricle, T2-weighted turbo spin echo imaging with fat suppression, dynamic first-pass perfusion imaging at rest and ~90–120 s following the administration of 0.4 mg of regadenoson in conjunction with 0.05 mmol/kg gadolinium contrast injection, and inversion-recovery late gadolinium enhancement imaging 10–15 min following intravenous injection of a total of 0.15 mmol/kg gadolinium contrast with inversion time adjusted to null normal myocardium. Left ventricular volumes and ejection fraction were calculated using cine short-axis planes. Presence and extent of increased T2 signal and/or late gadolinium enhancement were graded using standard 17-segment American Heart Association (AHA) model of the heart .Patients underwent simulation with 4D CT to account for respiratory motion. A PET/CT in the treatment position was obtained and fused with the treatment-planning CT. Target volumes were delineated as per the Alliance 80803 study . PatientPre and post-treatment CMR sequences were fused to the treatment-planning CT. Relevant cardiac anatomy including total heart and left ventricle were contoured. Standardized myocardial segmentation per the American Heart Association 17 segment model was used . ContourSerum biomarkers were collected at baseline and 3–5 months following completion of chemoradiation. Biomarkers included troponin-I, CRP, BNP, NT-pro-BNP, and CRP.t-test. Dose statistics to the heart, left ventricle and grouped heart segments were compared using paired t-test between patients with CMR evidence of myocardial injury and those without. Tests of cardiac function such as left ventricular ejection fraction (LVEF), left ventricular end systolic volume (LVESV), left ventricular end diastolic volume (LVEDV), cardiac output (CO), and systolic volume (SV) were compared using paired t-test between those with evidence of myocardial injury and those without. All statistics were performed using SPSS Statistical Software .Pre and post-radiation values for serum biomarkers were compared using paired n = 10) and one patient had squamous cell carcinoma. All patients completed baseline CMR and completed chemoradiotherapy. Ten patients underwent IMRT with photons and one patient was treated with proton beam therapy. One patient demonstrated complete response to neoadjuvant chemoradiation and did not have further therapy while the remainder underwent esophagectomy. One patient did not complete follow-up CMR or serum biomarkers and was excluded from the analysis. The median time from completion of chemoradiation to follow-up CMR and serum analysis was 3.9 months (range 3–5 months). Patient characteristics are shown in A total of 11 patients were enrolled from February 2016 to February 2018. The median age was 69 (range 37–80 years) and the majority of patients were male (82%). Patients had clinical stage T2 (18%) and T3 (82%) disease with clinical N0 (27%) or N1 (73%) nodal stage. The majority of patients had adenocarcinoma (p = 0.01). There was no significant difference in other quantitative end-points, including ejection fraction, in the three patients with myocardial damage or any quantitative end-points in the seven patients without myocardial damage. This data is shown in At baseline two out of 10 patients (20%) had pre-existing subepicardial fibrosis involving the basal or mid inferior/inferoseptal wall of the left ventricle, while the remaining patients (80%) did not have any evidence of pre-existing cardiac damage. Three out of 10 patients (30%) developed new structural findings of myocardial fibrosis and/or reversible ischemia involving the basal and mid inferior and inferoseptal walls. None of these three patients had prior evidence of cardiac damage. p = NS). In two out of three patients who had myocardial injury, the volume of involved basal or inferoseptal/inferior segments receiving 30 Gy was >60% of the total volume of those segments. Of note, the areas showing evidence of early radiation induced cardiac damage did not coincide with the segments of the heart receiving the highest dose of radiation.The basal or inferoseptal/inferior segments were contoured for each patient. Characteristics of radiation dose to the heart, left ventricle (LV) and involved segments for each patient are shown in n = 3) and those without (n = 7), there was still no significant difference in pre-post radiotherapy cardiac biomarkers  database that have correlated radiation for esophageal cancer with cardiac outcomes. Gharzai et al. analyzed 5,630 patients treated between 1973 and 2012 and found that patients treated with radiation had higher risk of cardiac death than those treated with surgery alone . These sUmezawa et al. published one of the first reports using CMR to evaluate radiation induced myocardial damage in patients treated for esophageal cancer. They enrolled 24 patients who had maintained complete response to curative radiotherapy for esophageal cancer for more than 6 months with a median interval from completion of radiotherapy to CMR of 23.5 months (range 6–88 months). They noted late gadolinium enhancement corresponding to radiation fields in 15% of heart segments that received 40 Gy and 21% of heart segments that received 60 Gy  for the publication of any potentially identifiable images or data included in this article.AMB: data analysis. CY: data collection. SK, PK, and MS: cardiac imaging. PB: cardiac imaging and contouring. AB: study enrollment and cardiac imaging. KU: content supervision and editing. All authors: contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Is the definition of heart failure too narrow, not allowing research into compensatory mechanisms, comorbidities, right heart function, and lymphatic function?A review of the absolute mortality of heart failure drugs and devices suggests a modest improvement in outcomes. Absolute mortality from common comorbidities, including renal insufficiency, arrhythmia, conduction deficits, pulmonary hypertension, anemia, obstructive sleep apnea, infection, inflammation, edema, ischemic heart disease, and diabetes II, is significant. The lymphatic function is involved in short, intermediate, and long-term compensation for a failing heart and plays a role in most of the comorbidities.A better definition of heart failure is: Heart failure is a complex clinical syndrome that results from any structural or functional impairment of right or left ventricular filling or ejection of blood and failure of peripheral compensatory mechanisms. Lymphatic function from the anatomic, fluid management, immune modification standpoints requires study. New therapies from this analysis will improve patients with congestive heart failure. Figure Heart failure is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood . CentralThe normal heart can accommodate a large range of pumping function from sleep, with low blood pressure and low cardiac output, to high pressure and high cardiac output during prolonged and extreme exercise. This range of performance is impressive and can rapidly change to accommodate the needs of the body by altering heart rate and venous and arterial tone. These adaptations occur nearly instantaneously. On an intermediate time scale, the body uses homeostatic mechanisms to adjust the volume status. These homeostatic mechanisms include renal function, lymphatic function, blood vessel properties, neuroendocrine system, and the autonomic nervous system. Other intermediate time-scale compensations include the musculoskeletal, hematopoietic, respiratory, and endocrine systems, and, in fact, all major organ systems and regulators of homeostasis. The intermediate compensations may take hours, days, or even months to adjust for a failing heart. Compensation on the longest time scale includes processes that remodel the structure of the heart. These mechanisms include cellular repair, hypertrophy, and fibrosis. The remodeling can be either positive or negative, allowing patient improvement or a steady decline. These processes take months to years to change the structure of the heart. Compensation in heart failure thus utilizes multiple peripheral mechanisms and varying time scales to help a structurally failing heart.As per the 2013 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Guideline for the Management of Heart Failure: “Heart Failure is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood” [The current definition of heart failure does not acknowledge there are two hearts. A better definition of heart failure is: heart failure is a complex clinical syndrome that results from any structural or functional impairment of right or left ventricular filling or ejection of blood and failure of peripheral compensatory mechanisms. The right heart should be included in the definition of heart failure. The right heart is a thin-walled, trabeculated crescent chamber that normally operates under low pressure. The left heart is a thick-walled ellipsoid ventricle that pumps into systemic high pressure. They share the interventricular septum. The septum under normal operation supports the left ventricle. Under conditions of elevated pulmonary pressure or electrical conduction abnormalities, it supports right ventricular function. The right heart and left heart pump in series. Failure of one results in the failure of both. Right heart failure due to left heart failure is a critical risk for mortality.Embryological development indicates that the right and left ventricles arise from two separate origins. The left heart arises from the heart tube while the right heart may derive, at least in part, from the anterior heart field  . The difThe classes of drugs used to improve central heart failure parameters overlap peripheral compensatory factors. Neuroendocrine medications, such as angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and neprilysin inhibitors (NI), also affect afterload. Medications that enhance lymphatic function include Nesiritide, phosphodiesterase inhibitors, sympathomimetics, and digoxin. Phosphodiesterase inhibitors, sympathomimetics, and digoxin alter contractility and preload through the enhancement of lymphatic function. Nesiritide affects both preload and afterload and compliance in addition to enhancing lymphatic function. The lymphatic function also influences the immune system, which is a major contributor to cardiac decompensation and non-cardiac comorbidities through inflammatory pathways. Medications altering the properties of blood vessels, such as spironolactone, ACEI, ARB, NI, and hydralazine/isosorbide dinitrate influence compliance and afterload. It is impossible to separate the benefits of these therapies in effects upon central parameters versus peripheral compensation. Improving peripheral compensation may be more important than the effect on central parameters. Drugs designed to improve peripheral compensation can have a significant effect on the morbidity and mortality of heart failure. In turn, comorbidities can worsen heart failure by a reduction in compensatory mechanisms.The comorbidities are renal insufficiency, arrhythmia and conduction deficits, pulmonary hypertension, anemia, obstructive sleep apnea, infection, inflammation, lymphatic dysfunction, edema, ischemic heart disease, ischemic mitral regurgitation, and diabetes II.Advanced heart failure specialists and pulmonary hypertension experts often do not consider the pericardium in advanced left and right heart failure. If either ventricle dilates to the limit of the pericardium, the diastolic pressures become equalized and physiology is like constrictive pericarditis. The septum demonstrates interventricular dependence - the Bernheim and the reverse Bernheim phenomena . The phyIn the setting of advanced heart failure, hypotension, renal insufficiency, anasarca, and ascites are manifestations of right heart failure. Beta-blockers used for the treatment of left heart failure are now counterproductive. The negative inotropic effects of beta-blockers further reduce right ventricular function. Most advanced heart failure patients are restrictive in diastolic filling and require a greater heart rate to empty the already full left ventricle. Increasing the heart rate with better emptying of the ventricle can reduce functional mitral regurgitation by decreasing ventricular volumes. Heart rate is a compensatory mechanism. A failing right heart and restrictive left heart require new therapies. In some cases, medications aimed at increasing right ventricular contractility and peripheral pulmonary vasodilation may be more beneficial than negative inotropes such as beta-blockers. Including the right and left heart in the definition of heart failure will encourage future investigations leading to new therapies.The musculoskeletal system, hematopoietic system, autonomic system, respiratory system, endocrine system, and regulators of homeostasis all have roles to play in peripheral compensation. Exercise and physical fitness have demonstrated that enhancing the musculoskeletal system leads to better outcomes in all disease processes. Exercise improves positive remodeling and takes time to accomplish. The means of compensation include increasing circulating stem cells and shifting the immune system to repair from degeneration. The compensatory enhancing intervention of cardiac rehabilitation has positive mortality and quality of life outcomes.The respiratory system has been an enigma in therapy. One of the major respiratory comorbidities is obstructive sleep apnea with a 25.6% absolute risk of mortality . CPAP foTables Models of heart failure do not incorporate major physiological systems. The lymphatic system is a major vascular system that is responsible for the compensation of cardiac dysfunction and repair of the heart and periphery. Despite the ability to transport 12 liters of fluid per day, the transport of stem cells to sites of injury, and the modification of the immune system, the lymphatic system is not considered in congestive heart failure. This system is responsible for the most common symptoms of heart failure - edema and dyspnea. The lymphatic function has a prominent role in most comorbidities that are responsible for cardiac mortality, including cardiorenal, infection, inflammation, and diabetes II. There is no systematic classification of drugs assigning positive or negative lymphangiotropy to the drug effect. Strategies to enhance lymphangiotropy should improve the quality of life by mobilizing the interstitial fluid. The paper "Alternative view of congestive heart failure exacerbations: Role of lymphatic function and inflammation" outlined this strategy . MilrinoUndiscovered lymphatic processes in heart diseaseLocation of Vegetation in EndocarditisLymphatic drainage of cardiac valves runs on the low-pressure side of the valve: the ventricular aspect of the aortic valve and the atrial aspect of the mitral valve. The lymphatic system is designed to control infection by inducing edema and decreasing systemic spread. The location of lymphatic drainage is the most plausible reason for the location of vegetation. Previous explanations invoke low sink hemodynamic swirling with endothelial damage and secondary infection of platelet fibrin nidus. Endothelial damage disrupts the infective lymphatic flow, with tissue edema. Bacteria are trapped in the dysfunctional lymphatic and grow to form the vegetation.Troponin Leaks Post-Surgery, With Sepsis, Critical Illness - Type 2 Myocardial InfarctionThe source of troponin in the above clinical syndromes is assumed to be the heart since troponin is reported to be specific only to the heart. The leak represents poor prognosis in the short term and is associated with long-term adverse cardiovascular outcomes . The manCardio-Renal Syndrome The pathophysiology of the cardio-renal syndrome has been elusive. It suggests a connection between the heart and kidney. The typical scenario is the presentation of a fluid-overloaded patient secondary to heart failure. The initial creatinine is normal. The patient receives a loop diuretic with a failure of diuresis and a rise in creatinine. The diuretic is held, and symptoms of heart failure are managed by various means while awaiting improvement in creatinine so diuresis can again be attempted. If the syndrome is not managed, renal dialysis or death ensues.Explanations of low systemic pressure or low cardiac output have not been proven. Elevated venous pressure appears to be one of the best predictors. Lymphatic drainage of the kidney is not considered. An experiment performed many years ago may be the reason lymphatic function is ignored in this syndrome. The experiment was to disrupt main lymphatic drainage from the kidney and the result was increased urine flow. Obstructing the outflow of the lymphatics will result in pressure within the glomerulus that favors tubular excretion. This condition is distinctly different from failure of the lymphangion that would increase glomerular pressure by edema formation with an unfavorable tubular flow. The hypothesis is that loop diuretics, in the setting of high venous pressures, reduces glomerular lymphangion amplitude and frequency, increasing interstitial edema of the kidney. The therapy is to provide medications that have positive lymphangiotropy, improving amplitude and frequency. The medications that accomplish this function are sympathomimetics, phosphodiesterase inhibitors, and Nesiritide, which increase lymphangion amplitude and frequency. Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, has great enthusiasm as a new agent to treat heart failure even in non-diabetic patients. The mechanism has not been elucidated. The ability to reduce glomerular pressure likely occurs by positive lymphangiotropy by this diabetic drug .Takotsubo CardiomyopathyTakotsubo cardiomyopathy is a transient left and sometimes right ventricular dysfunction, which has several anatomical presentations. The pathophysiology of this disorder has not been elicited; however, it is associated with abnormally high catecholamine states. The transient left ventricular function is associated with increased wall thickness as opposed to ischemia, which thins the walls. There is the classic apical form, which can involve the left or left and right apex in a non-coronary distribution, a mid-ventricular form, and a basal form. The reasons for this noncoronary distribution of dysfunction has not been elicited. A hypothesis is that the lymphatic penetration of the heart is segmental, involving only the apex, middle, or basal segments. Acute dysfunction of one or multiple distributions will result in myocardial interstitial edema with the distribution of left ventricular function noted. Improvement in lymphatic function and resolution of the edema allows myocardial recovery.The origin of lymphatics is unknown. If one assumes the human body is a product of evolutionary life, borrowing successful systems from its predecessors, it is likely this parallel circulatory system came from insects. Insects’ lymphatic circulation was the main mechanism for supplying hemolymph to a complex multicelled segmented life form. The system exposed to the environment also had to function as an immune gatekeeper. This system evolved more than 350 million years before the mammalian circulatory system of heart, arteries, capillaries, and veins. Speculation would suggest that this parallel circulatory system was added to the mammalian by incorporating deoxyribonucleic acid (DNA) from insect life forms - a chimera of sorts. The concept of adopting an entire system into another organism is a new and unsubstantiated concept. In terms of embryogenesis, the lymphatic system is first recognized two weeks after the appearance of the circulatory system. Although lymphatics frequently run in the same direction as arteries and veins, they appear to be independent in development and segmented. The lymphatic system is in every organ but is concentrated in the lung, gastrointestinal tract, and skin where the environment interacts with the mammalian organism.Relationship of inflammation and heart failureC-reactive protein (CRP) is a measure of the response of the immune system and has demonstrated clinical significance in myocardial infarction. In heart failure, CRP has a similar relationship. The chicken or egg debate exists as to whether inflammation is caused by heart failure due to poor perfusion of the gut, resulting in microbiome translocation or if inflammation decreases, lymphatic function with a decrease in peripheral lymphatic compensation. CRP is elevated when brain natriuretic peptide (BNP) is elevated. The elevation of CRP is associated with reduced function of the lymphangion. Inflammatory states cause negative lymphangiotropy, with a reduction in the amplitude and frequency of contraction. Injury begets swelling, and systemic inflammation begets heart failure. Diabetes II, influenza, infections, sepsis, and clotting are all inflammatory conditions and frequently coexist with heart failure. Treating inflammation in heart failure seems to be as reasonable a target as myocardial infarction.Education into practice Heart failure trials do not include compensatory mechanisms. Pharmacologic and pacing strategies for right heart failure are lacking. The accepted definition of heart failure does not include intermediate and long-term compensatory adaptations of non-cardiac peripheral systems. Amending the definition of heart failure to include peripheral compensatory mechanisms and right heart physiology could identify novel targets for investigation and ultimately aid in improving patient outcomes. The entire lymphatic vascular system has been disregarded. Dr. Massey would suggest that the term chronic lymphatic Insufficiency should be incorporated into the definition of heart failure. The new definition of heart failure suggests the following areas of investigation:Pharmacologic and mechanical enhancement of the lymphatic system to improve heart failure compensationPharmacologic and mechanical enhancement of the immune system to reduce inflammation and promote repair rather than fibrosisLymphatic function in comorbid conditions, cardiorenal, Takotsubo cardiomyopathy, infections, type 2 myocardial infarction, diabetes, and renal insufficiency need further investigation. The comorbidities of study populations need meticulous definition and changes in these comorbidities secondary to drugs or devices should be separate endpoints. In other words, did the intervention change the comorbidity, and did this change have a beneficial result on primary endpoints.Directing therapies toward renal protection, modifying the immune system , diagnosing and treating obstructive sleep apnea, anemia, and diabetes II can have a significant impact on heart failure mortalities. This impact may be greater than the guideline-directed medical therapies listed in Tables Heart failure trials need to be longer in duration to establish structural changes in the heart due to therapies.The new definition of heart failure that includes compensatory mechanisms and investigates both the left and right heart will lead to new strategies and new therapies, extending the scope of therapy beyond the heart. The new definitions will boost research in lymphatic function. The new definition of heart failure should be “Heart failure is a complex clinical syndrome that results from any structural or functional impairment of right or left ventricular filling or ejection of blood and failure of peripheral compensatory mechanisms.”


Timely diagnosis of cardiac iron overload is important for children with transfusion-dependent anaemias and requires modern measure methods. Nowadays, myocardial iron quantification is performed by magnetic resonance (MR) breath-hold techniques, sensitive to respiratory motion and unfeasible in patients who are unable to hold their breath. Free-breathing T2* mapping sequences would allow to scan children who cannot hold their breath for a specified duration. Our aim was to test a free-breathing T2* mapping sequence, based on motion correction by multiple signal accumulation technique.We used an electrocardiographically gated T2* mapping sequence based on multiple gradient echo at 3-T in 37 paediatric patients with haematologic disorders aged from 2 to 16. We compared T2* values of myocardium and signal-to-noise ratio of this new sequence with standard breath-holding T2* mapping sequence. T2* values were measured in the interventricular septum for both methods in studies with adequate image quality.r = 0.99, R2 = 0.98; p < 0.001). The free-breathing sequence had a higher signal-to-noise ratio  than the breath-holding sequence  (p = 0.03).All children were scanned without complications. Five patients were excluded from analysis because of the presence of respiratory artefacts on the T2* images with breath-holding technique due to patient’s inability to hold their breath. Breath-holding T2* was 19.5 ± 7.7 ms (mean ± standard deviation), free-breathing T2* was 19.4 ± 7.6 ms, with positive correlation (A free-breathing sequence provided accurate measurement of myocardial T2* values in children. A free-breathing motion corrected by multiple signal accumulation magnetic resonance (MR) protocol was compared to a breath-holding protocol at 3-T in 37 paediatric patients.The free-breathing multi turbo field-echo sequence resulted to be less sensitive to the breath motion and provided a higher signal-to-noise ratio than the standard breath-holding techniqueT2* mapping free-breathing technique makes the MR study less depended on the ability of patients to hold their breath and may pave the way for T2* myocardial quantification in children performing cardiac MR without the anaesthetic support.Iron overload is a condition caused by excessive accumulation of iron in the body and relates to hereditary as well as acquired hemochromatosis due to the repeated blood transfusions that become necessary in such conditions as congenital dyserythropoietic anaemia, thalassemia, sickle cell anaemia, aplastic anaemia and myelodysplasia . One of Until recently, the accumulations of iron in the body were estimated indirectly using serum ferritin level tests or by direct method such as liver biopsy with mass spectrometry of the samples , 9. HoweTissue Doppler echocardiography could help to provide an indirect measure of subclinical cardiac involvement in these patients. However, it does not allow the direct measurements of myocardial iron concentration . EndomyoThe clinical need for a non-invasive and reliable technique for the iron content myocardium measurement led to the use of magnetic resonance (MR) T2*-weighted pulse sequences. In 2001, Anderson et al.  firstly Electrocardiography (ECG)-gated multi-phase GRE sequences are widely used for iron assessment in the heart, but this technique requires the patients to hold their breath in order to avoid artefacts from respiratory movements .We expect that cardiac MR T2* free-breathing technique described in this article paves the way towards scanning most children with transfusion-dependent anaemias from 5 to 7 years of age without the need of anaesthetic support. MR scanning technique with breathing artefacts compensation was introduced in 2015 by Kellman et al. using a 1.5-T magnet in a sample of adult patients . HoweverThis was a prospective single-institution study performed in the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology during the period from 2017 to 2018. MR iron assessment examination, including cardiac T2* mapping, was conducted in all paediatric patients in accordance with the inclusion criteria of the study. Patients were scanned by both new and standard protocols to compare the image quality and resulting T2* values as well as to estimate the efficiency of the new sequence.Inclusion criteria were patients with transfusion-dependent anaemia under 18 years of age and with more than 10 red blood cell transfusions in the past medical history. Exclusion criteria were absolute contraindications to MR  and the refusal to sign informed consent. Fourteen out of 17 children were scanned under general anaesthesia in the group of patients from 2 to 7 years old. Three out of 17 children were scanned without anaesthetic support due to the parent’s refusal to apply anaesthesia for the MR investigation. Sevoflurane inhalation was used for the induction and maintenance of general anaesthesia. Rocuronium bromide injection was used as a muscle relaxant to achieve breath-holding during MR study. Drug dosage was adjusted according to the age and weight of each patient. Children over 7 years old were scanned without anaesthetic support.The local ethical committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology approved the study. Informed consent was received from all parents of patients.All patients underwent myocardial examination on a 3-T Achieva dStream system , using a 16-channel body coil. Scanning was performed using a multi-phase fast GRE sequence, which provides multiple echoes and allows to get cardiac short-axis projections with standard parameters for either breath-holding or free-breathing. In the latter case, respiratory motion activity is compensated by averaging of multiple acquisitions to reduce error of phase encoding. Scan parameters are presented in Table The T2* maps were generated automatically using the MR console . The mean T2* values were measured within the equal size elliptical ROIs in the interventricular septum for both acquisition techniques Fig. . To estiImage quality was assessed by measuring the signal-to-noise ratio (SNR) for one ROI in the middle of the interventricular septum and another one in the area of background noise , 25. SNRwhere SI (ivs) is the value of the signal intensity measured in the drawn ROI in the interventricular septum, and SD (air) is the standard deviation of the background noise.t test and Pearson correlation were used. The threshold for significance was set at 0.05.STATISTICA 8.1.  and Office Excel 2018  were used. Mean T2* value and SD were calculated for each ROI. The mean value for each case was used as the optimal T2* value while the SD was used as a measure of uncertainty. For patients, except those excluded from analysis, a scatterplot between T2* values were obtained. For the inter-reader reproducibility estimate, the results were analysed by Bland-Altman analysis. For the intra-reader reproducibility estimate, the coefficients of variation were obtained. To determine the normality of the T2* values distribution and SNR results, the Shapiro-Wilk test and the frequency distribution histogram were used. For non-normally distributed data, the pairwise Wilcoxon rank sum test was used. For normally distributed data, pairwise Student n = 14), Diamond–Blackfan anaemia (n = 13), dyserythropoietic anaemia 1 (n = 5) and acquired aplastic anaemia (n = 5). They were 11 females and 26 males (ratio 1:2.4).The study was performed in 37 patients aged from 2 to 16 years old (median age—8 years) who were under medical treatment at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, diagnosed with β-thalassemia (All patients successfully completed the MR study without complications. The children from 2 to 7 years of age (14 of 37 patients) underwent the scanning using general anaesthesia.p = 0.00001 and p = 0.001 respectively). Therefore, the pairwise Wilcoxon rank sum test was used. Wilcoxon rank sum test showed that the SNR of the FB-mTFE sequence was significantly higher  than that of the BH-mTFE  (p = 0.003)  or Diamond–Blackfan anaemia (n = 2) were scanned without anaesthetic support due to the parent’s refusal to apply anaesthesia for the MR investigation. The other two excluded patients (one 10-year old patient diagnosed with dyserythropoietic anaemia and one 16-year old patient diagnosed with acquired aplastic anaemia) could not hold their breath because of the complications of the primary disease. For all excluded patients, T2* maps obtained using the FB-mTFE sequence were suitable for T2* assessment. Figure Five of 37 studies (14%) were excluded from analysis because of insufficient image quality due to the inability of patients to hold their breath. Three of the excluded patients from 5 to 7 years of age with the diagnoses of the dyserythropoietic anaemia . The T2* value was 19.5 ± 7.7 ms (mean ± SD) for the breath-holding sequence and 19.4 ± 7.6 ms for the free-breathing sequence, without significant difference . For the breath-holding technique, the T2* distribution in the ROI was less homogenous. For the first reader, T2* value ranged from 0.4 to 8.8 ms (SD 1.5 ms) for the breath-holding sequence, from 0.2 to 3.9 ms (SD 0.7 ms) for the free-breathing sequence; for the second reader, from 0.4 to 7.6 ms (SD 1.3 ms) and from 0.2 to 3.3 ms (SD 0.6 ms), respectively.The T2* values of the 32 analysed patients for the breath-holding and free-breathing sequences were normally distributed   Fig. .Fig. 5MReliable data related to the iron level in the myocardium can be obtained using GRE sequences and measuring the T2* value. Thus, this approach has become an important diagnostic tool for planning and monitoring the chelation therapy in patients with transfusion-dependent anaemia . To thisIn our study, we compared the results of the T2* mapping using standard breath-holding technique and a multiple signal accumulation free-breathing technique and found that 14% of the breath-holding studies had a non-diagnostic quality due to the presence of respiratory artefacts. On the contrary, in these patients, free-breathing sequence was of adequate quality and could be used for T2* mapping.ECG-gated multiple signal accumulation techniques allow to compensate both respiratory activity of a patient. MR scanners with different magnetic field strengths are differently sensitive to the physiological movement, and multiple signal accumulation techniques with ECG-gating have been easily adapted to 1.5-T systems . In our In general, the free-breathing multiple signal accumulation scanning technique may provide a higher SNR than a single breath-holding scan. The mean T2* values measured for the same ROI were not significantly different between the two techniques, however the SD of T2* was smaller for the free-breathing sequence than for the breath-holding sequence, corresponding to more homogenous T2* values for the free-breathing myocardial mapping. Therefore, the free-breathing myocardial mapping technique demonstrates higher image quality compared to the standard technique for patients who could not clearly follow the breath-holding instructions, especially in patients aged from 2 to 7 years. Of note, based on our experience, it is rare that patients under 7 years of age are able to methodically hold their breath for 8–12 s.However, most of the haematologic patients from 5 to 7 years of age can lie in the MR scanner without any movement for 20–30 min. Despite the motionless of this patient group, the usage of the multi-phase GRE sequence without anaesthetic support is impossible due to the huge number of breathing artefacts, which make it difficult to generate the relaxometry maps and calculate the T2* values.Three of the patients in the age from 5 to 7 years were scanned without anaesthetic support. For these patients, five or more re-scans (repetition of the scans) were conducted for the breath-holding T2* analysis without successful results: images were corrupted by the respiratory artefacts. The duration of the studies was extended from 15 s to 2 min including attempts and preparation time. The use of the free-breathing sequence allows to reduce the number of re-scans due to the fuzzy holding of the patient’s breath and the absence of the breath-holding preparation increases the comfort of the study.The free-breathing protocol will help to optimise the investigation of patients aged from 2 to 7 years. Some cases will allow to omit anaesthesia or at least to reduce its depth, which is extremely important in paediatric practice. Despite the fact that the duration of the investigation by free-breathing technique with artefact compensation is longer than the standard breath-holding technique, in paediatric practice, the whole duration of the study will be reduced. In most cases, children do not manage to adequately hold breath from the first try, and the study continues with the repetition of the sequences several times. This makes it possible to consider the free-breathing T2* mapping technique potentially promising for the myocardium iron assessment also in other patients who are not able to hold their breath due to their health condition.Our study has some limitations. This work was made only on a 3-T scanner, and we cannot discuss the performance of this technique on scanners with another field strength. On the other hand, motion artefacts on 1.5-T scanners are usually less noticeable than on 3-T scanners, which allows us to speculate that this technique could be useful also for 1.5-T scanners. In addition, only 3 out of 17 patients under 7 years of age were scanned without anaesthetic support, which does not allow us to conclude on the possibility of scanning these patients without anaesthesia, but suggests that it can be possible. Further research is needed in patients under 7 years of age.In conclusion, the FB-mTFE sequence allowed to obtain good quality T2* myocardial maps at 3-T for patients with iron overload in different groups of haematological diseases. Free-breathing scans with multiple signal accumulation technique did not require additional research packages and also facilitated and shortened the duration of the investigation in young children under anaesthetic support and in some cases allowed to even refuse it. This approach may pave the way for scanning patients who are unable to hold their breath for medical reasons without anaesthetic support. Further studies in patients of different age ranges are required.


The aim of cardiac resynchronization therapy (CRT) is to improve cardiac function by delivering more physiological cardiac activation to patients with heart failure and conduction abnormalities. Biventricular pacing (BVP) is the most commonly used method for delivering CRT; it has been shown in large randomized controlled trials to significantly improve morbidity and mortality in patients with heart failure. However, BVP delivers only modest reductions in ventricular activation time and is only beneficial in patients with prolonged QRS duration. In this review, we explore conduction system pacing as a method for delivering more effective ventricular resynchronization and to extend pacing therapy for heart failure to patients without left bundle branch block (LBBB).The aim of conduction system pacing is to provide physiological ventricular activation by directly stimulating the conduction system. Current modalities include His bundle and left conduction system pacing. His bundle pacing is the most established method; it has the potential to correct left bundle branch block and deliver more effective ventricular resynchronization than BVP. This translates into greater acute haemodynamic improvements and observational data suggests that His-CRT results in improvements in cardiac function and symptoms. AV-optimized His bundle pacing is being investigated in patients with heart failure and long PR interval without LBBB, to see if this improves exercise capacity. More recently, a technique for pacing the left bundle branch has been developed. Early studies show potential advantages including low and stable capture thresholds.Conduction system pacing can deliver more effective ventricular resynchronization than BVP, which has the potential to deliver greater improvements in cardiac function. It may also provide the opportunity to extend pacing therapy for heart failure to patients who do not have LBBB. Further data is required from randomized trials to assess these promising pacing techniques. Cardiac resynchronization therapy (CRT) is as an important treatment for patients with heart failure and cardiac conduction system disease. Cardiac conduction system abnormalities, such as left bundle branch block, lead to inefficient ventricular contraction. The aim of CRT is to use pacing therapy to normalize cardiac activation in order to improve cardiac function.Biventricular pacing is the most established method for delivering cardiac resynchronization therapy, and its use is supported by the findings from several large randomized controlled trials , 2. WhenMore effective ventricular resynchronization: Despite biventricular pacing, morbidity and mortality remains high. In the CARE-HF trial treatment arm, mortality was 20% and 40% of patients reached the primary endpoint of death or hospitalization for a major cardiovascular event [ar event . BiventrAlternatives to LV lead placement: The development of more advanced tools and techniques has increased success rates of LV lead implantation, but failure of LV lead placement remains a limitation of BVP. It would be useful to have alternative options for delivering CRT, which ideally could be performed during the same procedure as the BVP attempt.Extending CRT to non-LBBB patients: BVP has only been shown to be beneficial in patients with a broad QRS, principally left bundle branch block (LBBB). There are other conduction abnormalities which also adversely affect cardiac function. These may be best corrected using alternative methods for delivering CRT.However, despite the success of BVP as a treatment, there are potential reasons to explore alternative methods for delivering CRT which include the following:In this review, we will discuss the potential role of cardiac conduction system pacing as an alternative method for delivering CRT and its potential to address these challenges.There are several different conduction system pathologies which can lead to less efficient ventricular contraction and are therefore potential treatment targets for cardiac resynchronization therapy.Left bundle branch block occurs in 20–30% of patients with heart failure , 5 and iDiastolic mitral regurgitation: delayed activation results in late ventricular contraction which can result in diastolic mitral regurgitation, which leads to reduced cardiac output Prolonged iso-volumetric contraction and relaxation times: reduces the time available for ventricular filling Prolonged left-sided AV delay: delayed left ventricular activation may also prolong left-sided AV delay, which may also adversely affect ventricular filling.Left bundle branch block results in delayed and less coordinated left ventricular activation, which results in less efficient ventricular contraction and therefore reduced left ventricular systolic function . It may PR interval prolongation is also associated with an increased risk of heart failure hospitalization and mortality in patients with heart failure –12. A prProlongation of atrioventricular delay leads to reduced ventricular filling time and may also cause diastolic atrioventricular valve regurgitation. Both mechanisms reduce overall cardiac output. Reduced cardiac output may be the mechanism for the adverse outcomes observed in patients with a long PR interval.Sub-analysis of the COMPANION trial found that patients with a prolonged PR interval received more benefit than patients with normal PR interval , which pRight bundle branch block leads to delayed activation and contraction of the right ventricle relative left ventricular activation/contraction. In patients with heart failure, this type of conduction disease is associated with higher mortality , 15. AltAs the beneficial effect of biventricular pacing has been observed predominantly in patients with QRS prolongation, it has been assumed that the main mechanism of action is delivered through ventricular resynchronization.However, when BVP pacing is delivered to patients with LBBB, it produces only modest ventricular resynchronization with relatively small reductions in QRS duration  and ventWe used computational modelling to investigate the mechanism through which BVP delivers it beneficial effect. Our findings suggested that up to two-thirds of the improvement in stroke volume achieved with BVP is achieved by shortening AV delay . Conduction delay occurring with LBBB has the effect of prolonging left-sided AV delay. The potential powerful effect of AV delay optimization provides support for the concept that prolonged AV delay may be an alternative treatment target for CRT.The modest ventricular resynchronization delivered with BVP implies that there is potential to deliver greater therapeutic benefit with CRT if more effective ventricular resynchronization can be delivered. Ploux et al. assessed ventricular activation time during intrinsic conduction and BVP, using non-invasive epicardial mapping Fig. . They foIn the computational modelling study, we found that delivering more effective ventricular resynchronization has the potential to deliver greater improvements in cardiac function .Furthermore, when BVP is delivered to patients with a narrow QRS duration, this results in prolongation in ventricular activation time compared with intrinsic conduction. Therefore, biventricular pacing causes ventricular dyssynchrony when delivered to patients with an intact ventricular conduction system. This ventricular dyssynchrony can be harmful as was demonstrated in the ECHO CRT trial , where BHis bundle pacing involves direct stimulation of the cardiac conduction system, at the level of the His bundle. The concept of a pacing modality capable of preserving and potentially restoring physiological conduction is very attractive, especially in heart failure patients.Preventing the deleterious effects of right ventricular pacing, delivering more effective cardiac resynchronization and avoiding complications associated with coronary sinus instrumentation are a few of the potential advantages.His pacing has been shown to be technically feasible  and implDirect stimulation of the left bundle can be achieved by implanting a lead within the ventricular septum via the right ventricle. This novel modality has gained widespread interest as it has potential advantages over other modalities. Left bundle branch pacing utilizes the cardiac conduction system therefore avoiding the left ventricular dyssynchrony caused by BVP. By targeting the more distal conduction system, it has the potential to correct more distal conduction system disease and early data suggests that capture thresholds are low and stable over time .Conduction system pacing has the potential to deliver ventricular resynchronization to patients with LBBB. It therefore represents a potential alternative to BVP when LV lead placement is not possible via the coronary sinus and possibly also as a method for delivering more effective ventricular resynchronization.The idea of correcting both left and right bundle branch blocks by pacing the bundle of His was established five decades ago by Narula et al. . At the More recently, Upadhyay et al. performed invasive mapping of the His bundle and LV septum in 72 patients with the 12-lead ECG appearance of LBBB, who were undergoing VT ablation ••. They Therefore, conduction system pacing has the potential to correct the disordered ventricular activation occurring during left bundle branch block and represents a novel modality for cardiac resynchronization.There is a growing body of evidence from observational studies, the majority of which are retrospective, that His-CRT is technically feasible Table . His-CRTFigure Therefore, these findings support the role of His-CRT as an alternative to BVP with a coronary sinus lead; however, prospective blinded endpoint data are required to confirm these findings.Left conduction system pacing has recently emerged as a further alternative method for delivering CRT. It has the potential advantage that by targeting the more distal conduction system, it may deliver normal physiological left ventricular activation to patients who have conduction block in the proximal left bundle rather than within the His bundle.Figure Observational data suggests that left conduction system pacing in patients with LBBB delivers shorter QRS duration and improvements in clinical outcomes . A potenDirect comparison with BVP is not yet available for left conduction system pacing and randomized trials have not yet been performed.While His-CRT shows promise as a method for delivering cardiac resynchronization, it must of course be compared with BVP which is supported by data from large randomized controlled trials. Data from adequately powered randomized controlled trials are not available to answer this question.p value 0.01) and greater reductions in left ventricular electrical dyssynchrony and that this translated into significantly larger improvements of acute haemodynamic function. In patients in whom His-CRT successfully delivered ventricular resynchronization, it delivered a 60% greater improvement in acute haemodynamic function [We have performed an acute study, using electrocardiographic imaging and a high-precision haemodynamic protocol to compare within-patient response to His-CRT and BVP. We found that His-CRT delivered significantly greater reductions in left ventricular activation time  [More recently, Upadhyay et al. conducted the His-SYNC trial which enrolled 41 patients who were randomized to receive either His-CRT or BVP. The findings were limited by significant crossover between groups, 48% in the His-CRT arm and 26% in the BVP arm. The intention-to-treat analysis found no significant difference in echocardiographic or clinical endpoints between the two treatment groups. Treatment-received analysis found a trend towards a greater echocardiographic response in the His-CRT group  •.In the His-SYNC trial, the most frequent reason for crossing over in the His-CRT arm was failure to achieve the target QRS shortening (defined as a QRS of < 130 ms or a reduction from baseline QRS of > 20%). The majority of these patients were thought to have non-specific intraventricular conduction delay in which QRS prolongation may be due to more distal conduction system disease or myocardial uncoupling rather than discreet conduction block within the bundle of His. His-CRT would therefore not be expected to shorten ventricular activation in this situation. Differences in patient characteristics may be one of the explanations for the differences observed in acute implant success rates with His-CRT in previous studies (52% •–90% 2727).Better characterization of underlying conduction disease may help with patient selection. LBBB defined using standard 12-lead electrocardiography is known to be a heterogeneous entity as it is associated with different patterns of ventricular activation on detailed invasive electrical mapping .Optimizing patient selection, by identifying patients who have conduction system block amenable to correction with His-CRT, would be useful in order to facilitate optimal recruitment for RCTs comparing His-CRT with BVP. Tung et al. found that the Strauss criteria were the most reliable 12-lead ECG criteria for identifying patients. However, specificity was only 55%. Alternative, ideally, non-invasive methods would be helpful. Non-invasive epicardial ECG mapping shows promise, and two main patterns of ventricular activation can be identified during left bundle branch block: global slow propagation and regions of apparent conduction block. In patients with regions of block, His bundle pacing was able to restore physiological activation .Therefore, His-CRT shows promise as an alternative to BVP for delivering ventricular resynchronization. Larger clinical endpoint trials are required to determine whether the promising results observed in acute, observational, and pilot randomized studies translate into improvements in long-term outcomes.While pacing therapy for heart failure is established in patients with LBBB, attempts to extend CRT to other groups of patients have been disappointing .A potential alternative target for pacing therapy for heart failure is a prolonged PR interval. As discussed above, PR prolongation is associated with adverse outcomes. Shortening a pathologically long PR interval appears to be an important mechanism through with CRT delivers it beneficial effect in patients with LBBB , 18.A prolonged PR interval can be corrected by pacing therapy with the aim of improving cardiac function, through optimization of ventricular filling. His bundle pacing, in theory, is the ideal way to deliver AV optimization since it enables AV delay to be corrected without introducing dyssynchronous ventricular activation, which has the potential to offset the beneficial effect of AV delay optimization.We assessed the acute impact of AV-optimized His pacing using high-precision invasive systolic blood pressure measurements. Patients with systolic heart failure, a PR interval > 200 ms, without LBBB  were recIn the HOPE-HF trial, we are assessing whether these improvements in acute cardiac function translate into improvements in exercise capacity. The HOPE-HF trial is a multicentre, double-blinded, crossover study comparing AV-optimized His pacing with backup pacing only . RecruitPeople who have a 12-lead ECG pattern of RBBB have a higher risk of death than those with normal QRS duration and pattern . It therBiventricular pacing may not be the optimal method for delivering cardiac resynchronization to patients with RBBB, since left ventricular activation may be preserved during intrinsic conduction, in which case LV pacing via the coronary sinus may produce more dyssynchronous left activation that occurs during intrinsic conduction, although some patients with a RBBB ECG morphology may also have left conduction system disease and delayed left ventricular activation , which mP = 0.0001) [His bundle pacing appears to be an option for delivering ventricular resynchronization to patients with RBBB. In an observational study of 37 patients, Sharma et al. found that His pacing reduced QRS duration in patients with RBBB, with a mean reduction of 27 ms ( 0.0001) . PatientProspective studies are required to confirm these promising findings.The first report of permanent His bundle pacing was in a group of patients with atrial fibrillation and left ventricular impairment who required AV node ablation to optimize ventricular rate control . This stAV node ablation renders patients pacing dependent and vulnerable to pacing-induced dyssynchrony which may lead to deteriorating in left ventricular function, especially in the presence of pre-existing impaired ventricular function. This outcome is more likely with right ventricular pacing but as discussed above, BVP also results in ventricular dyssynchrony in patients with a normal QRS at baseline.The advantage of His bundle pacing in this group of patients is that it allows normal physiological ventricular activation to be preserved following AV node ablation.Further observational studies have found His pacing to be technically feasible in the context of AV node ablation. AV node ablation can commonly be performed in the presence of a His lead without impacting on His lead capture. Improvements in left ventricular ejection fraction and NYHA class were observed with His pacing in combination with AV node ablation , 43.Right ventricular pacing results in dyssynchronous ventricular activation, which may lead to right ventricular pacing–induced cardiomyopathy –49. The p = 0.02). This difference was observed primarily in patients with ventricular pacing > 20% . The incidence of heart failure hospitalization was significantly reduced in patients who received His bundle pacing  [Delivering more physiological ventricular activation with conduction system pacing has the potential to protect from right ventricular pacing–induced cardiomyopathy. Observational data investigating His pacing supports this concept. Patients with a bradycardia indication for pacing were recruited into a non-randomized study taking place at two hospitals from the same healthcare provider. His pacing was attempted in 332 consecutive patients at one hospital, whereas 433 patients underwent right ventricular pacing at the other hospital. The primary endpoint of death, heart failure hospitalization or upgrade to BVP was significantly reduced in the His bundle pacing group  .If these promising findings are confirmed in randomized controlled trials, then this would be expected to lead to a change in clinical practice.No large randomized controlled trials have been performed, but based on the available observational data, the latest AHA guidelines recommend His bundle pacing (class IIb) in patients with block at the level of the AV node to preserve normal ventricular activation .Conduction system pacing shows considerable promise as a method for delivering pacing therapy for heart failure. However, there are still areas which require further work.Implant success rates have improved with the development of dedicated tools for delivering the lead to the His bundle. In a multicentre retrospective registry, Keene et al. found that implant success rate of 81% could be achieved with enthusiastic implanters using current technology, improving to 87% with greater implant experience . FluorosHowever, many operators still find His pacing technically challenging. Therefore, before there is large-scale uptake of this approach, more advanced tools are likely to be required. In the early days of biventricular pacing, left ventricular lead implantation via the coronary sinus was also challenging, and the development of multiple different implant tools and dedicated leads resulted in the high implant success rates we see now. The development of techniques for targeting the more distal conduction system with left conduction system pacing is also likely to lead to improvements in implant success rates.Lead macro-displacements appear to be relatively rare with His bundle pacing.However, lead intervention is required in ~ 7% of patients , 52. WhiMore prospective data is required to assess implant success rates and longer term pacing characteristics. While the results from observational and mechanistic studies with conduction system pacing have been encouraging, randomized controlled studies are now required to assess whether these findings translate in longer term clinical benefit.Conduction system pacing is a promising method for delivering pacing therapy for heart failure. Observational data suggests that it provides a viable alternative to BVP for delivering ventricular resynchronization to patients with LBBB. His-CRT can deliver more effective ventricular resynchronization than BVP and this translates in greater improvements in acute haemodynamic function. His-CRT also shows promise in patients with RBBB.Randomized controlled trials are now required to assess whether these promising findings translate into improvements in longer term clinical endpoints.AV-optimized His bundle pacing is being investigated in patients with heart failure and long PR interval, to see whether it improves exercise capacity, in a group of patients in whom BVP is not routinely recommended.


Very elegant invasive animal and human studies have demonstrated that in subjects with pressure overload due to severe aortic stenosis (AS), following aortic valve replacement (AVR), while myocyte regression is quite rapid, interstitial collagen content regression lags.hypothesize that this discord manifests as a thwarted improvement in diastolic function as related to LVH regression after AVR for AS.We Ten patients with severe, but compensated AS underwent 4 serial 3D cardiac MRIs (CMR) with 1.5 T EXCITE  out to 4 years . 3D LV volumetrics were measured. LV diastolic function was assessed by a phase velocity mapping slice placed at the tips of the mitral valve leaflets, acquired in a through-plane manner with temporal resolution of 25 ± 5 ms. Interrogation of resultant time-velocity curves was performed to resolve: 1) E:A ratio as mean and peak absolute and relative velocities 2) deceleration time. Figure 2, p < 0.05), neither were tightly correlated with improvements in diastolic function. However, using predictive modeling from historic controls, the improvement seen in diastolic function was incomplete and tardy. Specifically, while there were 4 patients that returned to normal diastolic function as per morphologic criteria, even these patients did not return to pre-morbid e:a ratios or deceleration times of the normal historic cohort. It followed that the remaining patients, except for one, improved only in arithmatic metrics. Importantly, while the LVH regresssed quickly, most occured within the first 6 months, there was a lag in diastolic function improvement by >12 months.All patients survived AVR and were available for serial follow-up over 4 time periods (mean 3 ± 1) out to 4 years. E:A ratios and/or morphology almost uniformly improved (9/10 pts) from 0.9:1 to 1.7:1 (p < 0.005), including 4 patients improving one complete grade. This was moderately well correlated with LV mass index regression . Deceleration time also improved . While EF improved , as did LV geometry (1.07 ± 0.2 to 0.94 ± 0.24 g/minterstitium, failing to be as heavily modulated by relief of pressure overload as are the myocytes, contributes to a paradoxical increase in diastolic stiffness. This interplay between collagen content and myocyte results in a less than expected improvement in myocardial diastolic properties following afterload relief contributing to residual dyspnea.Following AVR for severe AS, as expected, marked improvements in LV mass regression occur; however, improvements in diastolic physiology are incomplete and quite tardy, not paralleling structural changes. Pathophysiologically, it is likely that the


Light-chain (AL) amyloidosis is the most common type of systemic amyloidosis with poor prognosis. Currently, the predictors of cardiac involvement and prognostic staging systems are primarily based on conventional echocardiography and serological biomarkers. We used three-dimensional speckle tracking echocardiography (STE-3D) measurements of strain, hypothesizing that it could detect cardiac involvement and aid in prediction of mortality.We retrospectively analysed 74 consecutive patients with biopsy-proven AL amyloidosis. Among them, 42 showed possible cardiac involvement and 32 without cardiac involvement. LV global longitudinal strain (GLS), global radial strain, global circumferential strain and global area strain (GAS) measurements were obtained.The GLS and GAS were considered significant predictors of cardiac involvement. The cut-off values discriminating cardiac involvement were 16.10% for GLS, 32.95% for GAS. During the median follow-up of 12.5 months (interquartile range 4–25 months), 20 (27%) patients died. For the Cox proportional model survival analysis, heart rate, cardiac troponin T, NT-proBNP levels, E/e’, GLS, and GAS were univariate predictors of death. Multivariate Cox model showed that GLS ≤ 14.78% and cardiac troponin T ≥ 0.049 mg/l levels were independent predictors of survival.STE-3D measurements of LV myocardial mechanics could detect cardiac involvement in patients with AL amyloidosis; GLS and cardiac biomarkers can provided prognostic information for mortality prediction. Amyloidosis is a disease where the deposition of an amorphous protein-derived substance in the extracellular compartment results in damage to numerous organs. Light-chain (AL) amyloidosis is the most common subtype  and is eThere have been significant advances in cardiac imaging such as cardiac MRI and nuclear imaging for the diagnosis, risk stratification, amyloid burden and staging of CA. The deposition of amyloid in the heart leads to an increase in myocardial extracellular volume, which is readily detected by CMR through the late gadolinium enhancement (LGE). Nuclear imaging including pyrophosphate imaging aid in the quantification of amyloid load, and 123I-MIBG scintigraphy can detect cardiac sympathetic denervation in amyloidosis patients with cardiac involvement , 11. RecThe current study aimed to examine left ventricular (LV) myocardial strain in patients with AL amyloidosis by STE-3D to detect cardiac involvement, predict mortality, and to define the cut-off points for cardiac involvement in this population.We retrospectively analysed 74 consecutive patients who were newly diagnosed with immunoglobulin AL amyloidosis and referred to XiJing Hospital, Xi'an, China, for echocardiographic studies from October 22, 2014, through January 4, 2018. The diagnosis of immunoglobulin AL amyloidosis was made by histological confirmation of AL amyloid deposits in involved organs . The histologic diagnostic criteria were Congo red-positive deposition on light microscopy and nonbranching fibrils 8–10 nm in diameter on electron microscopy. Immunohistochemical staining confirmed single kappa or lambda light chain positivity. Immunofixation electrophoresis of blood and serum free light-chains also provided evidence of a monoclonal protein.We mainly used key ECG and echocardiographic criteria for CA in patients with confirmed light-chain immunoglobulin AL amyloidosis such as mismatches of low voltage ECG, and LVH on echo with a meanLV wall thickness greater than 12 mm without any other causes of LV hypertrophy, plus supportive evidence of cardiac involvement including elevated troponin and pro-BNP levels –17. The TTR gene mutation combined with Congo red staining were not included in the study. Patients with left ventricular ejection fraction (LVEF) < 50%, a history of hypertension or aortic valve disease, and other potential causes of LV hypertrophy were identified before enrolment and were excluded from the study.Patients with MTTR amyloidosis diagnosed by identification of Patients were categorized into stages I through IV based on scores according to the revised 4-point Mayo staging system . A scorePatients’ demographic characteristics, clinical data, electrocardiography and tissue biopsy results were obtained from hospital records. Echocardiographic studies were performed at the time of diagnosis for all patients. There was a maximum time interval of < 2 weeks between obtaining echo studies and performing biopsies. Patients were followed with the endpoint of all-cause mortality. Follow-up was obtained by reviewing the patients’ medical records or by telephone interviews with the patients or relatives and was completed before December 30, 2018. The study was performed in accordance with the principles of the Declaration of Helsinki and was approved by the institutional ethics committee. All patients were provided with a written informed consent by the department of nephrology or cardiology during they hospitalization at XiJing Hospital. We followed a strict institutional protocol regarding diagnosis, initial evaluation, treatment, and retrospective observation in this patient cohort.All echocardiographic studies were performed using an iE33 ultrasound system  with a 1.0–5.0 MHz broad-band transducer. The subjects were placed in the left lateral recumbent position, and the ECG was recorded simultaneously. Conventional echocardiography was performed with an S5-1 probe. The maximum LV wall thickness (MLVWT). LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), left atrial volume (LAV), LVEF, peak early filling (E-wave) and late diastolic filling (A-wave) velocities was measured according to the standardized American Society of Echocardiography protocol . The E/AAn X5-1 matrix-array transducer  was used to acquire full-volume 3D images from the apical four-chamber views. The images were adjusted by biplane mode to obtain images that included the entire LV with clear endocardial borders. The participants were asked to hold their breath during full-volume 3D data acquisition. The off-line analysis was performed by transferring full-volume 3D images to a TomTec workstation using analysis software . Apical two-chamber, three-chamber and four-chamber views were automatically selected at end-diastole.Once the user confirmed that the automatically selected views and the image frames were correct, the algorithm automatically identified the LV endocardial boundary at end-diastole. After this step, the reader could manually edit the boundaries. Subsequently, the LV was divided into 16 segments using standard segmentation and expressed as per segment, per level  mean, or global  mean. The 3D strain measurements derived included LV peak systolic global longitudinal strain (GLS), global radial strain (GRS), global circumferential strain (GCS), and global area strain (GAS), which is defined as the combination of GLS and GCS. GLS, GRS, and GCS were averaged over the 16 segments. Segment longitudinal strain included: basal, medial, and apical segment, apical to basal ratio , relative apical sparing . The peak value of each strain measurement was defined as its maximum absolute value with a positive sign. The observer was blinded to cardiac involvement or survival status.In all patients with AL amyloidosis, blood was collected for the measurement of the levels of myoglobin, troponin I, N-terminal proB-type natriuretic peptide (NT-proBNP), cardiac troponin T, serum and/or urine kappa lambda protein, and creatinine. Estimated glomerular filtration rate (eGFR) was calculated by CKD-EPI formula. The mean difference between kappa or lambda free-light chain (FLC) in the involved FLC and uninvolved FLC was reported as FLC-diff. Protein levels were measured from the 24-h urine collection.P value < 0.05 was considered to indicate statistical significance. Reproducibility statistical analyses were performed using MedCalc statistical software version 15.2.2 . Intra-observer variability was calculated by repeated measurements by the primary reviewer (CHL) 2 months after the initial measurement. Interobserver variability was calculated by comparing the original GLS and GAS calculation with that calculated by a blinded second observer (XLZ1).Intra-observer and interobserver variability was assessed using the intraclass correlation coefficient. A t tests and Wilcox on-rank sum tests when assumptions were not met. For the categorical variables, either Pearson’s chi-squared or Fisher’s exact tests were used. We studied echo parameters and STE-3D between the Cardiac Involvement (CI) and without CI. Based on the univariate analysis, clinically relevant parameters were grouped for multivariate logistic regression model by incorporating a set of variables that were most statistically significant and with potential clinical relevance.Continuous variables were expressed as mean ± SD or median IQR, and categorical variables as frequencies and percentages. The continuous data were compared using the Student’s P value < 0.05 was considered statistically significant.For the entire cohort, Kaplan–Meier analysis was used to estimate overall survival, and differences between groups were tested for statistical significance using the 2-tailed log-rank test. Overall survival was defined as the time from the date of initial diagnosis of AL to the date of death or last follow-up. In order to identify risk factors for mortality. Univariate cox proportional hazards regression analyses were used for each of the variables, Multivariate Cox regression analysis was performed by incorporating into the model a set of variables that were most statistically significant according to univariate analysis or based on their potential clinical relevance. All the statistical analyses were performed using SPSS statistical software  and MedCalc statistical software version 15.2.2 . P < 0.001), For the entire study population, all 32 patients without cardiac involvement were of Mayo stage I and II. Among 42 patients with cardiac involvement, 11 (26.2%) patients were with Mayo stage I and II, while 31(73.8%) patients were with Mayo stage III and IV.Total of 74 patients with AL amyloidosis were included : 42 (57%) with cardiac involvement (CI) and 32 (43%) without cardiac involvement (CI). Seventeen patients (40.5%) with cardiac involvement and three patients (9.4%) without cardiac involvement died during the follow-up. Patients’ baseline clinical characteristics and serological biomarker data are summarised in Table Conventional echocardiographic parameters are detailed in Table Three-dimensional speckle tracking echocardiography parameters are featured in Table The results of the univariate and multivariate regression analyses of predictors of cardiac involvement in patients with AL amyloidosis are demonstrated in Table ROC analyses were performed to determine the optimal thresholds associated with cardiac involvement Fig. . A baselFor GLS, the intra-class correlation coefficient for intra-observer agreement was 0.95 ; and the inter-observer agreement was 0.90 . For GAS, the intra-class correlation coefficient for intra-observer agreement was 0.93 ; and the interobserver agreement was 0.87 , reflecting substantial agreement for measurement of GLS and GAS.P < 0.05) between survivors and non-survivors. The univariable Cox regression survival analysis is shown in Table p < 0.001, respectively) , 20 (27%) patients with AL amyloidosis died, 9 died due to sudden death, 1 due to cerebral haemorrhage, 6 due to heart failure, 1 because of renal failure, 1 after gastrointestinal bleeding, and, 2 due to multi-organ failure. Tables This study comprehensively assessed cardiac properties of patients with AL amyloidosis analysing clinical, conventional echocardiography, serological biomarker and STE-3D derived myocardial function data. The primary findings of the study were as follows: GLS and GAS were significantly decreased in patients with cardiac involvement. The most prominent decrease was at the basal and medial segments, as manifested by the apical to basal strain ratio and relative apical sparing. GLS threshold ≤ 16.10% and GAS threshold ≤ 32.95% demonstrated predictive value in patients with AL amyloidosis. Abnormalities in GLS, GAS, apical/basal ratio and relative apical sparing assessed with STE-3D were also associated with reduced survival.AL amyloidosis is characterised by a relatively low burden of clonal plasma cells and involvement of multiple organs by immunoglobulin light chain-derived amyloid fibrils . The couKoyama et al.  demonstrOur study demonstrated the value of STE-3D parameters in identifying cardiac involvement in systemic AL amyloidosis. We found that patients with cardiac amyloidosis presented with considerable impairment in LV mechanics. They had decreased GLS, GAS, increased apical/basal ratio and relative apical sparing values. Our findings confirmed other published reports of longitudinal strain to predict cardiac involvement in patients with AL amyloidosis. LV longitudinal strain was markedly decreased in cardiac amyloidosis patients with the most prominent reduction in the basal segments while the apical strain was preserved. Basal strain impairment, relative to apical strain preservation, has been reported and serves as a useful discriminator between the AL-CA and other forms of myocardial hypertrophy such as systemic arterial hypertension, athletes and hypertrophic cardiomyopathy . Based oIn AL amyloidosis, GLS abnormalities were likely related to immunoglobulin deposition in the LV endocardium. Cardiac amyloid burden can be reflected by myocardial extracellular volume fraction . The motGlobal area strain (GAS) reflects the relative area of change that combines of both longitudinal and circumferential shortening . Given tWe feel that multi-modality imaging will play important roles for the diagnosis of AL amyloidosis with cardiac involvement. A recently published large European study used T1 mapping for the assessment of CA. A native T1 < 1036 ms was associated with 98% negative predictive value for CA whereas a native T1 > 1164 ms was associated with 98% positive predictive value for CA. The authors proposed using these cut-off values to exclude or confirm CA and to restrict the administration of contrast only to patients with intermediate probability . PrelimiOur study is a retrospective, single-center cohort with a relatively small sample size. In future studies, a sufficiently large number of patients with confirmed cardiac events will be important to verify the results of our survival analyses and to explore the value of other strain parameters. A single diagnostic gold standard such as cardiac biopsy was not used in all patients to define cardiac involvement. The reference values may vary among studies due to the use of different scanners and software algorithms for computing 3D strain. The STE-3D parameters GLS and GAS are not standardized yet, and the cut-off values identified in the current study might not be applicable when using a system different from our study. We did not have RV STE-3D data in our patients. Once validated in the future, RV STE-3D may potentially be utilized to assess the mechanics of the right ventricle and provide additional information for assessing prognosis in CA patients.The prognosis was poor for patients with AL amyloidosis and cardiac involvement. Early identification of patients with cardiac involvement is essential. Our data suggest that STE-3D measurement of the LV myocardial mechanics could identify early cardiac impairment and improve risk stratification in patients with primary systemic AL amyloidosis, and provide incremental benefit beyond standard assessments such as 2D echocardiographic metrics, troponin T and NT-proBNP.