Patients with heart failure with pulmonary edema may have declining left atrial (LA) function. Left atrial strain (LAS) imaging enables quantitative assessment of LA function. The aim of this prospective study was to assess the LA function and pulmonary edema in patients with heart failure evaluated by cardiopulmonary ultrasonography.Two-dimensional speckle-tracking echocardiography for LAS was performed in 115 consecutive patients with congestive heart failure. A semiquantitative B-lines score of pleural effusions was derived by pulmonary ultrasound almost at the same time by combined cardiopulmonary ultrasound.reservoir, 21.5 ± 4.9% vs. 9.2 ± 3.7% [P < 0.001]; LASconduit, 10.7 ± 3.5% vs. 5.1 ± 2.1% [P < 0.001]; LASpump, 11.3 ± 5.4% vs. 4.0 ± 2.7% [P < 0.001]), lower LVEF, TAPSE; and higher SPAP, E/e′, larger LA, LV, RV; more severe MR. However, there were no signiﬁcant between-group differences with respect to sex and body surface area. In patients with pulmonary edema, B-lines score was independently associated with LASreservoir ; LASpump  and LASconduit . On multiple linear regression, decreased LASreservoir  and elevated SPAP  were significantly associated with B-lines score in heart failure.Compared with those who did not have pulmonary edema, patients with pulmonary edema had lower LAS (LASDeclining LA function, especially the reservoir function, assessed by speckle-tracking echocardiography is related to the degree and occurrence of pulmonary edema in patients with left heart failure. Pulmonary edema is one of the most serious consequences of left heart failure. It is the main determinant of adverse outcomes, higher risk of hospitalization, and emergency department visits, and is evaluated as a treatment target in patients with heart failure . In patiThe main role of the left atrium (LA) is to regulate left ventricular filling and cardiovascular function. As a complex process, the LA acts as a reservoir during systole, a conduit for direct blood flow from the pulmonary veins into the left ventricle during the early diastolic period, and as an active pump in the late diastolic period of the left ventricle. LA function has been shown to predict left ventricular filling pressure and adverse cardiac outcome . DeclineHowever, there is a paucity of studies evaluating the prevalence and correlation of left atrial dysfunction in patients with heart failure who have pulmonary edema. In this study, we used cardiopulmonary ultrasonography for comprehensive and simultaneous assessment of the degree of pulmonary edema, left atrium strain, and other echocardiographic parameters in patients with congestive heart failure to explore the correlation of these indices with cardiogenic pulmonary edema.This was a prospective study conducted at an affiliated hospital of a medical college. Patients with congestive heart failure [diagnosis based on the 2016 ESC Guidelines ] who werExaminations were performed by qualified sonographers using the same equipment  and transducers (S5-1 phased-array probe [1–5 MHz] and L12-3 linear probe [3–12 MHz]). Cardiopulmonary ultrasonography was performed prior to initiation of intravenous diuretic therapy. Echocardiography was performed in the left decubitus position, supine, or near-to-supine position. Pulmonary ultrasound was performed with patients in supine or near-to-supine position.Two-dimensional, M-mode, and Doppler measures and indices were obtained using standard techniques outlined by the American Society of Echocardiography . Assessmconduit, a “positive” wave describing LA myocardial lengthening during passive conduit function); LA pump strain ; and LA reservoir strain  at both end-diastole  was used to observe the pleural lines (smooth and regular hyperechoic linear structure in cardiogenic pulmonary edema) with a linear-probe. Abnormal pleural lines can also generate B-lines such as due to interstitial lung disease  or pneumThe following B-line scoring method was used: The anterior and lateral chest wall was divided into seven-zones. B-line score was then calculated according to the degree of pulmonary edema . A scoret test, Wilcoxon rank-sum test, Chi-squared or Fisher's exact test as appropriate. Simple linear regression was used to assess relationship of B-lines score with LA reservoir, conduit, and pump strain and other echocardiographic and clinical parameters. Stepwise multivariate logistic regression analysis was applied to identify the independent predictors of pulmonary edema. All variables associated with P values <0.05 were included in multivariable analysis, and collinearity between dependent factors was checked. Model performance of LAS for detecting pulmonary edema was assessed using area under the curve (AUC) along with its 95% confidence interval (CI). Intra- and inter-observer variability for LA strain were assessed using analysis of limits of agreement and the intraclass correlation coefficient in 20 patients randomly selected from the study population by the same observer (H.L.) and a second observer (J.C.). Both observers were blinded to the results of pulmonary ultrasound assessments at the time of strain analysis. Analysis was performed using SPSS 20.0 software . P values <0.05 were considered indicative of statistical significance.Normally distributed continuous variables are expressed as mean ± standard deviation, while those with skewed distribution are expressed as median (range). Categorical variables are expressed as frequency (percentage). Between-group differences were assessed using unpaired n = 73), four patients had HFpEF. The majority of patients had coronary heart disease (52%) and hypercholesterolemia (52%), while 20% patients had type Ⅱ diabetes mellitus, and 32% patients had hypertension. Median (range) values of LA reservoir, conduit, and pump strain were 11.6 (2.9–30.8), 6.1 (1–19.4), and 5.1 (0.3–18.8), respectively. The baseline characteristics of the study population are summarized in Of the 155 consecutive patients screened, 13 patients were excluded because of atrial arrhythmias, 11 because of concomitant lung disease, 6 because of primary severe valvular heart disease, 5 because of renal failure, and 5 because of poor echocardiographic windows. Therefore, 115 patients  qualified the eligibility criteria. Eleven patients had HFpEF (LVEF > 50%) and 104 patients had HFrEF; among patients with pulmonary edema . Moreover, patients with pulmonary edema had lower LVEF, TAPSE; higher SPAP, E/e′, larger LA, LV, RV; and more severe MR. However, there was no significant between-group difference with respect to sex and BSA (reservoir (OR (95% CI) = 0.53[0.35–0.80], P < 0.01), PASP (OR (95% CI) = 1.33[1.05–1.68], P < 0.05) were the independent predictors of pulmonary edema.Patients with pulmonary edema had significantly reduced LAS and BSA . On stepn = 4) and HFrEF (n = 69).This analysis only included the group with pulmonary edema. Considering that only four patients had HFpEF in this group, we analyzed all cases including HFpEF ; LASpump ; LASconduit ; MR ; PASP ; E/e′ ; LV diastolic function ; LAindex ; LVGLS ; RV ; TAPSE ; and LVEF . However, B-lines score was not associated with age (P = 0.38), LVEDD (P = 0.86), or LVEDVindex (P = 0.74).B-lines score was independently associated with LASreservoir  and elevated SPAP  were significantly associated with B-lines score in heart failure . LASconduit cut-off value of less than 7.5% for pulmonary edema had 87.7% sensitivity and 85.7% specificity . LASpump cut-off value of less than 6.5% for pulmonary edema had 87.7% sensitivity and 81.0% specificity .We further investigated the value of these echocardiographic indices for identifying pulmonary edema by performing receiver operating characteristics (ROC) curve analyses. Area under the curve (AUC), optimal cutoff values, and corresponding sensitivity and specificity for pulmonary edema. Among all clinical and echocardiographic parameters analyzed, LASreservoir, LASconduit, LASpump were 0.95 , 0.91 , and 0.90 , respectively, for intraobserver variability assessment and 0.93 , 0.84 , and 0.88  for interobserver variability assessment.For assessment of inter-observer variability, two investigators (H.L. and J.C) independently performed strain measurements in a random sample of 20 patients in a blinded manner. The intraclass correlation coefficients of LASreservoir, LASpump, LASconduit values compared to patients with heart failure who did not have pulmonary edema. Compared to those without pulmonary edema, patients with pulmonary edema were older, had lower LVEF, TAPSE; and higher SPAP, E/e′, larger LA, LV, RV; more severe MR. On stepwise logistic regression analysis, LASreservoir and SPAP were identified as independent predictors of pulmonary edema. We further analyzed the correlation of left atrial function and other echocardiographic and clinical parameters with the degree of pulmonary edema in the group with pulmonary edema. We found a consistent reduction in LA strain levels in patients with more severe pulmonary edema; in addition, there was no association between the degree of pulmonary edema and LV dimension or volume. On multiple linear regression, decreased LASreservoir and elevated SPAP were significantly associated with the degree of pulmonary edema.In this study, we evaluated LA strain using a strain software that was developed for the left atrium, which is different from that used only for the evaluation of left ventricle. We found that patients with pulmonary edema had reduced LASreservoir rather than E/e′ was closely related to PAWP (The 2016 guidelines for assessment of left ventricular diastolic function mention E/e′ as an important and easily-obtained evaluation parameter; however, it is a less accurate parameter for estimating the LV filling pressure compared to invasive catheters –17. Clin to PAWP . LA stra to PAWP , 23. It It was reported that pulmonary edema develops acutely with LA hypertension . When lereservoir compared to other LA function and standard diastolic markers of elevated LA pressure and left ventricular filling pressure (reservoir, may remain at high risk of developing pulmonary edema decompensation, hospitalization, and even emergency department visits. The decrease in left atrial function should alert the clinician that such patients require diuresis and afterload reduction. In addition, patients with heart failure showing significant reduction in left atrial strain should be evaluated by pulmonary ultrasonography or chest x-ray to rule out pulmonary edema.LA reservoir and conduit function changes with LV compliance and impaired relaxation. In the univariate analysis, the association of LA reservoir, conduit strain, and B-line score reflects the mechanism of association of pulmonary edema with increased LA pressure and tension and impaired LA compliance. Cardiogenic pulmonary edema is the decompensated stage of left heart failure. Occurrence of pulmonary edema indicates severe increase in LA pressure, which impairs the atrial reservoir and conduit functions. In addition, our study showed a better correlation between LA reservoir strain decrease and increase in B-lines score in patients with pulmonary edema. This may be explained by the greater sensitivity of LASpressure . PatientIn our study, we attempted to highlight the decrease in the LA pump function in patients with left heart failure with pulmonary edema. Ramkumar et al. found that LA pump function is independent of LV function . DiffereFirst, this was a single-center study. The study population comprised exclusively of inpatients in the Department of Cardiology who could receive cardiopulmonary ultrasound evaluation. Second, sufficient image quality for strain analysis was needed, so 5 patients were excluded from our analysis. Third, we used noninvasive B-lines scores to evaluate the degree of pulmonary edema rather than invasive hemodynamic validation. Future studies should also employ invasive hemodynamic evaluation to better characterize the physiology of LA function in patients with pulmonary edema.In patients with HF, those with pulmonary edema have worse left and right heart function. The degree of pulmonary edema increases with the decrease in left atrial function. We demonstrated that LA reservoir function is more closely related with pulmonary edema compared to the other echocardiographic parameters. Therefore, non-invasively obtained LA deformation parameters may be used to predict the occurrence of pulmonary edema.


Troponin increase was independently associated with the cumulative incidence of all-cause hospitalization with an adjusted hazard ratio of 5.14 . Conclusions: The increase in cardiac troponin levels may be a reasonable surrogate marker of response to tafamidis therapy in patients with transthyretin cardiac amyloidosis.Background: Recent clinical trials have demonstrated that tafamidis  reduced all-cause mortality and the number of cardiovascular hospitalizations compared with placebo in patients with transthyretin cardiac amyloidosis. However, the optimal surrogate markers during tafamidis treatment remain unknown. Methods: Consecutive patients with transthyretin cardiac amyloidosis who received tafamidis in our institute between May 2019 and December 2022 were retrospectively evaluated. The prognostic impact of an increase in troponin I levels during tafamidis therapy was evaluated. Results: A total of 18 patients  were included. For 14-month tafamidis therapy on median, cardiac troponin I levels increased in five patients. The cumulative incidence of all-cause hospitalization was significantly higher in the troponin-increased group than in the others (100% versus 33%,  Amyloidosis is a group of diseases in which amyloid fibrils deposit in the extracellular spaces of different organs, ultimately leading to progressive multi-organ dysfunction . As a reTafamidis  binds to the thyroxine-binding site of transthyretin and stabilizes transthyretin tetramers . In the Recently, high-sensitivity cardiac troponin T (hs-cTnT) was proposed as a practical marker to screen cardiac amyloidosis . We hypoWe retrospectively evaluated consecutive patients who started tafamidis therapy between May 2019 and December 2022 to treat their ATTR-CM, which was diagnosed by the presence of amyloid deposits in their endomyocardium. All patients met society’s requirements for the administration of tafamidis [All patients received standard medical therapy, including diuretics for chronic heart failure, in addition to tafamidis. The management of heart failure was conducted by board-certified cardiologists. Permanent pacemaker implantation was performed in patients with advanced atrioventricular block. If the patients met the recommendation criteria for implantable cardiovascular defibrillator and/or cardiac resynchronization therapy , these tTafamidis was considered to be discontinued in several clinical scenarios after dedicated informed consent from patients and their relatives, including the requirement of non-pharmacological interventions, progression of frailty, and progression of heart failure .Medical records of all patients at the time of administration of tafamidis were retrospectively reviewed. Data on baseline demographic characteristics were collected, including the numbers of previous heart failure hospitalizations, the duration of heart failure, NYHA classifications, and the prevalence of implantable cardiac pacemaker. The presence of a monoclonal gammopathy of undetermined significance (MGUS) was defined as an abnormal serum free-light-chain ratio and detection of a monoclonal protein on serum or urine immunofixation electrophoresis .Plasma B-type natriuretic peptide (BNP), serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), serum albumin, and serum creatinine levels were measured immediately before tafamidis administration. Serum levels of cardiac troponin I and hs-cTnT were measured within three months before tafamidis administration. Levels of cardiac troponin I were re-evaluated from 1 to 12 months after tafamidis administration. Plasma BNP and serum troponin I concentrations were measured using a commercially available assay . Serum NT-proBNP concentrations were measured by Elecsys NT-proBNP immunoassay . Hs-cTnT concentrations were measured using a commercially available assay .We divided all patients into 2 groups according to the increase/non-increase in cardiac troponin I levels from baseline to 1 to 12 months after administration of tafamidis.Electrocardiographic data, including rhythm and QRS duration, were examined. Echocardiographic data, including interventricular septum thickness, left-ventricular ejection fraction, left-ventricle mass index, and the prevalence of aortic valve stenosis (>moderate) and tricuspid valve regurgitation (>moderate), were also investigated. The measurements of echocardiography were performed by physiological technicians and verified by echo cardiologists in a standard fashion as recommended by the American Society of Echocardiography’s guidelines ,15. The p < 0.05 were considered significant. Continuous data were described as median and interquartile range and were compared between two groups using the Mann–Whitney U test. Categorical data were compared between two groups by Fischer’s exact test.Statistics were performed using JMP pro ver17.0 . Variables with All cohorts were divided into two groups by the increase/non-increase in troponin levels during tafamidis therapy. Patients were followed during tafamidis therapy, which was defined as an observation period of this study. Patients were censored when they terminated tafamidis.Cumulative incidence of all-cause hospitalization and worsening heart failure hospitalization were assessed using by the Kaplan–Meier method as primary outcomes. We calculated the event rate of total hospitalizations and heart failure hospitalizations per year during the tafamidis treatment period.p < 0.05 in the univariable analyses were included in the multivariable analyses.The impact of troponin increase on all-cause hospitalization was evaluated by Cox proportional-hazard ratio regression analyses. Several baseline characteristics were included in the univariable analyses as potential confounders, in addition to the troponin increase. Variables with The baseline demographics data of the enrolled 18 patients are shown in p < 0.05 for all). There were three patients (17%) with concomitant MGUS (IgG-κ type), all of which were in the troponin-increased group.There were five patients with troponin increase during tafamidis therapy. In the other 13 patients, cardiac troponin I levels remained unchanged . The nump > 0.05 for all).The levels of BNP and NT-proBNP on median were 222 and 1898 pg/mL, respectively . The levp = 0.034; p = 0.047). There were no significant differences between the two groups in terms of baseline echocardiographic parameters and medication data  months in the entire cohort . Four pap < 0.0001; p = 0.058; No patients died during tafamidis therapy. The cumulative incidence of all-cause hospitalization was significantly higher in the troponin-increased group  and heart failure hospitalization (event rate: 0.81 versus 0.17 events per year).p = 0.048; In the multivariable analyses, troponin increase was independently associated with the cumulative incidence of the all-cause hospitalization with an adjusted hazard ratio of 5.14  in cardiac amyloidosis is associated with mortality and morbidity, as well as higher incidence of pacemaker implantation . In our No studies evaluated the trend in hs-cTnT during tafamidis therapy, except for one study . This stThe current recommendation for optimal patient selection for tafamidis therapy is limited to NYHA class I or II. However, such a symptom-based classification is subjective. Furthermore, prognostic impacts of any objective markers, such as BNP level, have not been demonstrated thus far. In the previous study, baseline plasma BNP levels and estimated glomerular filtration rate were not associated with clinical outcomes .In this study, we found that the increase in troponin levels was an independent predictor of worse prognosis, even after adjusting for baseline potential confounders, including baseline troponin levels, serum NT-proBNP levels, and QRS duration. We agree with the importance of baseline characteristics for risk stratification and optimal patient selection for tafamidis therapy, but according to our findings, a trend in troponin levels during tafamidis therapy may also have an additional prognostic impact.Other markers may also be useful to follow during tafamidis therapy. However, Oche et al. demonstrated that several clinical parameters obtained during tafamidis therapy were not associated with future clinical outcomes.According to our findings, we highly recommend following serum cardiac troponin levels to assess the efficacy of tafamidis, which may predict future clinical outcomes. Tafamidis therapy may be considered to be terminated in patients with persistently increased troponin levels despite tafamidis therapy, considering its cost effectiveness .This study was conducted retrospectively with a very small sample size at a single institute, and the observation period was just 14 months on median. One patient with the variant type was included in the study, and the clinical response of tafamidis may differ from those with the wild type, whereas the ATTR-ACT trial included both types and the clinical benefit of tafamidis was shown in both types.There were no data on exercise capacity and quality of life. We have no global myocardial strain data in the echocardiography. We could not exclude the influence of concomitantly performed pharmacological and non-pharmacological therapies, other than tafamidis therapy.An increase in cardiac troponin I levels during tafamidis therapy was independently associated with worse clinical outcomes in patients with ATTR-CM. An increase in troponin levels may be a practical surrogate biomarker to monitor and assess the clinical efficacy and predict future response to tafamidis therapy. Clinical implications of troponin-guided therapeutic strategies should be validated in the future study.


The 2022 ESC ‘Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery’ have endorsed use of cardiac troponin (cTn) T and I, to help improve perioperative outcomes.2Over 300 million surgical procedures are performed annually, with demand for surgery likely to increase in the coming years with an aging population.2The guideline recommends the use of cTn in patients at higher risk in two situations: firstly, for preoperative risk stratification, and secondly, for the detection of perioperative myocardial infarction/injury (PMI), using an active surveillance strategy involving serial cTn measurements, starting preoperatively and continuing on postoperative days 1 and 2.2–5 First studies estimated that PMI is much more common than expected (16% in high-risk patients)3 and a major contributor to 30-day mortality after non-cardiac surgery within 30 days.6 Most patients with PMI do not exhibit typical ischaemic symptoms,6 making the asymptomatic presentation insidious. In fact, asymptomatic PMI has been shown to have a similar impact on 30-day mortality as symptomatic PMI .3Perioperative myocardial infarction/injury, defined as an acute increase in cTn concentration compared to preoperative concentration, is a pathophysiological hallmark of nearly all perioperative cardiovascular complications and can easily and inexpensively be detected by serial measurements.infarction due to thrombotic plaque rupture, to type 2 myocardial infarction caused by demand–supply mismatch due to bleeding, hypotension, or tachyarrhythmias, to acute heart failure and severe sepsis causing myocardial injury.4The term PMI includes ‘infarction/injury’ to highlight that at time of detection via acute cTn increase, the predominate aetiology of cardiomyocyte injury remains to be determined. The causes of PMI vary widely, from type 1 myocardial 5 Beside the difference in associated outcome, the time from diagnosis of PMI to further complications is also markedly shorter in PMI of the acute heart failure (median 3 days) compared with those with type 2 myocardial infarction or tachyarrhythmia (median 13 days). Hence, the window of opportunity to improve outcome is dependent of aetiology as well. In most cases, the first investigation following clinical evaluation will be a transthoracic echocardiography, ideally performed on the day of PMI detection.5Due to this heterogeneity, detailed clinical evaluation of patients with PMI is paramount. While all aetiologies are associated with worse outcomes, stark differences exist according to presumed aetiology, with 1-year mortality reaching 49% in PMI of acute heart failure type, 40% in tachyarrhythmia type, and 39% in primarily non-cardiac cause PMI.Figure 1) focusing on determining the underlying aetiology and implementing aetiology-specific treatment strategies from the non-surgical setting, with the aim of improving perioperative outcomes by interdisciplinary collaboration following non-cardiac surgery.2The current guidelines proposes a diagnostic and management algorithm (


The management ofthis disease can be challenging since it often culminates in refractorypulmonary edema and multi-organ failure. We present the case of a 50-year-oldmale who was admitted in cardiogenic shock following myocardial infarction.After successful revascularization, percutaneous mitral valve repair using theMitraClip Several attempts to wean frommechanical circulatory support (MCS) using an extended catecholamine regime withdobutamine and norepinephrine failed because of recurrent pulmonary edema and theonset of multiple organ failure. In this critical situation, an LVAD implantationwould have been associated with a prohibitively high mortality risk. Decision wasmade for percutaneous MitraClip® implantation to allow ECMELLA weaningand organ recovery.A 50-year-old male patient presented with acute ST-elevation infarction. He underwenta left heart catheter, revealing a total occlusion of the proximal circumflexartery. Under intra-aortic balloon pump support, he underwent interventionalrecanalization with coronary drug-eluting stent implantation. A transthoracicechocardiographic examination revealed a severe secondary mitral valve regurgitation(grade III) due to left ventricular dilatation (LVEDD = 56 mm) and a severelyreduced of the left ventricular ejection fraction (LVEF 10%) . New Yor® implantation,the patient stabilized and pulmonary edema was resolved , mitral valve regurgitation was significantly reduced tograde I . There was no significant stenosis after clipping (dp mean =3 mmHg). LVEDD dropped from 56 to 50 mm. After MitraClipresolved . Within ® system is arapidly developing approach for selected patients suffering from mitral valveregurgitation. Clip implantation can be performed safely in high-risk heart failurepatients with functional mitral regurgitation, whose surgical risk is prohibitivelyhigh or who are considered inoperable.1 PMVR has been shown to improvehemodynamic parameters, symptoms, and re-hospitalization in this challenging patientgroup.2 Although reverse cardiac remodeling at mid-term follow-up hasbeen reported after successful MitraClip® implantation in heart failurepatients with depressed left ventricular ejection fraction, left ventriculardysfunction seems to progress in patient with end-stage heart failure.3 Even if theprogression of the underlying disease cannot be stopped, MitraClip®implantation can temporarily improve hemodynamics and reduce symptoms. This enableshigh-risk patients in multi-organ failure to recover and to reduce the risk ofsubsequent surgery. In our case, this strategy enabled successful ECMELLA weaningand organ recovery, allowing for the implantation of a continuous-flow leftventricular assist device (CF-LVAD). LVAD implantation was performed in the usualway, without any interaction with the implanted two clips. Based on the availableliterature, implantation of CF-LVAD appears safe in patients with previously placedMitraClips®, with no need for additional open mitral valvesurgery.4 This case may serve as proof-of-concept and demonstrates thepotential role of PMVR in stabilizing patients, and supporting organ recovery toallow optimal conditions for elective surgery, and potentially reducingperioperative risk and mortality. Additional treatment costs for the MitraClipdevice must be taken into account, but in our case, could be amortized by shorteningthe intensive care period.Percutaneous mitral valve repair (PMVR) using the MitraClip® system is feasibleunder simultaneous VA-ECMO and Impella® support and can be effective instabilization, recompensation, and recovery in severely compromised patients withsevere secondary mitral valve regurgitation and cardiogenic shock. This conceptprovides a reasonable bailout strategy in selected patients allowing for theirstabilization before LVAD implantation, likely to reduce perioperative mortality andto improve the outcome.The presented case shows that PMVR using the MitraClip


Except for the left atrial volume to cardiac index, all other chamber ratios significantly correlated with hemodynamics. Left to right ventricular ratio cut point <0.82 has high sensitivity (91% and 97%) and specificity (88% and 85%) for identifying significant elevations of mPAP and PVR, respectively (AUC 0.90 and 0.95), outperforming atrial ratios . Manual LV:RV basal dimension ratio correlates strongly with semiautomated volume ratio  and is an expeditious alternative with comparable prognostic utility (AUC 0.90 and 0.95). LV:RV dimension ratio of <1.03 and ≤0.99  is a simple metric that can be used for CTEPH outcome prediction.CT pulmonary angiography is commonly used in diagnosing chronic thromboembolic pulmonary hypertension (CTEPH). This work was conducted to determine if cardiac chamber size on CTPA may also be useful for predicting the outcome of CTEPH treatment. A retrospective analysis of paired CTPA and right heart hemodynamics in 33 consecutive CTEPH cases before and after pulmonary thromboendarterectomy (PTE) was performed. Semiautomated and manual CT biatrial and biventricular size quantifications were correlated with mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and cardiac output. The baseline indexed right atrioventricular volumes were twice the left atrioventricular volumes, with significant ( Pulmonary thromboendarterectomy (PTE) is the treatment of choice in eligible patients as it provides excellent symptomatic and prognostic improvement . Within rognosis ,4, thererognosis . Post-surognosis . The larrognosis  showed tWhile the correlation between the extent of technically accessible disease and PH severity is an important determinant for predicting hemodynamic improvement , post-suThe ventricular adaptations in CTEPH pathophysiology are well documented. Disease progression is characterized by worsening RV remodeling and RV dysfunction. Diastolic RV pressure increases in combination with low left ventricular (LV) preload and underfilling results in LV diastolic impairment . The atrWe undertook this study to determine if non-ECG-gated CTPA can be used to evaluate atrioventricular size in CTEPH and if the CT-derived chamber quantification before and after pulmonary thromboendarterectomy (PTE) can help identify patients with significant residual PH and thereby provide a noninvasive measure for long-term outcome prediction. This retrospective study was approved by the Institutional Review Board (IRAS project ID 280472), and the need for informed consent was waived. The main aim of our study was to evaluate the biatrial and biventricular chamber sizes using CTPA before and after PTE. Our standard departmental policy is to perform CTPA and right heart catheterization (RHC) in all CTEPH patients prior to and 3–4 months following PTE. Of the 53 consecutive adult (>18 years) CTEPH patients who had undergone PTE between Jan 2014 and 2019, complete paired datasets  were available for 44 cases. Following a consensus decision, 11 patients were excluded due to suboptimal CT image quality , and 33 paired cases were included in the final evaluation. Clinical and laboratory data, including body surface area, atrial fibrillation, WHO functional class, renal function and BNP, were routinely assessed and extracted via the electronic medical record. Echocardiographic evidence of tricuspid regurgitation and its severity was recorded. Images were acquired on a 128-slice configuration scanner  using our routine non-electrocardiographic-gated protocol with the following standard acquisition parameters: 0.8 pitch, 0.6 mm collimation, table speed 61.4 mm/rotation, 0.5 s rotation time, tube current 100 mAs and tube voltage 80–120 kVp. Scanning was performed in a craniocaudal direction from the thoracic inlet to the diaphragm following injection of 70–100 mL Omnipaque 350  at rates of 5 mL/s. Bolus tracking technique was performed with CARE bolus software , with the region of interest placed on the main pulmonary trunk and the trigger threshold set at 130 HU. Sequential axial images were reconstructed at a 1-mm slice thickness at a 1 mm interval using SAFIRE  iterative reconstruction and a standard 512 × 512 matrix size.The time interval between CTPA and RHC pre-PTE varied between 1 and 19 days (median 1 day), while post-PTE, the 2 procedures happened either on the same day or within a 1-day interval. The CT cardiac chamber quantification was performed in accordance with the well-established international recommendations in echocardiography ,13 by twBiatrial and biventricular volumes were measured by semiautomated volume segmentation using a commercially available software . As specific postprocessing software might not be readily available to all CT readers, we also did simpler manual measurements of atrial volumes and the ventricular basal dimension ratio. Manual contouring for atrial volumes was performed using the Vitrea Advanced Visualization multimodal platform . Biventricular length was measured from the 4-chamber plane, extending from the widest basal portion of the RV to the LV endocardium . The ven2). The calculated volumes were indexed to body surface area. The time taken for loading and processing by the automated system and manual measurements was recorded. A detailed description of the methodology used for deriving the CT metrics is outlined in All length measurements were recorded in centimeters (cm) and all area measurements in centimeters squared  tracings were obtained at end-expiration (mean of 3 tracings in sinus rhythm or 5 in AF). Cardiac output (CO) measurements were made using the thermodilution or Fick method. PVR (Wood units/WU) was calculated by (mPAP − mPAWP) ÷ CO. The various CT metrics were correlated with thresholds of mPAP ≥ 38 mm Hg and PVR ≥ 5.3 WU for adverse outcome prediction, as these hemodynamic values had been shown to be predictive of death [t-test or Mann–Whitney U test for normal and non-normal data, respectively. Categorical variables are displayed as n (%), and differences were assessed using Fisher’s exact test. Intraclass correlation coefficient (ICC) estimates and their 95% confidence intervals for inter- and intra-observer variability in CT measurements were calculated. Correlation analysis was performed using the Pearson correlation coefficient or the Spearman’s rank test where the data were non-normal. Univariate analysis and multivariate stepwise logistic regression were used to identify atrial and ventricular size metrics that predicted elevated mPAP and PVR. Receiver operating characteristic (ROC) curves with area under the curve (AUC) values were used to compare the predictive ability of the various size metrics/ratios, and the optimal cut-points were defined by the Youden index. A p-value of ≤0.05 was considered statistically significant.Continuous normal data are presented as the mean (±1 standard deviation). Non-normal data are presented as the median (interquartile range). Continuous data were compared with a two-tailed Student’s Paired pre- and post-operative catheterization data were used for evaluation of the various CT measures in the prediction of adverse hemodynamics. This was with the assumption that the relationship between static atrial/ventricular geometry and hemodynamics should remain reasonably constant regardless of operative status.p < 0.001). Preoperatively, 55% of cases had mild, and the remainder had moderate or severe tricuspid regurgitation (TR). Post-PTE, there was significant improvement, with 94% demonstrating either complete resolution or only mild residual regurgitation. No patient had tricuspid ring annuloplasty or valve replacement at the time of PTE. The baseline characteristics are outlined in p < 0.001). Significant improvements in hemodynamics were observed following surgery; mean pulmonary artery pressure (mPAP) fell from 45 ± 11 mmHg to 27 ± 12 mmHg (p < 0.001), and pulmonary vascular resistance (PVR) dropped from 9.0 ± 4.2 WU to 3.1 ± 1.9 WU (p < 0.001) with the increase in cardiac output (mean cardiac index (CI) 2.1 ± 0.7 to 2.6 ± 0.7; p < 0.001). The intraclass correlation coefficient (ICC 95% CI) for the 2 readers for CT chamber measurements was 0.99 (0.96–1.00) and 0.96 (0.76–0.99) for atria and ventricles, respectively. Preoperatively, the indexed RA volumes were more than twice the LA volumes, and the indexed RV volumes were twice the LV volumes. Following surgery, there was a significant augmentation of left heart filling, resulting in an increase in LA and LV volumes and a concomitant fall in the RA and RV volumes (p ≤ 0.05) with invasive hemodynamics. Of all metrics, ventricular volume ratio was most closely related to mPAP, PVR and CI  had stronger relationships with hemodynamic parameters than individual chamber measurements. Except for the indexed LA volume to cardiac index (LAVi–CI) relationship, all other chamber volumes and ratios were otherwise significantly correlated , but the LV:RV volume ratio  outperformed the LA:RA volume ratio . A ventricular ratio cut point of ≤0.82 had a high sensitivity and specificity for identifying significant elevations of both mPAP and PVR.The combination of atrial and ventricular measurements did not provide any additive effect, as of all the assessed atrial and ventricular ratios, stepwise logistic regression showed that only the LV:RV diameter ratio independently predicted adverse hemodynamics.2; RAVi mean bias 1 ± 23.3 mL/m2). There was overall good agreement between manual and semiautomated measurement of biatrial volumes with LAV and RAV intraclass correlation coefficients (ICC 95% CI) at 0.84 (0.70–0.91) and 0.88 (0.80–0.92), respectively. Manual assessment systematically overestimated biatrial volumes compared to semiautomated measurement . We then tested the ability of the manual LV:RV basal dimension ratio to predict adverse hemodynamics. The LV:RV dimension ratio cut points of <1.03 and ≤0.99  showed excellent performance (p < 0.001) for mPAP ≥ 38 mmHg (AUC 0.87) and PVR ≥ 5.3 WU (AUC 0.95), respectively. This technique had a sensitivity and specificity of 84% and 82% for predicting elevated mPAP and 86% and 92% for elevated PVR  and specificity (88% and 85%) for identifying significant elevations of mPAP and PVR, respectively (AUC 0.90 and 0.95).The CT-derived ventricular volume alterations with increased RV and decreased LV size before surgery can be explained by CTEPH pathophysiology. PVR elevation due to the anatomical obstruction by the thromboembolic material leads to RV dysfunction. With increasing pressure overload, RV contractility increases to preserve systolic function. However, there is a worsening of diastolic function with progressive RV hypertrophy and remodeling. An increase in RA compliance and distensibility augments RV filling and performance to conserve cardiac output and prevent RV failure. LV diastolic impairment is also common in CTEPH and normalizes after successful PTE ,15. A dep < 0.001) but a weaker correlation with mPAP (p = 0.003) and no correlation with CI. This could be due to several technical factors. Previous studies [Another consequence of this interdependence mechanism is the compression and decrease in LA size caused by the enlarging RA. With the growing appreciation that atrial function may be an early and sensitive marker of right heart remodeling and coupling , we also studies ,21 have  studies , whereasIt must be emphasized that CTPA measurements predicted PVR better than mPAP elevation. This is because the determinants of pulmonary artery pressure include both PVR and RV contractility. While RA size and RV contractility are inversely related , the nonWe acknowledge that tricuspid regurgitation can be an important confounder as it is common in CTEPH and contributes to RA enlargement. In our cohort, there was significant improvement in TR post-PTE without any targeted intervention to the tricuspid valve at the time of surgery. This is consistent with previous observations that TR is secondary in nature, specifically due to tricuspid leaflet tethering from RV enlargement and associated annular dilatation ,25. AlteThe reproducibility of CT cardiac chamber quantification is confirmed by the excellent interclass correlation in our study. Hence, chamber measurements can easily be performed on baseline CTPA acquired for CTEPH diagnosis and on the follow-up CTPA performed for evaluation of residual disease post-PTE. The good agreement between semiautomated and manual measurements for both atrial and ventricular volumes is encouraging. as it allows CT readers to evaluate cardiac chamber size on a routine PACS workstation even if they do not have access to dedicated software. Finally, the manual LV:RV basal dimension ratio may be an expeditious alternative to the automated ventricular volume ratio as it offers comparable prognostic utility. Our study has some limitations. The sample size is small, but CTEPH is a relatively uncommon condition, and furthermore, only proximal CTEPH is amenable for surgery, further limiting the cohort size. As CTPA was performed without ECG gating, it was not possible to measure the chamber size at a consistent point in the cardiac cycle. While ECG-gating may potentially improve accuracy, we believe our approach reflects real-world clinical practice, as most institutions perform CTPA without ECG-gating. Manual assessment is operator-dependent, but our quantitative data demonstrated excellent intraclass correlation, and there was overall good agreement between the techniques. We acknowledge that the sophisticated ‘method of discs’ volumetric calculation would have better accounted for atrial geometric distortion (compared to our chosen area–length method) but would have required additional software to compute. We wanted to propose a simple approximation that did not require the latter. The primary findings of our study support the assertion that it is feasible to perform cardiac chamber measurements in CTEPH on non-ECG-gated CT and identify high-risk patients with persistent PH post-PTE. As the management of residual PH is challenging, often requiring individualized treatment regimes, this noninvasive measure by CT can help in the detection of patients at a higher risk of long-term postoperative morbidity and mortality and hence will benefit from closer monitoring and also help in triaging such cases for invasive right heart catheterization. While volumetric atrial assessment on CTPA is achievable as well as reproducible, it was outperformed by ventricular metrics for the prediction of adverse hemodynamics. Furthermore, a simple LV:RV dimension ratio of <1.03 and ≤0.99  can identify significant elevations of mPAP and PVR, respectively. We do not propose CTPA-derived cardiac chamber size measurements as a substitute for right heart catheterization but rather as a surrogate noninvasive “biomarker”, particularly as CTPA is a commonly performed investigation for CTEPH diagnosis and has the potential to provide additional data for prognostication. Prospective studies in large-volume CTEPH specialist institutions will be needed to validate whether cardiac chamber measurements on CTPA can be used to guide treatment decisions in combination with other established risk assessment tools.


Echocardiography has historically been used as a screening tool with abnormalities triggering the need for advanced imaging, and as a tool to assess cardiac function. Regional wall thinning or aneurysm formation in a noncoronary distribution may indicate granuloma infiltration. Thinning of the basal septum in the setting of extracardiac sarcoidosis carries a high specificity for cardiac involvement. Abnormal myocardial echotexture and eccentric hypertrophy may be suggestive of active myocardial inflammation. The presence of right-ventricular involvement as indicated by free-wall aneurysms can mimic arrhythmogenic right-ventricular cardiomyopathy. More recently, the use of myocardial strain has increased the sensitivity of echocardiography in diagnosing cardiac involvement. Echocardiography is limited in prognostication, with impaired left-ventricular (LV) ejection fraction and LV dilatation being the only established independent predictors of mortality. More research is required to explore how advanced echocardiographic technologies can increase both the diagnostic sensitivity and prognostic ability of this modality in CS.Cardiac sarcoidosis (CS) is a rare inflammatory disorder characterised by the presence of non-caseating granulomas within the myocardium. Contemporary studies have revealed that 25–30% of patients with systemic sarcoidosis have cardiac involvement, with detection rates increasing in the era of advanced cardiac imaging. The use of late gadolinium enhancement cardiac magnetic resonance and  Sarcoidosis is a multisystem chronic inflammatory disorder characterised by the presence of noncaseating granulomas within affected organs ,2 The ae18F-flurodeoxyglucose positron emission tomography (FDG-PET) have largely superseded the use of endomyocardial biopsy (EMB) in the diagnosis of CS [The reported prevalence of cardiac sarcoidosis (CS) is increasing due to a notable step-up in new diagnoses following the incorporation of advanced cardiac imaging into routine clinical assessment . Late gais of CS . EMB speis of CS . HoweverTransthoracic echocardiography (TTE) is the most widely available and established non-invasive imaging modalities. TTE can be used throughout the patients’ diagnostic and management pathway, while the ability to identify CS patients at high risk due to LV impairment adds prognostic value. TTE has historically been used as a screening tool to trigger the need for advanced imaging when regional or global myocardial abnormalities are discovered. Over the last two decades, technological advancements including harmonic imaging and contrast echocardiography have driven improvements in image quality. Three-dimensional (3D) echocardiographic imaging now provides more accurate measurement of left-ventricular (LV) cavity volumes and ejection fraction (EF) . The intThe aim of this article is to provide a detailed contemporary review of the literature regarding the detection, surveillance, and prognostication of CS using conventional and advanced echocardiographic techniques.The diagnosis of CS remains challenging due to the variation in disease severity and presenting symptoms, along with potential phenotypic overlap with other infiltrative disorders, cardiomyopathies, and coronary artery disease. However, due to the high morbidity associated with CS, screening patients with known extracardiac sarcoidosis (ECS) is important. The 2014 Heart Rhythm Society (HRS) consensus statement recommends screening on the basis of cardiac symptoms , electrocardiogram (ECG), and TTE . The preOver the past three decades, various clinical criteria for the diagnosis of CS have been published including the 1993 Japanese Ministry of Health and Welfare (JMHW) guidelines which were refreshed in 2006, the World Association for Sarcoidosis and Other Granulomatous Disorders (WASOG) 2014 guidelines, and the Japanese Circulation Society 2016 guidelines ,18. HoweSeveral TTE abnormalities increase the likelihood of a patient with systemic sarcoidosis having cardiac involvement and should trigger LGE-CMR ± FDG-PET to confirm the diagnosis (p < 0.001) [TM have been used with abdominal ultrasound to better identify hepatosplenic sarcoid lesions [The presence of a RWMA is an important signal of cardiac involvement. At the time of diagnosis, 35–50% of patients will have RWMA on TTE . The LV < 0.001) . Contras lesions ,25. In eThinning and akinesis of the basal septum are among the more characteristic features of CS, present in 2–4% of patients with a CS diagnosis ,26. One p < 0.001) [In CS, granuloma infiltration most commonly affects the LV rather than RV myocardium. Autopsy studies report a prevalence of RV involvement of 36–39% ,30. Rece< 0.001) . RV invo< 0.001) . SensitiValvular dysfunction in CS is rare and usually secondary to chamber dilatation or papillary muscle inflammation causing functional atrioventricular valvular regurgitation . The prePericardial abnormalities on TTE can be seen in 19% of sarcoidosis patients . PericarIncreased LA volume index may represent advanced LV myocardial disease associated with diastolic dysfunction, or the development of atrial arrhythmias. Direct sarcoid involvement of the LA is rare, with necropsy studies reporting a 7% prevalence . Atrial Myocardial deformation imaging is of value in the early detection of LV dysfunction in CS patients  Figure . The comGLS is significantly more impaired in patients with systemic sarcoidosis compared to healthy controls ,46,47,48A significant reduction in LV GLS, even in the presence of preserved LVEF LVEF > 50%), is associated with diagnosis of CS ,50  [Regional circumferential strain values are significantly more impaired in the mid-myocardial and epicardial layers, compared to the endocardial layer . In theo 0.0001) . FurtherImpairment of RV systolic function, as measured by M-mode TAPSE and tissue Doppler imaging (S’), is a late sign in CS, representing significant RV free-wall scar or pulmonary hypertension. RV strain shows promise in identifying cardiac involvement of sarcoidosis at an earlier stage, but data are limited. Studies have compared RV strain parameters in suspected and confirmed CS patients against healthy controls ,47. RV Gp = 0.001) [LA wall deformation is assessed in three different phases: reservoir , conduit (passive ventricular diastole), and contractile phase . Approximately 40% of atrial function is provided by the reservoir phase compared to 35% and 25% for the conduit and contractile phases, respectively . Peak at= 0.001) ,57. TherThree-dimensional transthoracic echocardiography (3DE) affords a more accurate and reliable appraisal of complex cardiac structures. 2DE relies on geometric assumptions to measure chamber size and EF, and there is increased inter-operator variability in measurements when endocardial definition is suboptimal. 3DE is less reliant on plane position and makes fewer assumptions about chamber size. Direct volume measurements are more accurate and reliable. For instance, the RV is a particularly challenging structure to assess due to its geometric complexity. 3DE has proven superiority over 2DE in assessing RVEF and RV end-diastolic volume . In addiThe cornerstone of management in CS surrounds the identification and treatment of active inflammation, left-ventricular systolic dysfunction (LVSD), and arrhythmias. The disease course can be unpredictable; therefore, regular surveillance of CS patients is paramount, more so in those presenting with heart failure or a substantial inflammatory burden. FDG-PET plays a central role in identifying patients that would benefit from tailoring of immunosuppressive therapy and repeat imaging 6–9 months after initial induction therapy is recommended . Serial The major echocardiographic determinant of long-term outcome in CS remains LVEF. The sequelae of active inflammation followed by chronic myocardial fibrosis result in wall stiffening and initially regional systolic dysfunction. Multiple regions of hypokinesis eventually contribute to global systolic decline. Scarring and subsequent adverse remodelling (LV dilatation) of the myocardium further contribute to dyssynchronous and ineffective LV contraction. Increased severity of LVSD and greater LV end-diastolic diameter (LVEDD) are key determinants of mortality in CS patients, even following corticosteroid therapy . Every 1Two prior studies have shown that a GLS value worse than −17% may be a useful prognostic marker in a general systemic sarcoidosis population with preserved LV systolic function ,50. In tIn CS, the RV is prognostically important as patients with RV LGE on CMR  or FDG uPulmonary hypertension remains an important cause of mortality in sarcoidosis patients, independent of other organ involvement. Sarcoidosis-associated pulmonary hypertension (SAPH) confers a 10-fold increase in mortality in sarcoidosis patients and has a prevalence of 18.8% using TTE . The impTTE has a useful clinical role in CS due to its widespread availability and low cost relative to other imaging modalities. The potential of 3DE in the diagnosis and prognosis of CS patients has yet to be fully explored, particularly 3D speckle-tracking strain. Furthermore, deep learning (a machine learning method) algorithms have been developed for use on TTE images to predict the presence of various cardiomyopathies with high accuracy. To date, one study has developed a deep learning algorithm to distinguish CS patients from healthy subjects . The preEchocardiography plays an important role in the screening, surveillance, and management of CS patients. This role continues to grow due to advancements in echocardiography technology and software. Incorporation of myocardial strain analysis adds to the value of the study and should be considered routine. Detailed attention should be paid by the echocardiographer and clinician to specific abnormalities that increase the likelihood of CS and act as a trigger for more advanced imaging. A multimodality approach remains paramount when making the diagnosis and determining which patients would benefit from risk prevention measures. Nevertheless, challenges lie ahead. Currently, research has been largely confined to case–control and observational studies with large variation in the criteria used to diagnose CS. More prospective trials are required to fully understand the role of advanced echocardiography in all stages of decision making.


Left ventricular and left atrial strain are sensitive and reliable markers for evaluating cardiac function in patients with type 2 diabetes mellitus (T2DM), with interactions between the two parameters. The present study aimed to analyze the correlation between global longitudinal strain (GLS) of the left ventricle and glycated hemoglobin (HbA1c) levels in patients with T2DM.A total of 292 patients clinically diagnosed with T2DM were selected and divided into three groups according to HbA1c level. The strains of the left atrium and left ventricle in the three groups of T2DM patients with different HbA1c levels were compared. Univariate and multivariate  linear regression analyses were performed to assess the relationship between strain indicators and HbA1c levels. Generalized additive models were used to examine the relationship between strain indicators and HbA1c levels.p < .05). Univariate and multivariate linear regression analyses revealed that, as HbA1c levels increased, the absolute value of GLS gradually decreased (p < .001). Curve fitting revealed a positive correlation between HbA1c level and GLS, which was not affected by left atrial function.There were significant differences among the three groups in terms of age, microalbuminuria, total cholesterol, fasting blood glucose, postprandial blood glucose, and HbA1c level, and left atrial conduit longitudinal strain (LAScd) and GLS (Left ventricular GLS was independently correlated with HbA1c level in patients with T2DM and was not affected by left atrial function. Among T2DM patients with preserved LVEF, left ventricular GLS, an essential indicator reflecting subclinical changes in the left ventricle, exhibited a positive correlation with increasing HbA1c levels and was not influenced by left atrial function. Due to its high prevalence and associated disability and mortality rates, it has become a serious global health problem.Conventional echocardiography is a commonly used modality for screening and assessing cardiac structural and functional damage in patients with diabetes; however, LV ejection fraction (LVEF) cannot sensitively reflect changes in LV function. In recent years, the development of noninvasive ultrasound imaging techniques has facilitated the determination of subclinical cardiac function. Global longitudinal strain (GLS) of the left ventricle, determined by speckle tracking, is a useful metric for the early identification of subclinical myocardial contractile dysfunction.22.1Data were selected from a consecutive cohort of 302 patients diagnosed with T2DM, who were hospitalized in the Department of Endocrinology at The First People's Hospital of Changzhou  from January to December 2021. Inclusion criteria were as follows: Diagnosis of T2DM according to the American Diabetes Association standards33.1General patient data, including age, sex, body mass index (BMI), duration of diabetes, systolic blood pressure, diastolic blood pressure, heart rate, and history of hypertension and coronary artery disease, were collected. Biochemical analysis was performed on all subjects using standard laboratory techniques. We collected blood samples from patients on the second morning of admission on an empty stomach. We used a fully automatic biochemical analyzer  to measure FPG, HbA1c, total cholesterol (TC), triglycerides (TG), high‐density lipoprotein (HDL), low‐density lipoprotein (LDL), microalbuminuria, creatinine, urine albumin‐to‐creatinine ratio (UACR), and brain natriuretic peptide (BNP).3.2A color Doppler ultrasound diagnostic device equipped with M5S and 4V probes  were used. The echocardiogram examination was simultaneously completed on the second day of hospitalization. All subjects were positioned in the left lateral decubitus position and encouraged to breathe calmly while electrocardiogram was recorded simultaneously. Simpson's biplane method was used to assess end‐diastolic volume, end‐systolic volume, and LVEF. Standard apical four‐, two‐, and three‐chamber images of the left ventricle, the standard horizontal short‐axis section of the mitral valve, the horizontal short‐axis section of the papillary muscle, and the apical horizontal short‐axis section images were acquired in two‐dimensional (2D) mode. The images of all patients were digitally stored for subsequent analysis. Image acquisition and analysis were completed independently by two attending physicians, and the averaged values were taken. Pulsed‐wave Doppler was used to measure peak velocities of early diastolic (E wave) and late diastolic (A wave) mitral valve flow, and the E/A ratio was calculated. Tissue Doppler imaging was used to measure the early diastolic mitral annulus velocity (e′) and to calculate the E/e′ ratio.3.3Calculation of LV GLS: The AFI component of the EchoPAC 203 version  software package automatically tracked the endocardial and epicardial boundaries of the left ventricle, displaying the 17‐segment 2D strain‐time curve and bull's‐eye plot of the left ventricle. If tracing was poor, the endocardial line was adjusted manually, and the image was reread. If accurate tracking could not be achieved for >2 segments after adjustment, the patient was excluded. The software automatically calculated LV GLS, which was used as a metric to evaluate LV systolic function.Measurement of left atrial volume and strain function: One point was taken at the midpoint of the mitral annulus and another point on the endocardium at the left atrial roof. The system automatically sketched and displayed the left atrial endocardial contour. Local manual adjustments were made so that the depiction fitted the boundary. The software automatically generated a left atrial time‐volume curve, and the analysis calculated left atrial maximum volume (LAVmax), left atrial minimum volume (LAVmin), and left atrial presystolic volume (LAVpre). Meanwhile, LASr, left atrial conduit longitudinal strain (LAScd), and left atrial contraction longitudinal strain (LASct) were calculated.3.4http://www.R-project.org) were used for data analysis. The data were stratified according to statistics and HbA1c tertiles. Continuous variables are expressed as mean ± standard deviation (SD) or median , while categorical variables are expressed as frequency (percentage). The χ2 test , one‐way analysis of variance , and Kruskal–Wallis test (for skewed continuous variables) were used to analyze differences between groups.SPSS version 25 (IBM Corporation) and R version 3.4.3 (p < .10), it was included as a potential confounder in the final model. The generalized additive model (GAM) was used for curve fitting. Differences with p < .05 were considered to be statistically significant.To investigate the association between LV GLS and HbA1c level, three different models were constructed using univariate and multivariate linear regression methods, including unadjusted, partially adjusted, and fully adjusted models. In multivariate regression analysis, if the regression coefficient of HbA1c changed by >10% after introducing a factor in the basic model or excluding a factor in the full model, or if the factor was significantly associated with GLS , 98 patients, the mean age was 59.81 ± 10.06 years, n = 47 for men; Group C (12.3 ± 1.4), 97 patients, the mean age was 57.91 ± 10.26 years, n = 56 for men. The basic clinical characteristics of the three groups are shown in Table p < .05). As HbA1c level gradually increased, the GLS value also gradually increased . There was no statistical significance in conventional echocardiographic , left atrial volume , and left atrial strain  indicators among the three groups .A total of 302 patients with T2DM were included in this study, 3 patients had atrial fibrillation, 5 patients had poor ultrasound image quality, 2 patients were diagnosed as coronary heart disease, and 292 patients were finally included Figure . A total4.2p < .05). Specific data are reported in Table Univariate linear regression analysis was performed using LV GLS as the dependent variable and HbA1c along with other factors as independent variables. Results indicated that patient BMI, microalbuminuria, LVEF, and FBG were potential factors affecting LV longitudinal strain (GLS) . In the HbA1c tertile groups, as HbA1c levels increased, GLS values also gradually increased .The results of univariate and multivariate linear regression analyses examining the relationship between LV GLS and HbA1c (continuous variable and tertile groups) are summarized in Table 4.4df = 1, p < .001, F = 41.533), revealing an approximately linear relationship between the two  significantly altered the association between GLS and HbA1c across the various subgroups Figure .5In this study, among T2DM patients with preserved LVEF, LV GLS, an essential indicator reflecting subclinical changes in the left ventricle, exhibited a positive correlation with increasing HbA1c levels and was not influenced by left atrial function. Research has demonstrated that, in most patients with diabetes and subclinical cardiac abnormalities, these abnormalities can be reversed if detected early.T2DM is a metabolic disease caused by various factors, and is characterized by a low‐level inflammatory state and endothelial dysfunction, which increases the risk for cardiovascular disease(s). T2DM can lead to myocardial dysfunction, initially manifesting as subclinical dysfunction, and gradually developing into DCM and HF. DCM is a specific type of cardiomyopathy resulting from diffuse myocardial fibrosis, myocardial hypertrophy, and diabetic microangiopathy.The effects of hyperglycemia on the heart can manifest early; however, patients may not exhibit overt symptoms. Echocardiographic research involving diabetic populations primarily concentrates on LV structure and function; however, conventional parameters, such as LVEF, fail to accurately represent subtle changes in LV systolic function. Results of our study also revealed no statistical differences in conventional echocardiographic parameters, such as LVEF and E/e′ ratio, among individuals with varying HbA1c levels. Speckle tracking echocardiography is a highly sensitive technique that facilitates early detection of overall alterations in LV function. Decreased circumferential and longitudinal strain rates can be identified merely a few weeks after the onset of diabetes.p ≤ .05). Consequently, when studying the relationship between GLS and HbA1c level, the index LAScd may serve as an important confounding factor. After adjusting for confounding factors in this study, including the LAScd index of left atrial strain, the independent association between LV GLS and HbA1c levels was confirmed. Research by Zairi et al. demonstrated that the decline in LV GLS in children with type 1 diabetes was correlated with increased HbA1c levels.There is a close interaction between left atrial and LV function,There were several limitations to the present study, the first of which was the small sample size, which may not have been representative of the entire T2DM population, thus necessitating validation through larger‐scale studies. Second, the determination of LV GLS depended on the image frame rate, and image quality may have affected the accuracy of speckle tracking.In conclusion, results of our study demonstrated that, for T2DM patients with preserved LVEF, as HbA1c levels rise, LV GLS, a crucial indicator reflecting subclinical changes in the left ventricle, was independently associated with GLS and remained unaffected by left atrial function. For T2DM patients with poor blood glucose control and substantial fluctuations, proactive blood glucose management and early intervention should be used to help delay or even reverse myocardial damage and prevent the worsening of cardiac function.Min Xu designed the study and carried out the study, data collection and analysis. Jinmei Gao wrote the manuscript and Mingxia Gong revised the manuscript. Xiaohong Jiang and Ming Chen designed part of the experiments. Shu Jiang and Zhenni Yang collected the T2DM patients. All authors read and approved the final manuscript.The authors declared no conflict of interest.


Severe aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and cardiac metabolic alterations with evidence of steatosis and impaired myocardial energetics. Despite this common phenotype, there is an unexplained and wide individual heterogeneity in the degree of hypertrophy and progression to myocardial fibrosis and heart failure. We sought to determine whether the cardiac metabolic state may underpin this variability.We recruited 74 asymptomatic participants with AS and 13 healthy volunteers. Cardiac energetics were measured using phosphorus spectroscopy to define the myocardial phosphocreatine to adenosine triphosphate ratio. Myocardial lipid content was determined using proton spectroscopy. Cardiac function was assessed by cardiovascular magnetic resonance cine imaging.P=0.02). Myocardial triglyceride content levels were overall higher in all the quartiles with a significant increase seen across the AV pressure gradient quartiles . While all AS groups had evidence of subclinical LV dysfunction with impaired strain parameters, impaired systolic longitudinal strain was related to the degree of energetic impairment . Phosphocreatine/adenosine triphosphate was not only an independent predictor of LV wall thickness  but also strongly associated with myocardial fibrosis , suggesting that metabolic changes play a role in disease progression. The metabolic and functional parameters showed comparable results when graded by clinical severity of AS.Phosphocreatine/adenosine triphosphate was reduced early and significantly across the LV wall thickness quartiles  with a progressive decline with increasing disease severity (Q4, 1.48 [1.18–1.70]; A gradient of myocardial energetic deficit and steatosis exists across the spectrum of hypertrophied AS hearts, and these metabolic changes precede irreversible LV remodeling and subclinical dysfunction. As such, cardiac metabolism may play an important and potentially causal role in disease progression. A gradient of myocardial energetic deficit and steatosis exists across the spectrum of hypertrophied aortic stenosis hearts, and these metabolic changes precede irreversible left ventricular remodeling and subclinical dysfunction. Impaired cardiac energetics occur before a significant increase in left ventricular wall thickness and has a significant association with impairment in myocardial strain and development of myocardial fibrosis, which is likely to be relevant clinically. Modulating myocardial metabolism may prove to be a promising strategy in improving outcomes of patients with aortic stenosis. We are currently testing this intriguing possibility in a clinical trial (NCT05256758) evaluating the effect of metabolic modulation on cardiac physiology in moderate-severe aortic stenosis.Sosnovik and ElmariahSee Editorial by 2Aortic stenosis (AS) is characterized by both progressive valve obstruction and left ventricular (LV) hypertrophic remodeling Figure . Convent3 This is believed to contribute to impaired cardiac energetics, which in animal studies precedes cardiac dysfunction and LV hypertrophy (LVH).4 Similar metabolic changes are also seen in established LVH, with a shift away from free fatty acid use toward glucose but also an uncoupling of glycolysis and glucose oxidation, again resulting in an altered energetic state.5It is not yet fully known why there is wide individual variation in the hypertrophic response to the same degree of pressure overload. Whether metabolic interactions play a causal role in disease progression remains unclear. The early metabolic change in pressure overload is a shift toward glucose use rather than fatty acids to produce adenosine triphosphate (ATP).5 and heart failure.6 It correlates not only with the degree of LVH and dysfunction but has also been shown to be a predictor of mortality.8 Thus, although both pressure overload and LVH are related to the metabolic changes seen in AS, their relative contributions are unknown. Given the direct coupling of ATP metabolism and contractile function, metabolic alterations are an attractive marker to identify individuals who are more vulnerable to LV failure in AS.The myocardial phosphocreatine/ATP ratio, an index of cardiac bioenergetic state, is reduced in both animal and human models of myocardial hypertrophyThis was a prospective observational cohort study where 74 asymptomatic AS participants were recruited from outpatient valve clinics across 3 sites in the United Kingdom: Oxford University Hospital National Health Service Trust, Oxford, Great Western Hospital National Health Service Trust, Swindon, and Royal Berkshire Hospital, Reading. Thirteen healthy volunteers were recruited. All participants provided written informed consent. The study received approval from a Research Ethics Committee . The research was conducted in accordance with institutional procedures and the Declaration of Helsinki. The data that support the findings of this study are available from the corresponding author upon reasonable request.Comprehensive baseline clinical characteristics and history were obtained using a standardized structured proforma and were completed from source clinic record data and patient questionnaires. AS severity for participation in the study was determined by outpatient echocardiographic findings fulfilling at least 2 criteria using a combination of peak velocity, aortic valve gradient, and estimated valve area as detailed below in the inclusion criteria.2; moderate AS: Vmax<4 m/s; peak gradient, <60 mm Hg; mean gradient, <40 mm Hg; aortic valve area>1 cm2; severe AS: Vmax>4 m/s; peak gradient, >60 mm Hg; mean gradient, >40 mm Hg; aortic valve area<1 cm2, no other significant valvular pathology, no contraindication to MR imaging.Asymptomatic mild-to-severe AS with at least 2 criteria on routine echocardiogram—mild AS: peak velocity, Vmax<3 m/s; peak gradient, <30 mm Hg; mean gradient, <20 mm Hg; aortic valve area>1.5 cm2, significantly impaired renal function .Known coronary artery disease , presence of other underlying cardiomyopathy, LV ejection fraction <50%, uncontrolled hypertension, type 1 or type 2 diabetes, liver impairment, body mass index (BMI), >40 kg/mParticipants with AS underwent venous blood sampling for full blood count, renal and liver function, lipid profile, natriuretic peptide test, glucose, and free fatty acids. All participants were asked to fast 4 to 6 hours before the study visit.9 Image analysis for atrial and ventricular volumes was performed offline using a semiautomated system  in accordance with Society for Cardiovascular Magnetic Resonance guidelines.10All participants were scanned in a fasted state (at least 6 hours fast) before study assessments. Cine images were acquired for cardiac volume analysis using a Siemens 3T Prisma MR system  using steady-state free precession cine imaging as previously described.For LV wall thickness analysis, LV epicardial and endocardial contours were identified in end-diastole and end-systole, and planimetry was performed using semiautomated analysis software tools . The maximum LV wall thickness was curated by an independent operator  from the basal short-axis views of the left ventricle in end-diastole. Right and LV trabeculations were excluded from wall thickness measurements. Measurements were checked randomly by an independent operator .Late gadolinium enhancement (LGE) was performed with an inversion-recovery–prepared, single shot gradient echo sequence after a 5- to 7-minute time delay subsequent to the administration of 0.3 mmol/kg of a gadolinium-based contrast agent (Dotarem). The inversion time was adjusted for optimal nulling of normal myocardium. LGE was analyzed qualitatively in terms of whether it was present or absent by 2 experienced CMR readers.11 creating a square grid of parallel tag lines. A horizontal long-axis image and a short-axis image at the mid-ventricular level were acquired. Postprocessing analysis was performed using cardiac image modeller-Tag software . From the mid short axis, peak systolic circumferential strain (CS) rate and diastolic CS rate were derived. From the horizontal long axis, peak systolic longitudinal strain rate and diastolic longitudinal strain rate were determined.Tagged MR images were acquired with an ECG-triggered segmented k-space fast gradient echo sequence with spatial modulation of magnetization in orthogonal planes,1H/31P surface coil  over their hearts in the isocentre of the magnetic resonance imaging system. We used single volume depth-resolved surface coil spectroscopy. This technique involves positioning of the voxel in the interventricular septum parallel to the receive coil, avoiding chest wall muscles. Three saturation bands are added to further suppress signals originating in chest wall and in the liver.12 At our center, standard operating procedures are followed for the positioning of the volume of interest, which removes any significant user variability in the acquisition of data. The results are then automatically generated from the acquired data using OXSA Matlab post processing tool13  fitting routine by an experienced operator); thus, there is no significant interobserver variability. The fitted phosphocreatine and ATP signals were corrected for partial saturation, using literature values,14 before calculating the phosphocreatine/ATP ratio as phosphocreatine/average ATP or phosphocreatine/γ-ATP depending on spectral quality. The reported phosphocreatine/ATP was also corrected for blood signal contamination.15 While the variability of MRS is often cited as a limitation, current techniques typically yield a variability of 13% for phosphocreatine/ATP ratios, which is in the same range as LV volumes and functional assessment on CMR scanning and echocardiography.17Phosphorus magnetic resonance spectroscopy (MRS) was performed at rest on a 3T magnetic resonance imaging scanner . Participants were positioned supine with the center of dual-tuned 1H-MR spectra were obtained from the mid-interventricular septum as previously described.18 Spectroscopic acquisitions were performed using single-voxel water-suppressed stimulated echo acquisition mode spectroscopy sequence with ECG trigger at end-expiration to minimize motion artifacts following local SOPs. Twenty-five times water-suppressed spectra were acquired over 5 breath holds to measure myocardial triglyceride content (MTG) signal, and 3 times spectra without water suppression, acquired in an additional breath hold, thus 6 breath holds were involved in the acquisition of this data, with a total acquisition time of ≈10 minutes (giving the patients sufficient time to breath in between the breath holds). Spectra were analyzed using OXSA toolbox as previously described.13Myocardial 18MTG was calculated as a percentage relative to unsuppressed water: ×100. This technique has been shown previously to have an intrasubject coefficient of variation of 19% for lipid quantification with breath-holding at 3T.19 Postcontrast T1-maps were acquired 15-minute post-administration of an intravenous gadolinium-based contrast agent (Dotarem). T1-maps were acquired in 1 mid-ventricular short-axis slice matched to cine image and images post-processed as previously described.20Myocardial T1-mapping was performed using the ShMOLLI 5(1)1(1)1 sequence as previously published.R1 of blood and myocardium was calculated as R1=1/T1 for both native and postcontrast maps. Hematocrit was measured on a blood sample drawn on the same day, immediately before the CMR scan. Extracellular volume (ECV) was calculated using the equation:ECV=(1−hematocrit)×(ΔR1 myocardium/ΔR1 blood)Figure As the clinical grading of AS severity can often be discordant and does not follow a linear relationship with disease process, we chose to divide patients into quartiles of LV wall thickness (LVWT) and aortic valve gradient (AVG) to understand the relationship between myocardial metabolism and the disease process. LVWT was defined as the maximum wall thickness in the basal short-axis views of the LV in end-diastole. To investigate the relationship between myocardial metabolism and pressure overload, participants were divided into quartile groups based on peak AVG, derived from echocardiography, and LV pressure gradient .t test, Mann-Whitney U test, ANOVA with Bonferroni correction, or a Kruskal-Wallis test with Bonferroni correction. Ordered medians were compared for variables that were not normally distributed, that is, phosphocreatine/ATP and MTG content using the Jonckheere-Terpstra test. Categorical data were compared using Pearson χ2 test or Fisher exact test. Pearson and Spearman rank coefficients were determined to assess correlations. Correlation between categorical and continuous variables was performed using Kruskal-Wallis or Mann-Whitney U tests. Multivariable linear regression was performed using Spearman partial correlation analysis. A P<0.05 was considered significant. All statistical analyses were performed with IBM SPSS Statistics, Version 28 and GraphPad Prism .All normally distributed data (Kolmogorov-Smirnov test) are expressed as mean±SD. Non-normally distributed cardiac metabolism data is presented as median (interquartile range). Categorical data are presented as frequencies (%). Continuous variables were compared using a Student 2) with varying degrees of AS and 13 normal controls  were studied.Seventy-four patients , LV mass index  and LV end-diastolic volume  showed a stepwise increase across the quartiles. Although LV ejection fraction was similar, and normal across the quartiles, peak systolic longitudinal strain  was normal in Q1 (−15±0.97%) and impaired with increasing wall thickness . Peak systolic longitudinal strain correlated with LV mass index (P<0.001). Peak systolic CS despite reducing numerically across the quartiles , overall remained in the normal range (−15% to −20%).21LVWT 22 showed a significant stepwise reduction across the increasing LVWT quartiles .LV diastolic function indicated by early diastolic longitudinal strain rate r=−0.53; P<0.001), CS  and diastolic CS rate .When controlled for AV gradient, there was significant correlation between LVWT and peak systolic longitudinal strain (P=0.02). However, most of the reduction (9%) in the phosphocreatine/ATP occurred between Q1 and Q2 . On partial correlation analysis, controlling for AV gradient, age, and BMI, there remained a significant relationship between LVWT and phosphocreatine/ATP .Myocardial phosphocreatine/ATP reduced by 10% in median across the increasing LVWT quartiles . On controlling for AGE, BMI, and AV gradient, MTG did have a significant association with LVWT .MTG was numerically higher in Q2 (1.40) compared with Q1 1.13) highlighting the early presence of steatosis with values remaining higher across Q2 to Q4 compared with Q1. Steatosis, however, did not progressively worsen with wall thickness across the quartiles , BMI  and phosphocreatine/ATP  were independent predictors of LV wall thickness. This highlights the importance of energetics in the hypertrophic process.On multivariate regression analysis with LVWT as dependent variable and LVG, MTG, BMI, age, and phosphocreatine/ATP as independent variables, only LV gradient . Similarly, % ECV increased progressively through the quartiles , being abnormal in Q3 and Q4 (Table S1). Normal ECV range (27.5±3.5%).23Myocardial native T1 values increased progressively from Q2 to Q4 . On controlling for LVG, age, and BMI, there was significant correlation between LVWT and presence of LGE , Table S2. There was no significant relationship between steatosis and myocardial fibrosis .Presence of LGE was also seen to increase progressively across the quartiles, with the highest percentage of cases in Q4 .Participants in Q1 were younger  with lower average systolic BP (136±18 mm Hg). All quartiles were matched in rest of the characteristics (P<0.001) and LV mass index. Longitudinal strain reduced across the increasing AVG quartiles . CS was lower in Q4 compared with others, and there was a step wise reduction in early diastolic CS rate  across the ordered groups. On partial correlation controlling for LVWT, only CS had a significant association with AVG .With increasing pressure load, there was an increase in LVWT . In contrast, MTG increased significantly (by 42%) across the increasing AVG quartiles . When controlled for LVWT, there was no significant relationship between AVG quartiles and phosphocreatine/ATP  or MTG content .Myocardial phosphocreatine/ATP reduced across the increasing AVG quartiles .Native T1 and ECV were lower in Q2 to Q3 and then increased in Q4 .Areas of LGE were identified in overall 34% of patients with increasing prevalence across the quartiles, highest in Q4 . Further details available in the Supplemental Material .When assessed against total LV pressure load (AV gradient and systolic blood pressure), there was similar trend of increasing steatosis and reducing energetics across the quartiles, with total LV pressure significantly associated with steatosis (P=0.03), and myocardial steatosis numerically increased across the groups (P=0.05). Details in Table S7 and Figure S6).Next, we divided patients into normal controls, mild-moderate AS, moderate AS, and severe AS groups based on their echocardiographic findings, we observed similar metabolic signature as seen on the quartiles. There was a significant reduction in cardiac energetics at mild-mod AS stage . Longitudinal strain was impaired earlier than CS in Q3 and Q4. This is in keeping with previous studies, which have demonstrated LVH to cause impaired longitudinal function in pressure overload despite normal ejection fraction. Circumferential and radial strain impairment occurs later and is also related to hypertrophy.24Despite normal LV ejection fraction, there was convincing evidence of subclinical LV impairment with reduction in both systolic and diastolic strain parameters early, which worsened with disease progression. Impairments in longitudinal strain, CS, and CS rate were driven by increase in LVWT . The metabolic changes described in this study, that is, reduced energetics and myocardial lipid accumulation support the metabolic substrate shift known to occur in AS—from fatty acids to glucose, subsequent increased glucose uptake and glycolysis with either no change or decrease in glucose oxidation. These adaptations improve myocardial oxygen efficiency but are associated with depletion of the energy reserve compound, phosphocreatine, while maintaining ATP levels until decompensation ensues.26 Reduced energetics levels could potentially be one of the driving factors in the development of LVH necessitating increased muscle mass to allow maintenance of normal contractile function in face of altered ATP production.Previous studies have demonstrated that significant energetic impairment is already established in moderate-severe AS.Further, we show here that the energetics worsen as LVWT increases and hypertrophy becomes established. Cardiac phosphocreatine/ATP was found to be an independent predictor of LVWT.27 Despite this, whether a relationship between LVWT and MTG exists in AS remains unknown. We show here that presence of steatosis is seen earlier than moderate AS and before the development of significant hypertrophy. These findings support the hypothesis that metabolic changes as previously studied in animal and human models of AS29 occur prematurely and potentially drive or accelerate LVH and subsequent fibrosis and decompensation.Similarly, myocardial steatosis is known to be well established in moderate-severe AS and related to LV systolic strain impairment.30 Presence of myocardial replacement fibrosis as seen on LGE was related significantly to LVWT (P<0.001). This is congruent with previous studies showing that development of hypertrophy is associated with myocyte apoptosis resulting in focal sites of replacement fibrosis, which may be important in the transition from compensated hypertrophy to heart failure.31 The novel finding from this study is that the presence of fibrosis is related to reduced phosphocreatine/ATP (P=0.03).Findings from the study are consistent with previous studies showing that replacement fibrosis seems to occur late and is irreversible.23This would also explain findings from previous histological studies that show an association between myocardial fibrosis at the time of valve replacement and both impaired recovery of LV systolic function and poor long-term outcomes after valve replacement.Overall, this study demonstrates that energetic impairment precedes significant change in LVWT from baseline and potentially exacerbates the hypertrophic response once it has developed, with progression to subclinical contractile dysfunction and myocardial fibrosis.Steatosis also is related to LVWT but does not seem to have a causal relationship with development of hypertrophy.P<0.001; LVG and LVWT, P=0.07 when controlled for AVG, LVG data presented in supplement). Myocardial strain was impaired despite normal EF but only CS impairment was related to pressure overload. This reiterates the findings from previous studies that LV strain impairment in AS is driven by geometric changes in LV secondary to hypertrophy than AV gradient itself.32Both LVWT and LV mass index increased with increasing AV gradient quartiles, but this was secondary to AV gradient with no significant additional effect of systolic blood pressure  than AV gradient alone (P=0.07), independent of LVWT. Thus, highlighting the benefit of blood pressure control in AS for preventing/reducing cardiac lipotoxicity.34 Phosphocreatine/ATP ratio reduced significantly across the increasing pressure overload quartiles, but this reduction did not correlate to the degree of pressure overload.MTG increased progressively across the pressure overload quartiles (both AV and LV gradients) with significant difference between the quartile groups. Total LV gradient had added impact on myocardial steatosis . Dr Myerson’s research is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Center. Dr Valkovič is supported by a Sir Henry Dale Fellowship from the Wellcome Trust (No. 221805/Z/20/Z). Dr Rider is supported by a British Heart Foundation Senior Clinical Research Fellowship (FS/SCRF/22/32014). Drs Neubauer and Rider acknowledge support from the Oxford NIHR Biomedical Research Center and the British Heart Foundation Center of Research Excellence. Dr Valkovič also acknowledges the support from the Slovak grant agencies VEGA  and APVV .None.Tables S1–S7Figures S1–S5


Our understanding of the various forms of conduction system pacing, cardiac resynchronization therapy (CRT), and their clinical role in the treatment of heart failure continues to evolve. The previous year regaled us with a flurry of studies, which have advanced our understanding and piqued our interest in their clinical role.1 in patients in sinus rhythm. This experience involved 9 centers in 3 continents. A heterogeneous population of 112 non-sequential patients underwent placement of a permanent left bundle pacing lead and a CRT lead, with clinical and echocardiographic follow-up. Implantation was successful in 91 patients (81%), a respectable real-world number, and there were no serious complications. Echocardiographic remodeling occurred in 63%, while a clinical response was documented in 76%, a commendable result considering that the patient population included some patients who had failed to respond to CRT in the past, while others had right bundle branch block. Of interest, the echocardiographic and clinical responses were significantly superior in patients with left bundle capture versus left ventricular septal pacing when combined with CRT.The International LBBAP Collaborative Study Group reported their experience with left bundle branch pacing combined with CRT2 which can be compensated for by CRT.The diverse patient population prevents us from drawing too many conclusions, but these intriguing results make good theoretical sense. While the site of block is proximal in most patients with cardiomyopathy and left bundle branch block, there are varying degrees of functional block or delay distally in many, which cannot be completely overcome by left bundle pacing alone; CRT can stimulate areas with delayed conduction and complement intra-ventricular synchrony, while the proximal conduction system is activated antegrade by left bundle stimulation. Also, left bundle pacing cannot always be accomplished in every patient, and left septal pacing introduces a small but physiologically significant delay in activation of the lateral wall of the LV,3 This randomized prospective trial employed a crossover design; 50 patients with persistent AF, left ventricular ejection fraction < 40%, narrow QRS (or right bundle branch block), and adequate rate control  underwent atrioventricular junction ablation and implantation of His bundle, right ventricular, and coronary sinus branch pacing leads. Patients were randomized to His-bundle pacing or biventricular CRT, with crossover at 9 months. The primary endpoint was echocardiographic remodeling, and secondary endpoints included quality of life assessment and brain natriuretic peptide measurements. Thirty-eight patients completed the trial; 7 of the 12 remaining patients died and 5 were lost to follow-up.Building on the conduction system pacing theme, Huang et al. compared His-bundle pacing with CRT in patients with AF and reduced ejection fraction in the ALTERNATIVE-AF trial.Among the patients who completed the trial, the overall response rate at 18 months was 94.7%, an exceptional result; only 2 patients failed to show improvement. The left ventricular ejection fraction improved from 32.6% ± 6.4% to 53.9% ± 11.9% after the first 9 months with His-bundle pacing and from 34.6% ± 4.6% to 51.3% ± 7.4% with CRT during the same period. This slightly greater response (4.5%) achieved with His-bundle pacing was statistically significant, and this difference was maintained after 18 months. The left ventricular end-diastolic dimension improved equally with both pacing modalities, as did the New York Heart Association functional class, quality of life measures, and brain natriuretic peptide levels.4 The relatively young age  and healthy state  of the study population support implant success, as does the absence of conduction system disease. The overall response rate of 95% also excludes the 12 patients who died or were lost to follow-up. Further, cardiomyopathy was arrhythmia-mediated in the majority, with only 2 patients having an ischemic etiology; a superior response rate is not unexpected in this population. These excellent results may not be reproducible in an older, sicker population or with other, less-experienced operators in the real world of clinical practice.This trial is remarkable in many respects. The 100% success with His and CRT leads is a testament to the skill, experience, and persistence of the implanting physician. A recent meta-analysis of His-bundle pacing trials showed a more modest 79.8% success rate.5 Whether this becomes a concern over the long term remains to be seen. Longer-term follow-up during larger randomized trials will be needed to answer these questions.Both CRT and His pacing following atrioventricular node ablation produced excellent reverse remodeling. The slightly better response to His pacing is not unexpected since no form of biventricular CRT can replicate the perfectly synchronous contraction engendered by activating the normal conduction system. In the medium term, there was no clinical difference between His pacing and CRT in New York Heart Association class or quality of life measures. It is uncertain whether this difference will prove to be clinically important in the long term. Our experience with CRT tells us that dyssynchrony-mediated ventricular remodeling can take many years to develop. While His pacing thresholds were exceptional (0.9 ± 0.6 mA at 18 months) in the study, this has not been the general experience in other centers, where His pacing thresholds are generally significantly higher and tend to rise with time.3 echoed the work of Brignole and colleagues,7 who elegantly demonstrated the importance of rate regularization in the noteworthy APAF-CRT trials.Another important aspect of this trial was that the patients included did not have uncontrolled ventricular rates during atrial fibrillation (AF); the arrhythmia-induced cardiomyopathy was not necessarily rate-related but instead due to the irregularity of the ventricular rate during AF. Rate regularization rather than rate control was the likely mechanism for improvement. In this regard, Huang et al.9 Even strict control of the rate during AF does not ameliorate the underlying pathology, as shown in the RACE-II trial.10 Perfect rate regularity can be achieved by ablation of the atrioventricular node and pacing of the ventricles. In older pace-ablate trials, the benefit of rate regularity was negated by the adverse effects of right ventricular pacing–induced dyssynchrony.11 In the ALTERNATIVE AF and APAF-CRT trials, His-bundle pacing or CRT eliminated the adverse effects of right ventricular pacing and allowed the benefits of rate regularity to emerge. ALTERNATIVE AF showed profound reverse remodeling and symptomatic improvement, and the larger APAF-CRT trial demonstrated a striking reduction in total mortality and hospitalizations for heart failure.We are all aware of the negative effects of tachycardia on ventricular function, but the deleterious effects of an irregularly irregular rate are less well recognized even though the underlying physiology is well understood.12 but it must be recognized that many patients fail AF ablation. A meta-analysis evaluating the long-term outcomes of 6,167 patients who underwent a single radiofrequency ablation procedure for AF revealed that only 54.1% of paroxysmal AF patients and 41.8% of non-paroxysmal AF patients maintained sinus rhythm at 1 year.13 When maturation of technology allows speedy and reliable conduction system pacing, this, possibly coupled with CRT, may turn out to be the treatment of choice for such patients.These trials re-awaken our interest in adopting a pace-ablate strategy for patients with refractory AF and heart failure. Restoration of sinus rhythm with AF ablation was shown to improve survival in the landmark Catheter Ablation vs. Standard Conventional Treatment in Patients with LV Dysfunction and AF (CASTLE-AF) trial,