Invasive measures of microvascular resistance in the culprit coronary artery have potential for risk stratification in acute ST‐segment–elevation myocardial infarction. We aimed to investigate the pathological and prognostic significance of coronary thermodilution waveforms using a diagnostic guidewire.P=0.007 and 0.011, respectively), and both pathologies were more prevalent in patients with a bimodal morphology. On multivariate analysis with baseline characteristics, thermodilution waveform status was a multivariable associate of microvascular obstruction  and myocardial hemorrhage , but the relationship was not significant when index of microvascular resistance (IMR) >40 or change in index of microvascular resistance (5 per unit) was included. However, a bimodal thermodilution waveform was independently associated with all‐cause death and hospitalization for heart failure , independent of index of microvascular resistance>40, ST‐segment resolution, and TIMI  Myocardial Perfusion Grade.Coronary thermodilution was measured at the end of percutaneous coronary intervention, (PCI) and contrast‐enhanced cardiac magnetic resonance imaging (MRI) was intended on day 2 and 6 months later to assess left ventricular (LV) function and pathology. All‐cause death or first heart failure hospitalization was a pre‐specified outcome (median follow‐up duration 1469 days). Thermodilution recordings underwent core laboratory assessment. A total of 278 patients with acute ST‐segment elevation myocardial infarction EMI  had coronary thermodilution measurements classified as narrow unimodal (n=143 [51%]), wide unimodal (n=100 [36%]), or bimodal (n=35 [13%]). Microvascular obstruction and myocardial hemorrhage were associated with the thermodilution waveform pattern (The thermodilution waveform in the culprit coronary artery is a biomarker of prognosis and may be useful for risk stratification immediately after reperfusion therapy. In acute ST‐segment–elevation myocardial infarction survivors, coronary thermodilution waveforms depicted using a diagnostic guidewire at the end of percutaneous coronary intervention provides information that is linked with microvascular injury.A bimodal thermodilution waveform is independently associated with adverse clinical outcomes, including all‐cause death and heart failure in the longer term.A bimodal thermodilution waveform is a biomarker for prognostication in survivors of acute ST‐segment–elevation myocardial infarction.Risk assessment of failed reperfusion in patients undergoing emergency percutaneous coronary intervention for acute ST‐segment–elevation myocardial infarction is challenging.Use of a diagnostic guidewire at the end of the percutaneous coronary intervention has emerging clinical utility for risk assessment.Classification of the coronary thermodilution waveform categorization is a novel approach to identify at‐risk subgroups that has the potential to translate into real‐world practice merits assessment.Percutaneous coronary intervention (PCI) for acute ST‐elevation myocardial infarction (STEMI) routinely leads to successful coronary reperfusion.Microvascular obstruction usually passes undetected in clinical practice. Standard measures of myocardial reperfusion, including TIMI  Myocardial Perfusion Grade and corrected frame count, or ST‐segment resolution on the ECG, lack sensitivity and reproducibility.The index of microvascular resistance (IMR) is a direct invasive measure of microvascular function that can be performed routinely in the cardiac catheterization laboratory immediately after revascularization to identify patients with failed reperfusion. IMR is inversely associated with left ventricular (LV) function post‐MIBecause downstream microvascular resistance influences coronary blood flow, the characteristics of the thermodilution waveform in the culprit coronary artery reflect microvascular dysfunction and infarct pathology in patients with acute STEMI.The data, analytic methods, and study materials will be made available on request to other researchers for purposes of reproducing the results or replicating the procedure. The study was approved by the West of Scotland Research Ethics Committee, reference 10‐S0703‐28, and informed consent was obtained from each patient.Between July 14, 2011 and November 22, 2012, 278 STEMI patients with acute STEMI who were reperfused predominantly by emergency PCI were prospectively enrolled . All patients gave informed consent to undergo a diagnostic guidewire‐based assessment at the end of the PCI procedure, then CMR 2 days and 6 months later, and follow‐up for health outcomes in the longer term. Patients with a contraindication to CMR, such as a pacemaker or severe renal dysfunction, were not enrolled.Thermodilution curves were manually acquired after PCI of the infarct‐related artery using a dual‐sensor pressure‐ and temperature‐sensitive coronary guidewire . The diagnostic wire was calibrated outside the body, equalized with aortic pressure at the ostium of the guide catheter, and then advanced to the distal third of the culprit artery. We used guide catheters without side holes to allow delivery of a saline bolus into the coronary ostium. Care was also taken to ensure that the guide catheter was properly intubated and that the catheter was flushed with saline, thereby removing contrast medium that could potentially interfere with the measurements. The injections were preceded by a 2‐mL bolus of 200 μg of nitrate.Thermodilution curves in the culprit coronary artery were obtained by repeated manual injections of 3 mL of room‐temperature saline during maximal hyperemia induced by continuous intravenous infusion of adenosine (140 μg/[kg·min]). The average of the 3 values was taken as the mean hyperemic transit time. Following injection of the saline bolus into the coronary artery, the reduction in temperature of the coronary blood was detected by the thermistor at the distal end of the guidewire. The thermodilution curve  was recorded in real time  and available for analysis . IMR was calculated as the product of simultaneously measured distal coronary pressure (mm Hg) and mean hyperemic transit time (seconds), as previously described.Thermodilution waveforms were analyzed by a trained observer (S.N.Y.) who was blind to all of the magnetic resonance imaging (MRI) and clinical data. S.N.Y was trained and supported by D.C. and C.B. The waveforms were classified into 3 groups according to the shape of the thermodilution curve: sharp unimodal, wide unimodal, and bimodal Figure . The meaCMR was performed on a Siemens MAGNETOM Avanto  1.5‐Tesla scanner with a 12‐element phased‐array cardiac surface soilThe presence of acute infarction was established based on abnormalities in cine wall motion, rest first‐pass myocardial perfusion, and delayed‐enhancement imaging in 2 imaging planes.The extent of myocardial edema was defined as LV myocardium with pixel values (T2) >2 standard deviations from remote myocardium.A 12‐lead ECG was obtained before coronary reperfusion and 60 minutes afterwards. The extent of ST‐segment resolution on the ECG assessed 60 minutes after reperfusion compared to the baseline ECG before reperfusion®; GE Healthcare, Chicago, IL) and information technology equipment . The angiograms were analyzed by trained observers  who were blinded to all other clinical and MRI data. The TIMI coronary flow gradeCoronary angiograms were acquired during usual care with cardiac catheter laboratory x‐ray .Twenty subjects were randomly selected from the 278 patients, and the thermodilution pattern of these 20 subjects was analyzed repeatedly. The interobserver (D.C. and S.N.Y.) and intraobserver reliability for the visual assessment of thermodilution waveforms was assessed using weighted Cohen κ. Univariable and multivariable associations were assessed using binary logistic regression or linear regression. Logistic regression was used to identify potential clinical predictors of all‐cause death or heart failure hospitalization, including patient characteristics, CMR findings, IMR, and thermodilution waveform pattern. The Akaike information criterion was used to assess the relative quality of the statistical models. All A total of 278 patients had thermodilution performed in the culprit coronary artery (Table P=0.007), worse flow in the culprit artery at the end of the procedure (P=0.026), a higher proportion with Killip class III and IV heart failure (P=0.003), and a higher circulating monocyte count (P=0.011). A bimodal waveform was also positively associated with the circulating concentration of NT‐proBNP  (P=0.006) . Eighty‐four (30%) patients had an IMR >40 units. An IMR >40 occurred in 16 (11%) patients in the narrow unimodal group, 45 (45%) patients in the wide unimodal group, and 23 (66%) patients in the bimodal waveform group, respectively (P<0.001).The median (interquartile range) IMR of the bimodal morphology group was higher than those in the narrow and wide unimodal groups  and at follow‐up (P=0.001) were lower in the bimodal group.The CMR findings at baseline and 6 months were grouped by the type of culprit artery thermodilution waveform Table . The LV P=0.002 and 0.004, respectively)  Table , and proIn a binary logistic regression model with baseline characteristics, thermodilution waveform status was a multivariable associate of microvascular obstruction revealed by CMR 2 days post–myocardial infarction Table . This reP>0.05) or an IMR (per 5 unit) (P>0.05) was included.Thermodilution waveform status was a multivariable associate of myocardial hemorrhage Table , but thiP=0.024) (Table IMR (5 unit difference) was a multivariable associate of change in LV end‐diastolic volume, independent of thermodilution waveform status  Table .Thermodilution waveform status, IMR>40, and IMR (for a 5‐unit change) were not associates of changes in LV ejection fraction Table .P=0.031), independent of IMR>40, ST‐segment resolution, and TIMI Myocardial Perfusion grade (Table P=0.080) when infarct size was included in the model  participants died or experienced a heart failure episode. The occurrence of a bimodal thermodilution waveform was independently associated with all‐cause death and heart failure hospitalization  patients died during follow‐up. IMR alone was not associated with death (Table .8% patieThe main findings of our study are these: (1) thermodilution in the culprit coronary artery was straightforward and feasible to perform in a comparatively large number of patients with acute STEMI, and intraobserver and interobserver variabilities for classification of the waveform morphologies were reasonably high; (2) thermodilution waveform type was associated with IMR. A bimodal waveform was a multivariable associate of microvascular obstruction; however, this relationship was no longer significant when IMR was included (either IMR [for a 5‐unit change] or IMR>40); (3) IMR (for a 5‐unit change) was an independent predictor of myocardial hemorrhage; (4) a bimodal thermodilution waveform was a multivariable associate of adverse clinical outcomes during follow‐up, including after adjustment for IMR>40.Taken together, these results indicate that a bimodal waveform is an associate of adverse clinical outcomes post–myocardial,infarction and may be useful for risk stratification of STEMI patients immediately after reperfusion therapy. Waveform classification and IMR have relative merits. The waveform classification represents a binary approach to risk stratification, whereas IMR and other indices (such as hyperemic microvascular resistance derived using Doppler) provide a continuous measure of microvascular dysfunction and in this sense may be more informative.Fearon et al first reported that an IMR>40 measured after angiographically successful primary PCI was an independent predictor of adverse clinical outcome.Fukunaga et alIn our study, microvascular obstruction and myocardial hemorrhage were associated with thermodilution waveform pattern, and each pathology was more prevalent in patients with a bimodal morphology; however, this relationship was not independent of other characteristics when assessed in a multivariable regression model. Instead, our results showed that IMR (for a 5‐unit change) was a stronger associate of microvascular obstruction and myocardial hemorrhage. Logistic regression analysis showed that bimodal thermodilution waveform status was a stronger predictor of all‐cause death and heart failure hospitalization than IMR. When infarct size measured on CMR 2 days later was included, the prognostic significance of IMR was lost. IMR (for a 5‐unit change) was the only independent predictor of infarct size during follow‐up on multivariate analyses Table . The assOur study extends that of Fukunaga et al.Similar to IMR (for a 5‐unit change), a bimodal thermodilution waveform is a stronger predictor of adverse clinical outcome than ST‐segment resolution on ECG, or angiographic flow grades and may be useful for risk stratification of STEMI patients immediately after reperfusion. IMR is independently associated with microvascular obstruction and myocardial hemorrhage, and because it is a continuous value, it holds the potential to quantify the efficacy of novel reperfusion therapies designed to restore microvascular perfusion and limit infarct size. This possibility is currently being assessed in a randomized, controlled phase 2 clinical trial of low‐dose alteplase (10 and 20 mg) or placebo directly administered into the culprit coronary artery after reperfusion but before stenting .Our study adds to previous investigations using coronary thermodilution for risk assessment in patients with acute STEMI. We conclude that a bimodal thermodilution waveform identifies high‐risk patients who may benefit from more intensive follow‐up and medical therapy.Our study took place in a single center, and further research in other hospitals is warranted. Only 13% of patients had a bimodal waveform, limiting to some extent its clinical impact. The waveform classification was undertaken post hoc using a core laboratory approach. The diagnostic accuracy of clinician‐reported waveform classification during real‐world practice merits further assessment.This work was supported by the British Heart Foundation Centre of Research Excellence Award (RE/13/5/30177), the British Heart Foundation Project Grant PG/11/2/28474, the National Health Service, and the Chief Scientist Office. Professor Berry was supported by a Senior Fellowship from the Scottish Funding Council.Siemens Healthcare provided work‐in‐progress imaging methods. Based on an institutional agreement with the University of Glasgow, Professor Berry has acted as a consultant to Abbott Vascular. Professor Oldroyd has acted as consultant to Abbott Vascular. These companies had no involvement in the current research or the article. The remaining authors have no disclosures to report.Data S1. Supplemental MethodsTable S1. Multivariable Associations Between Clinical Characteristics at Presentation, Including Thermodilution Waveforms, IMR (for a 5‐Unit Change), and the Change in LV End‐Diastolic Volume at 6 Months in Patients With Acute STEMITable S2. Multivariable Associations Between Clinical Characteristics at Presentation, Including Thermodilution Waveform, IMR (for a 5‐Unit Change), and the Change in LV Ejection Fraction at 6 Months in Patients With Acute STEMITable S3. Multivariable Associations Between Clinical Characteristics at Presentation, Including Thermodilution Waveforms, IMR (for a 5‐Unit Change), and Infarct Size 6 Months Later in Patients With Acute STEMIClick here for additional data file.


In multivariate analysis, a PICP ≤ 163 ng/ml was associated with a positive CRT response  independently of the presence of LBBB, QRS duration, LV lead position or non-ischemic cardiomyopathy. Altogether, the present findings show that a lower degree of cardiac fibrosis is associated with a positive response after CRT implantation. PICP evaluation before CRT implantation could help improve patient selection.Cardiac fibrosis is associated with heart failure and poor prognosis. Fibrosis biomarkers have been poorly evaluated as a tool to predict cardiac resynchronization therapy (CRT) response generating conflicting results. The present study assessed the predictive value of cardiac fibrosis biomarkers on CRT response. Patients underwent clinical examination, echocardiography and blood fibrosis biomarker evaluation prior to CRT implantation. At six months, a positive response to CRT was defined by a composite endpoint of no death or hospitalization for heart failure, and presence of left ventricular (LV) reverse remodeling (decrease in LV end-systolic volume ≥15%). Sixty patients were included in a multicenter study. At 6 months, 38 were positive responders to CRT and reached the response criteria (63%). Compared to non-responders, CRT responders displayed lower concentration levels of the fibrosis biomarkers procollagen type I C-terminal propeptide [PICP 135[99–166] ng/ml  Initial research on resynchronization therapy was purely clinical, enabling the establishment of recommendations for the implantation of CRT based on the presence of symptomatic heart failure (NYHA II to ambulatory IV) with left ventricular dysfunction (LVEF ≤ 35%) and electrical dyssynchrony (QRS duration ≥130 ms and QRS morphology)5.Cardiac resynchronization (CRT) is an effective treatment in addition to optimal drug therapy for heart failure with reduced ejection fraction (HFrEF)6. Myocardial fibrosis has been identified as a determinant of the prognosis of cardiomyopathy progression8 as well as an indicator of a poorer prognosis of HFrEF10.Unfortunately, the mechanisms underlying the response to CRT are poorly understood. As a result, 20 to 40% of patients implanted with CRT are non-responders irrespective of the endpoint chosen to assess CRT response12. These biomarkers have been only sparsely studied in the setting of CRT14 and we hypothesize that lower levels of collagen peptides are likely associated with a better CRT response.Extracellular matrix turnover, measured by circulating collagen peptides, is associated with ventricular remodeling in the case of hypertension after myocardial infarction and to excess mortality in the context of HFThe aim of this first-known dedicated prospective study was to assess the contribution of the quantification of myocardial fibrosis by means of serological determination of collagen peptides prior to implantation in predicting the response to CRT.5.Written consent for this prospective multicenter cohort study was obtained from each patient after receiving the appropriate information. PREFAC-CRT (NCT02018029) obtained the ethical approval from the French Ethics Committee and the French National Agency for Medicines and Health Products Safety and was conducted in accordance with European Society of Cardiology (ESC) guidelines5. Non-inclusion criteria were: pregnancy; contraindication to CRT; atrial fibrillation; non-affiliation to a social security scheme; disability.Patients were included according to the following criteria: age ≥18 years; indication for CRT according to the ESC 2012 guidelines; expected life expectancy greater than 1 year with good functional status; optimal pharmacological treatment of HFPatients responding to CRT were defined at 6 months post-implantation by absence of hospitalization for HF or cardiovascular death defined by terminal heart failure death  or sudden cardiac death related to ventricular arrhythmia documented on device monitoring and by a decreased indexed left ventricular end-systolic volume (LVESVi) of more than 15% (ΔLVESVi ≥ 15%) measured by 2D echocardiography.Medical workup at inclusion, prior to CRT implantation, included a clinical examination, resting transthoracic echocardiography, 6-minute walking test, quality of life score (Minnesota Living With Heart Failure Questionnaire: MLWHFQ), as well as a blood sample in conjunction with a serum biobank of cardiac fibrosis biomarkers. Ischemic heart disease was defined as a LV systolic dysfunction related to a previous cardiac event . Non-ischemic dilated cardiomyopathy (DCM) was defined as a reduced LVEF not attributable to an ischemic, valvular or pacemaker-induced cardiomyopathy.®, Katy, TX, USA) were used for determination of serum collagen peptide concentrations, namely: (i) biomarkers of collagen synthesis: PINP , PICP  and PIIINP ; and (ii) a biomarker of collagen degradation: ICTP 16. Each patient sample was measured in duplicate, following the recommendations of the manufacturer. For the four determinations, intra-assay and inter-assay precision was <10% and <12%, respectively.ELISA kits  in accordance with the recommendations of the American Society of Echocardiography and the European Association of Cardiovascular ImagingIn each investigating center, implantation and programming methods were left to the discretion of each operator with the goal of the highest rate of biventricular pacing. Information regarding venous anatomy (number and position of the coronary veins), the position of the leads as well as programming parameters was collected. Post-procedural complications were also duly noted.Sample size estimation was determined in order to highlight an effect-size equal to 0.5 for a two-sided type I error at 0.01 (correction due to multiple tests) and a statistical power greater than 90%. With an expected rate of responders ranging between 50% and 70%, it was initially proposed to include 300 patients. However, further exploratory sequential analyses were performed to evaluate effect-size and estimate statistical power. As a result, with an effect-size of 0.89 , a total of 60 patients allowed achieving a statistical power greater than 80%.Statistical analyses were performed using Stata . All statistical tests were two-sided and a p-value < 5% was considered statistically significant. Continuous data are expressed as mean ± standard-deviation or median [interquartile range], according to statistical distribution . Comparisons among CRT responses were performed using the chi-squared or Fisher’s exact tests for categorical data, and using Student’s t-test or Mann-Whitney test (when assumptions of the t-test were not met) for continuous data. Hedge’s g bias-corrected effect size and its 95% confidence interval were computed and plotted for each biomarker. To analyze relationships between biomarkers, remodeling and LVESVi, Pearson or Spearman’s correlation coefficients were computed, applying a Sidak’s correction to take into account multiple comparisons.A multivariable analysis  was thereafter performed to study the predictive factors of CRT response. The covariates were determined according to univariate results and clinical relevance. Particular attention was given to the study of multicollinearity and interactions between covariates 1) studying the relationships between the covariables and 2) assessing the impact of adding or deleting variables in the multivariable model. Following this multivariable analysis, a receiver operating characteristic (ROC) curve was plotted for the final model, along with computation of the area under the curve (AUC) and its 95% confidence interval. In order to assess the contribution of PICP to CRT-response prediction, two multivariable models were generated: one with LBBB, dilated cardiomyopathy, QRS duration (without PICP) and lateral LV lead position and the second using the same covariates plus PICP. The models were thereafter compared using the Likelihood-ratio test (LR test), the Akaike Information Criterion (AIC) and the Bayesian information criterion (BIC).18. Thus, a bootstrap procedure20 was performed from the original sample, from which the bootstrap estimates associated with each covariate and their associated standard errors were averaged from replicates. Results are shown as adjusted odds-ratios and their 95% confidence interval.Since bootstrap validation does not require distributional assumptions , the latter can provide more accurate inferences when the data are not well behaved or when the sample size is smallFinally, to take into account potential confounders in the analysis of the effect of PICP on CRT response , a sensitivity analysis was carried out, using a propensity score analysis with logistic regression model, to assess the propensity for patients to be in the PICP < 163 group, in which dilated etiology, LBBB and QRS duration were considered as covariates. The relationship between CRT response and PICP was subsequently analyzed using inverse propensity score weighting. Results are shown as odds-ratios and 95% confidence interval.Sixty patients were included and successfully implanted (80% CRT-D). Early repositioning of the left ventricular lead was necessary in one patient while another was treated for early device infection. For the latter two patients, follow-up was only initiated once their CRT system was fully functional. At 6 months, 56 patients underwent transthoracic echocardiography; of the remaining 4 patients, 3 died from terminal cardiac failure while one patient underwent a heart transplant. At 6 months, 38 patients (63%) were responders to CRT Fig. .Figure 1vs. 0.79 ± 0.87, p = 0.04, QRS duration at 6 months was 152 ± 39 ms vs. 147 ± 26 ms, p = 0.57, QRS thinning was 8 ± 37 ms vs. 25 ± 30 ms, p = 0.005 and 6-meter walking distance improvement was 8 ± 93 vs. 1 ± 152, p = 0.6 in non-responders and responders, respectively , DCM , wider QRS duration , a better quality of life  and a LV lead positioned in a lateral vein of the coronary sinus . Patients not responding to CRT more often had respiratory insufficiency  and required positive inotropic amines in the month preceding implantation .Patients who responded to CRT more frequently had, prior to CRT implantation, a LBBB  and PIIINP  levels than non-responders. Patients with a higher inverse remodeling (ΔLVESVi ≥ 30%) had a lower PICP than non-responder patients , DCM  or QRS duration ≥ 150 ms  ] (Table –46.7] (Tvs. 57 without PICP) and BIC (61 vs. 65).PICP effect size (on CRT response) was 0.89 0.34–1.44] (Table –1.44 (Ta20) display a higher PICP level; 2) left ventricular remodeling is inversely associated with the degree of biological fibrosis despite the presence of electrical dyssynchrony or non-ischemic heart disease; and 3) a low PICP level (≤163 ng/ml) is independently associated  with a positive response to CRT; PICP thus adds a new value in predicting CRT response, in addition to the above classical typical parameters validated as CRT response predictors.This novel prospective study enabled assessing the impact of myocardial fibrosis evaluated by circulating collagen peptides on the response to CRT. The findings obtained herein highlight several major elements in the understanding of the response to CRT that could not be previously explained by isolated analysis of electrical or mechanical dyssynchrony. These new elements notably include: 1) the response to CRT is associated with a lower PICP rate prior to implantation while CRT non-responders who are otherwise expected to respond 22. The present study shows that despite the presence of typical response factors, these non-responder patients have a higher serum PICP. Patients with advanced heart diseases, with a significant degree of fibrotic remodeling, have a limited response to CRT23, partly explaining why these patients do not improve despite the presence of classical predictive factors. Thus, evaluation of PICP prior to CRT implantation would enable a better identification of patients prone to respond to CRT, including those expected as responders.More than a decade of research has not allowed implementing a reliable additional criterion in the selection of CRT responders. We demonstrate herein that PICP ≤ 163 ng/ml was associated with a 7.8-fold increase in the likelihood of being a responder (p = 0.023) and was also correlated with LV remodeling at 6 months. This translates to a greater degree of myocardial fibrosis at implantation24. By limiting LV scar pacing and harboring aspecific conduction disorders, these scars ultimately reduce CRT response. MRI provides accurate localization of focal scars, although to a lesser extent with regard to quantification of the interstitial fibrotic infiltrate in the ventricular myocardium as a whole. Quantifying this infiltrative and diffusive fibrosis remains challenging, despite the advent of promising new imaging sequences8. Response to cardiac resynchronization is likely more dependent on the overall volume of interstitial fibrosis25. In this respect, collagen peptides and notably PICP are of prime interest, since they allow a quantitative assessment of the fibrotic burden of the myocardium, albeit with no localizing value. Non-invasive myocardial fibrosis quantification could therefore represent the missing link in the individual evaluation of patients with CRT.Focal fibrotic myocardial scars are identified using imaging techniques27. Collagen peptides have been poorly used in the study of CRT response by determining the degree of myocardial fibrosis prior to implantation in addition to yielding conflicting results. Lopez-Andres et al. observed that increased Galectin-3 and PIIINP were associated with adverse long-term cardiovascular outcomes but did not predict the response to CRT12. These findings are inconsistent with a retrospective analysis of the MADIT-CRT trial, where Galectin-3 elevation was inversely correlated with heart failure and death after CRT28. Umar et al.14 also highlighted the potential impact of collagen peptides (PINP) to predict CRT response without direct comparison of PICP with PINP.Biomarker candidates for assessing cardiac fibrosis in clinical practice are rareet al. showed that collagen type I turnover (higher PICP/ICTP ratio in responders) influenced the long-term response to CRT (12 months), similarly to their previously published study13. Unfortunately, PICP was not independently evaluated from other response criteria. Surprisingly, they described a higher level of fibrosis associated with CRT responders in contrast with data provided by Umar et al.14, Lopez et al.12 as well as the present study in which patients with lower levels of fibrosis were prone to respond to CRT. The reason for this discrepancy is unknown, but may be related to variations in CRT indications as a result of guideline evolution, inconsistent CRT response criteria based either on left ventricle remodeling (LVESVi > 10% at 6 months14), functional status , morbidity (major cardiovascular outcomes28) or a composite thereof , somehow poorly correlated29, and lastly a lack association between histological myocardial fibrosis in human biopsies30 and fibrosis biomarkers such as Galectin-3 and PINP. The method of collagen peptide assessment does not appear to be a probative explanation since radioimmunoassay was used in the Umar et al., Lopez et al. and Garcia-Bolao et al. studies.With regard to PICP, Garcia-Bolao 31 whose dysregulation in synthesis/degradation balance increases their accumulation. Clinically, the serum level of PICP is strongly associated with the total fraction of type I collagen in the myocardium32, particularly in instances of heart failure or diastolic dysfunction34. PICP and PIIINP are associated with the presence of myocardial fibrosis in tissue biopsies as opposed to ICTP or PINP or Galectin-327. Our results confirm PICP as a promising fibrosis marker that is both minimally invasive and reproducible.Collagen peptides are associated with the total volume of type I and III collagens constituting the majority of the extracellular matrix35, part of the myocardial fibrosis is reversible by anti-fibrotic treatments. CRT, as also the case for standalone cardiac electrical dyssynchrony therapy, does not appear to impact the rate of fibrosis14, albeit with conflicting results13 and thus requires further dedicated studies. Unfortunately, evaluation of collagen peptides after CRT implantation was not performed in the present study but would be of great interest especially with the impact of antifibrotic drugs.The biological evaluation of cardiac fibrosis is an attractive and credible alternative to standard imaging techniques. While minimally invasive, it would also allow improving patient management and contribute to the understanding of the mechanisms of HF and the response to CRT. The systematic measurement of PICP prior to CRT implantation, would optimize such management, especially those with a high PICP level. Identifying less responding patients could enable more aggressive management, whether medically or interventionally. Although we did not observe an association between the prescription of anti-fibrotic treatments (e.g. MRA) and collagen peptide levels, non-responder patients could benefit from an intensification of these molecules before and/or during CRT implantation. As demonstrated in post-acute myocardial infarction36.In terms of study limitations, it should be emphasized that our study comprises a limited population sample. However, the validity of this cohort is confirmed by the identification of conventional CRT response criteria. In addition, despite the small sample size of this study, we nonetheless demonstrate the clinical value of PICP both at baseline and in multivariate analysis. More precisely, PICP effect size  can be considered high and relevant, according to Cohen’s recommendations25. CRT non-responders had a lower rate of LV lead implantation in the lateral vein of the coronary sinus. A non-optimal position is associated with a higher non-response which could overwhelm the role of fibrosis although the former had a limited size effect in our population .


Pulmonary edema is a cardinal feature of heart failure but no quantitative tests are available in clinical practice. The goals of this study were to develop a simple cardiovascular magnetic resonance (CMR) approach for lung water quantification, to correlate CMR derived lung water with intra-cardiac pressures and to determine its prognostic significance.Validation Cohort: LWD was compared to left ventricular end-diastolic pressure or pulmonary capillary wedge pressure in 19 patients with heart failure undergoing cardiac catheterization. Prospective Cohort: LWD was measured in 256 subjects, including 121 with heart failure, 82 at-risk for heart failure and 53 healthy controls. Clinical outcomes were evaluated up to 1 year.Lung water density  was measured using a widely available single-shot fast spin-echo acquisition in two study cohorts. p < 0.05). In the prospective cohort, mean LWD was 16.6 ± 2.1% in controls, 17.9 ± 3.0% in patients at-risk and 19.3 ± 5.4% in patients with heart failure, p < 0.001. In patients with or at-risk for heart failure, LWD >  20.8%  was an independent predictor of death, hospitalization or emergency department visit within 1 year, hazard ratio 2.4 .Within the validation cohort, CMR LWD correlated to invasively measured left-sided filling pressures  contains supplementary material, which is available to authorized users. Pulmonary edema is a central feature of heart failure found in > 50% of patients with acute decompensated  or ambulCardiovascular magnetic resonance (CMR) is an attractive tool for the assessment of pulmonary edema because the image signal intensity is directly proportional to water density. CMR methods for the quantification of lung water have been validated against gravimetric measurements , 12 and The study was approved by the University of Alberta Health Research Ethics Board and written informed consent was given by all study participants. Consecutive patients with a clinical diagnosis of heart failure referred to a tertiary care centre for cardiac catheterization were screened for enrollment. Those aged < 18 years, unable to provide informed consent, or with a contraindication to CMR were excluded. Left ventricular end-diastolic pressure (LVEDP) or pulmonary capillary wedge pressure (PCWP) was measured prior to angiography, with values recorded at end-expiration. Patients underwent CMR within 2 h following the cardiac catheterization once hemostasis had been achieved. B-type natriuretic peptide (BNP) levels were assessed using a Biosite Triage reagent pack  read in an automated Access 2 immunoanalyzer  at Alberta Health Services Laboratory Services- Edmonton, Alberta.A prospective cohort of healthy controls and patients with or at-risk for heart failure were included from the Alberta HEART study . PatientAll subjects were imaged on a 1.5 T scanner . Cardiac structure and function were acquired using balanced steady-state free precession cine sequence with retrospective electrocardiogram (ECG) gating and during 8–12 s breath-holds. Ventricular volumes and mass were measured using commercially available image analysis software, Syngo Argus,  by an experienced CMR interpreter (IP).1 weighting, with a repetition time > 5 s. Each image acquisition was repeated 3–7 times during free breathing for a total scan time of 5 to 7 min.Lung water was measured using a half-Fourier single-shot turbo spin-echo (HASTE) pulse sequence using the body coil for signal excitation and reception. Typical imaging parameters included a matrix size of 128 × 66 with a 360 × 270 mm field of view, 8 mm slice thickness (20 mm gap between slices), 4/8ths partial Fourier, 3.4 ms echo spacing, 780 Hz/pixel bandwidth, 12 ms echo time, a 120°-180° refocusing pulse flip angle and ECG gating with image acquisition during diastasis. Ten to twelve sagittal slices covered the right and left lungs with one image acquired per heartbeat and slice interleaving to minimize TAn abbreviated protocol was used in the prospective cohort. This included identical imaging parameters but the acquisition of only one sagittal slice in the right lung at the largest cross-sectional area and 20 repeats during free-breathing (repetition time > 5 s) for a total scan time of ~ 2 min. Lung water images were acquired approximately 30 min following supine positioning at the onset of the CMR exam in all subjects.The lung water acquisition and processing procedure is outlined in Fig. An additional abbreviated 1D lung water analysis was performed in all subjects as shown in Fig. Lung water density in the validation cohort was derived as the signal average from: (1) the entire lung volume (non-discarded slices), (2) the left or right lung, separately, or 3) the rectangular 1D profile. Figure  the rectp < 0.1) from univariate testing. P values < 0.05 were considered statistically significant. Coefficient of variation and intra-class correlation coefficient between the two interpreters was calculated for reproducibility analysis. Statistical analysis was generated using MATLAB  and SAS software .Continuous variables are presented as mean ± standard deviation and compared using the Student’s t-test and one-way ANOVA. Categorical variables are presented as counts and frequencies and compared using a χ2-test or exact test. Correlations between lung water density, left-sided filling pressure and BNP were assessed using the Spearman’s rank correlation coefficient. In the prospective cohort, patients with “wet lungs” were identified as LWD greater than the mean + 2 standard deviations for healthy controls (LWD >  20.8%). Clinical outcomes  within 1 year from CMR were obtained from in-person follow-up and electronic records. The International Classification of Diseases codes (version 10) recorded in main diagnosis field were used to identify health service utilizations for heart failure or cardiovascular reasons including cerebrovascular bleed/infarction, myocardial ischemic syndrome, arrhythmia and labile blood pressure. Kaplan-Meier curves for time to clinical events within 1 year from CMR were constructed. Proportional hazard regression was used to identify predictors of a composite event  for patients with or at-risk for heart failure including LWD as well as known predictors of outcomes . The mulNineteen patients with heart failure  were recruited into the validation cohort after excluding 4 patients with incomplete hemodynamic data and one with CMR image artifacts. The heart failure etiology included dilated cardiomyopathy in 7, cardiac allograft failure in 4, ischemic cardiomyopathy in 4, valvular heart disease in 3 and pulmonary hypertension in one. Ten of the 19 patients were studied during a hospitalization for acute decompensation while the remaining 9 were tested in an ambulatory setting. Two-hundred and fifty-six subjects , with lung water imaging from the prospective Alberta HEART cohort were included, 121 patients with heart failure, 82 at-risk for heart failure and 53 healthy controls . The correlation between left-sided filling pressure (LVEDP or PCWP) and LWD ranged from R = 0.71 to 0.80, depending on the image analysis region  for LWD yielded Rp < 0.001 for ANOVA  as well as in the subgroup of patients with heart failure, hazard ratio 2.8   in a heart failure cohort undergoing cardiac catheterization, CMR-derived LWD correlated to invasively measured left-sided filling pressures; (2) LWD was shown to be less than 20.8% in a healthy control group, with no dependence on age or gender; and (3) in patients with or at-risk for heart failure, LWD > 20.8% predicted clinical outcomes at 1 year in multivariable analysis, with early separation of the survival curves.While filling pressures were used to confirm an association between LWD and cardiogenic pulmonary edema, a uniform relationship is not expected. Specifically, the accumulation of lung water reflects the integrated effects of capillary wall permeability, hydrostatic and oncotic pressures  as well The need for reproducible and quantitative tests for the evaluation of acute decompensated heart failure, particularly as an entry criteria in therapeutic trials , has recPatients with HFpEF remain a challenging group to manage clinically and drug trials to date have been negative, possibly due to the inclusion of those with non-cardiac causes for exercise intolerance . In factLung water density independently predicted clinical outcomes for patients with or at-risk for heart failure at 1 year in a multivariable model controlling for known predictors of mortality . Interes1) field used for excitation and signal reception. While body coil spatial profiles are considerably more uniform than surface coils, there remains variations in received signal intensities that are independent of water density, particularly at higher static magnetic field strengths. Due to the effects of respiratory phase on lung water signal intensity [There are several approximations in the CMR methodology that could contribute to systematic errors. It was assumed that the liver signal on CMR corresponds to a water density of 70%. Hepatic fatty infiltration or congestion or alternatively iron overload could affect CMR signal intensity and thus lead to an underestimation or overestimation of LWD, respectively . Howeverntensity , 31 we oLung water quantification by CMR is feasible in patients with heart failure. Increased LWD correlates with intra-cardiac filling pressures, is predictive of cardiac events and thus has potential prognostic relevance for patients with heart failure.Additional file 1:Table S1. Clinical Characteristics and Outcomes for Patients with Symptomatic Heart Failure from the Prospective Cohort, Stratified by Lung Water Density. (DOCX 17 kb)


PAH progression rate inCOPD is usually slow (an increase of < 1 mmHg per year). However, the presence ofeven moderate PAH is a strong predictor of mortality.2 During stable periods of the disease, the increase in meanpulmonary artery pressure is usually mild to moderate. However, severe PAH mayoccasionally occur in COPD patients COPD.3Chronic obstructive pulmonary disease (COPD) is a serious public health problem, and isoften related to smoking.4 2D-STE strain can not only quantify theoverall RV function, but it can also identify discrete, localized contractile losses,providing information regarding the pathophysiological mechanisms that lead to rightventricular failure.5 In aheterogeneous group of patients, RV lateral wall longitudinal strain showed a strongcorrelation with RV ejection fraction calculated by cardiac magneticresonance.6 Peak longitudinalstrain is a significant prognostic determinant in PAH patients, with greater valuecompared to other known clinical and echocardiographic predictors ofmortality.7Conventional two-dimensional (2D) echo parameters allow a reasonable assessment of RVFunction. In the 1990s, the use of tissue Doppler (TD) to measure the intramyocardialvelocity gradient allowed measuring the rate of myocardial strain and its percentage(strain rate and strain). About ten years ago, the speckle tracking technique, based onthe tracking of the speckles which two-dimensional echo images, allowed assessingmyocardial strain without limitation by the DT insonation angle.8 Although 2D-STE iswidely used in various clinical conditions, the guidelines on echocardiographicevaluation of RV function strongly recommends including other measures intoechocardiographic examination and report.9 In addition to the fact that there are no reference values, RV ST2Dcan be influenced by image quality, reverberation and other artifacts.10Several studies have used 2D-STE in chronic PAH patients. Several authors advocate thismethod for serial evaluation of PAH patients since RV free-wall strain has proved anindependent predictor of clinical deterioration and mortality after medical therapy isinitiated.11 In this issue, Kanar et al. evaluated the RV function using2D-STE with 46 COPD and 32 control patients.12 The authors compared the 2D-STE values for the two groups andfor patients before and after a pulmonary rehabilitation program. The conventionalparameters for 2D-echo and 2D-STE showed a similar correlation between COPD and controlpatients, but RV longitudinal strain showed greater sensitivity in examining therelationship between RV function and exercise tolerance. The main limitations arepointed out in the article. There is no information on whether 2D-STE measurements weremade in apnea or at the time of pre and post PR breathing. Since RV is sensitive topreload variations, the values could be influenced by respiratory variation. In anycase, the usefulness of ST2D to evaluate RV in COPD was well demonstrated. Althoughthere is controversy on the effectiveness of pulmonary rehabilitation programs inPAH,13 the authorsdemonstrated in an original way, i.e., through ST2D, that RV improves after PR, thuscreating new perspectives for the use of PR in COPD patients.The literature clearly shows the benefit of pulmonary rehabilitation (PR) programs. Aprospective randomized study showed the effectiveness of respiratory training as anadditional treatment of severe chronic PAH.


P < 0.001), but no significant difference was found among the 3 segments of LS in the CTEPH group (P = 0.263). When we used the cutoff value recommended by the American Society of Echocardiography guidelines to identify abnormal RV function, 30 CTEPH patients (50%) by tricuspid annular plane systolic excursion (TAPSE), 42 patients (70%) by fractional area change (FAC), 20 patients (33.33%) by RV index of myocardial performance (RVIMP), and 46 patients (77%) patients by GLS were determined to have abnormal RV function, respectively. Among multiple RV function indicators, TAPSE, FAC, GLS, basal-DL, and N-terminal pronatriuretic B-type natriuretic peptide showed significant differences between CTEPH patients with mild (WHO II) and severe symptoms (WHO III/IV) , while RVIMP and basal-DT showed no significant difference . Pearson correlation analysis showed that GLS has no correlation with sPAP as evaluated by echocardiography in CTEPH patients , and a weak to moderate correlation with RA area , the RV diameter , and the RVFW thickness . On receiver operating characteristic analysis, GLS has the largest area under the curve to identify RHF when the cutoff value was − 13.45%, the sensitivity was 78.2%, and the specificity was 84.6%, separately. Our study demonstrated that the depression of regional LS of RVFW is more pronounced in the basal and middle segments in CTEPH patients. Also, the longitudinal movement is much more important than the transverse movement when evaluating RV systolic function. As compared with conventional parameters, RVFW GLS showed more sensitivity to identify abnormal RV function and had the largest AUC for identifying RHF. Additionally, GLS showed no correlation with sPAP and a weak correlation with right heart morphological parameters in our CTEPH cohort.Right ventricular (RV) function is a significantly important factor in the determination of the prognosis of chronic thromboembolic pulmonary hypertension (CTEPH) patients. Speckle-tracking echocardiography (STE) is an angle-independent new technique for quantifying myocardial deformation that is capable of providing data on multiple parameters including longitudinal and transverse information of the myocardium. In the present study, we aimed to study the advantages of STE-derived parameters in identifying RV dysfunction in CTEPH patients. Sixty CTEPH patients  and 30 normal controls  were enrolled in this study. RV free wall (RVFW) systolic peak longitudinal strain (LS) including the basal, mid-, and apical-segments and the basal longitudinal and transverse displacement  were measured by STE. Global LS (GLS) of the RV was calculated by averaging the LS value of the 3 segments of RVFW. Clinical data of CTEPH patients were collected. CTEPH patients were divided into 2 subgroups according to the World Health Organization function classification. Clinical right heart failure (RHF) was defined as the presence of symptoms of heart failure and signs of systemic circulation congestion during hospitalization. The apical segment LS of the RVFW was lower than that in the basal and mid-segments in the control group ( Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease characterized by pulmonary artery thromboembolism and vessel obstructive remodeling, with progressive increased pulmonary vascular resistance , 2. In sWe studied consecutive CTEPH patients at our hospital between November 2015 and December 2017 who had been diagnosed according to the diagnostic algorithms for CTEPH [Two-dimensional (2D) and Doppler echocardiography were performed using the Vivid E9 ultrasound system  by a senior doctor. Cardiac quantification was in accordance with the recommendations of the ASE guidelines .2D STE data for RV were obtained via the RV-focused apical 4-chamber view. Four cardiac cycles of RV imaging with a mean frame rate of 49 frames/s ± 8 frames/s were recorded for analysis. RVFW longitudinal strain (LS) was measured offline using the EchoPac software BT113 . The endocardial border of the RV was traced manually, and a region of interest (ROI) including the RVFW and septum was automatically generated, with the ROI width adjusted to a minimum. The RV myocardium was divided into 6 segments . The peak systolic LS was a negative percentage value, indicating tissue contraction/shortening . We recorded the LS of the basal, mid-, and apical RVFW and calculated the RV GLS by averaging the value of the 3 segments  and transverse displacement (DT) were also generated. We recorded the basal DL and DT of the RVFW for analysis. The mid- and apical-DT/DL values were excluded because of the small value and great dispersion.The reproducibility of RV GLS, TAPSE, FAC, and RVIMP was assessed in a subgroup of 30 randomly chosen subjects. The correlation coefficients of interobserver variability for these were 0.683, 0.790, 0.533, and 0.583, respectively.t test for normal distribution data and the Mann–Whitney U test for abnormal distribution data. Categorical variables between the 2 groups were compared using Pearson’s Chi-Squared test. One-way analysis of variance and Student–Newman–Keuls q (SNK-q) test were used to compare the segmental strain of the RVFW. The Pearson correlation coefficients of sPAP, RAA, RVD, and RVFW thickness with GLS were tested in all subjects and only in the CTEPH group separately. Receiver operator characteristic (ROC) analysis was performed to compare the area under the curve (AUC) of RV function parameters to identify RHF in the CTEPH group. A 2-tailed P value of < 0.05 was considered to be statistically significant.Statistical analysis was performed with SPSS 19.0 . Continuous variables were presented as means ± standard deviations (SDs) or medians with interquartile ranges. Categorical variables were presented as numbers and percentages. Continuous variables between the 2 groups were compared by independent-sample In all, 60 CTEPH patients (92.3%) and all normal subjects 100%) successfully underwent STE. Only 5 CTEPH patients were excluded from the analysis due to poor echogenicity. The baseline characteristics of the included CTEPH patients are summarized in Table 00% succeP = 0.000) and the CTEPH group . This result indicated that longitudinal movement is predominant in RVFW contraction.As compared with the normal controls, CTEPH patients showed significant enlarged right heart dimension, increased RVFW thickness, dilated pulmonary arteries, and smaller LV size, with decreased RV function indicated by both conventional and STE-derived variables Table . UnexpecInterestingly, when we used the cutoff value recommended by the ASE guidelines to identify abnormal RV function, we found 30 CTEPH patients (50%) by TAPSE (< 17 mm), 42 patients (70%) by FAC (< 35%), 20 patients (33.33%) by RVIMP (> 0.54), and 46 patients (77%) by GLS (< 20%) to have abnormal RV function. This means that RV GLS identifies a higher number of patients with impaired RV systolic function as compared with conventional measurements.When comparing echocardiographic and clinical variables in mild and severe symptom CTEPH patients, we found that WHO III/IV patients had more enlarged right hearts, but that there was no significant difference in RVFW thickness, PA diameter, or pulmonary artery pressure between the subgroups. Among multiple RV function indicators, TAPSE, FAC, GLS, basal-DL, and NT-proBNP showed significant differences, while RVIMP and basal-DT did not Table . These rP < 0.0001); RAA ; RVD ; and RVFW thickness  when including all subjects (both control and CTEPH groups). However, if only CTEPH patients were included, then GLS showed no correlation with sPAP  and a weak to moderate correlation with RAA ; RVD ; and RVFW thickness .According to Pearson correlation analysis Fig. , we founP = 0.263).The results of ROC analysis are showed in Table STE imaging is a new method that provides speckle tracking of natural acoustic markers in myocardium; as such, it is angle-independent and not influenced by heart translational motion, which is a potential concern with TAPSE by M-mode measures. STE-derived parameters include both LS/displacement and DT. GLS of RVFW has shown a good correlation with RVEF by CMR  and has The main findings of our study are as follows. First, STE-derived parameters can evaluate the RVFW systolic contraction in a more comprehensive way. According to the analysis of the regional and global STE-derived parameters, we found that the depression of regional LS of RVFW is more pronounced in the basal and middle segments in CTEPH patients. Also, the longitudinal movement is much more important than the transverse movement when evaluating RV systolic function.Second, although both conventional and STE-derived parameters can detect RV dysfunction in CTEPH patients, the sensitivity, repeatability, and value of prediction of RHF are different. GLS showed more sensitivity to identifying abnormal RV function with a cutoff value of − 20% as compared with conventional parameters and had the largest AUC for identifying RHF. The inter-observer variability of GLS is acceptable (better than that of FAC).Third, GLS showed no correlation with sPAP and a weak correlation with right heart morphological parameters in our CTEPH cohort. These findings remind us that, in CTEPH patients with RV dysfunction, the level of pulmonary artery pressure can not completely and truly reflect the degree of impaired RV function.CTEPH patients had significant morphological and functional changes in our study, characterized by right heart enlargement and RV dysfunction. Because of pulmonary artery thromboembolism and vessel obstructive remodeling, pulmonary vascular resistance and RV afterload increased progressively in CTEPH patients. The ventricles adapt to the increased afterload by increasing wall thickness and myocardial contractility. Due to the smaller thickness and high compliance of the RV wall, the compensatory ability is often insufficient and maladaptive remodeling is more likely to occur in the right heart . Our stuIn our study, we found that the depression of RVFW strain in CTEPH patients was more pronounced in the basal and middle segments. Sunbul et al. reported similar results when comparing RV longitudinal deformation parameters and exercise capacity in CTEPH patients . These fWe found that TAPSE, FAC, RVIMP, and STE-derived parameters all are capable of indicating RV dysfunction in CTEPH patients. This was consistent with findings reported in other studies that compared echocardiographic parameters to CMR parameters –18. HoweTAPSE is easy to measure and not heavily dependent on image quality, so the repeatability was obviously better than other indexes. But it only represents the annular longitudinal movement of RVFW and slightly less sensitive to identify impaired RV function than FAC and GLS. In our study, RVIMP has the lowest sensitivity and smallest AUC to identify abnormal RV function, especially in severe patients with RHF. This may be due to the elevated RA pressure that shorten the isovulumetric relaxation period.Based on these findings, we believed that STE-derived longitudinal global and regional parameters had advantages in identifying RV dysfunction in clinical practice.r=-0.23, P = 0.08). Li et al. [r = 0.597, P < 0.001). The conditions of the CTEPH patients included in our study were severe, including 53% patients with heart function of WHO III/IV, and this may explain this result. As we know, pulmonary artery pressure is determined by the cardiac output and the pulmonary vascular resistance. When RV function decreases obviously, the output of the right heart drops, and the measured pulmonary arterial pressure will not increase even if the pulmonary vascular resistance increases with the progression of the disease. It reminds us that, in clinical practice, it is the morphological and functional parameters but not the level of pulmonary artery pressure that reflects the degree of impaired RV function.We found GLS does have correlations with sPAP by echocardiography and right heart remodeling parameters if we included all control and CTEPH patients, and RV basal diameter showed the largest correlation coefficient. However, unexpectedly, when we only included CTEPH patients for analysis, there was no correlation between GLS and sPAP. This is somewhat different from the reports of other studies. Wright et al.  studied i et al.  studied There are few limitations of our study. First, it is a single-center study and its sample size is relatively small because CTEPH is not a common disease. Second, we did not include pulmonary thromboembolism patients whose pulmonary artery pressure was slightly elevated (35–50 mmHg by echocardiography). Whether STE-derived GLS can detect subclinical abnormal RV function or not is unknown in this cohort; however, this question is interesting and we hope to study it in the near future. Third, not all patients underwent RHC during the time of this study; some of the data of RHC were collected from previous records. Considering the long time interval between RHC and echocardiography, we used the sPAP evaluated by Doppler echocardiography but not mPAP obtained by RHC for correlation analysis, and this is not the ideal choice. Finally, RV strain analysis was unable to evaluate the outlet portion function, though this area is considered as a lesser contributor to the overall RV function. Maybe 3-dimensional RVEF can compensate for this.Our study demonstrated that STE-derived parameters can evaluate the RVFW systolic contraction in a more comprehensive way. The depression of regional LS of RVFW is more pronounced in the basal and middle segments in CTEPH patients. Also, the longitudinal movement is much more important than the transverse movement when evaluating RV systolic function. As compared with conventional parameters, RVFW GLS showed more sensitivity to identifying abnormal RV function with a cutoff value of − 20% and had the largest AUC for identifying RHF. Additionally, GLS showed no correlation with sPAP and a weak correlation with right heart morphological parameters in our CTEPH cohort.


Right ventricular (RV) dysfunction predicts adverse outcome in peripartum cardiomyopathy (PPCM). We recently demonstrated beneficial effects associated with the prolactin release inhibitor bromocriptine at different doses when added to standard heart failure therapy in PPCM. Here, we evaluated for the first time the therapeutic potential of bromocriptine particularly in PPCM patients with RV involvement.n = 10) compared with long-term bromocriptine treatment  in addition to guideline-based heart failure therapy in patients with an initial RVEF < 45% on the following outcomes: (1) change from baseline (Δ delta) in RVEF, (2) change from baseline in left ventricular EF (LVEF), and (3) rate of patients with full LV recovery (LVEF ≥ 50%) and (4) rate of patients with full RV recovery (RVEF ≥ 55%) at 6-month follow-up as assessed by cardiac magnetic resonance imaging.In this study, 40 patients with PPCM were included, of whom 24 patients had reduced RV ejection fraction (RVEF < 45%). We examined the effect of short-term . RVEF increased from 38 ± 7 to 53 ± 11% with a delta-RVEF of + 15 ± 12% in the 1W group, and from 35 ± 9 to 58 ± 7% with a Δ RVEF of + 23 ± 10% in the 8W group (Δ RVEF 1W vs 8W: p = 0.118). LVEF increased from 25 ± 8 to 46 ± 12% with a Δ LVEF of + 21 ± 11% in the 1W group, and from 22 ± 6 to 49 ± 10% with a Δ LVEF of + 27 ± 9% in the 8W group (Δ LVEF 1W vs 8W: p = 0.211). Full LV recovery was present in 50% of the 1W group and in 64% of the 8W group (p = 0.678). Full RV recovery was observed in 40% of the 1W group and in 79% of the 8W group (p = 0.092).Reduced RVEF at initial presentation was associated with a lower rate of full cardiac recovery at 6-month follow-up  contains supplementary material, which is available to authorized users. Peripartum cardiomyopathy (PPCM) is a major cause of pregnancy-related heart failure with a considerable rate of morbidity and mortality with a considerable risk of life-threatening arrhythmia –3. MyocaWe recently demonstrated in a multicenter, randomized controlled trial that treatment with the prolactin release inhibitor bromocriptine in addition to guideline-recommended heart failure therapy is safe and improves LV function and clinical outcome in PPCM . Our resIn the present substudy, we examined the effects of prolonged bromocriptine treatment compared to short-term treatment in addition to guideline-recommended heart failure therapy  on RV anThis is the first study to evaluate the impact of a therapeutic strategy on RV function in PPCM. The results may help to improve treatment options for PPCM patients with biventricular dysfunction and more severe clinical course.This is a substudy of a recently reported prospective, randomized, controlled trial, conducted in 12 participating centers in Germany . The triFrom June 2010 until September 2015, 140 patients at 12 centers were screened for eligibility and 68 patients were enrolled in the trial. In brief, eligibility requirements at screening included an age of at least 18 years, new onset PPCM within a time-window of 5-month postpartum according to the definition by the Study Group on PPCM from the Heart Failure Association of the European Society of Cardiology (ESC) . As for the left ventricular function, 50% of the patients with RV dysfunction in the 1W group showed full functional LV recovery (LVEF ≥ 50%), 30% partial recovery (LVEF between 35% and < 49%) and 20% no recovery (LVEF < 35%). In the 8W arm, the respective rates were 64% for full functional recovery, 21% for partial recovery, and 15% for no recovery , Fig. After 6-month follow-up, 40% (4 of 10) of the patients with RV dysfunction in the 1W group showed full functional RV recovery RVEF ≥ 55%), 40% (4 of 10) partial recovery (RVEF from 45 to < 54%) and 20% (2 of 10) no recovery (RVEF < 45%). In the 8W arm, the respective rates were 79% (11 of 14) for full functional recovery, 14% (2 of 14) for partial recovery, and 7% (1 of 14) for no recovery  and the 8W group  . Interestingly, this correlation was no longer present at follow-up in neither one of the treatment groups . Moreover, we did not observe a shift of the slopes towards one particular ventricle at follow-up indicating that the treatment did not affect one ventricle more than the other .At baseline, a significant correlation between RVEF and LVEF was found in both the 1W group  bromocriptine treatment in addition to guideline-based heart failure therapy in PPCM patients with right ventricular involvement is associated with high rate of RV and LV improvement; (2) bromocriptine treatment in this patient population reaches high probability of full RV and LV recovery; and (3) no significant differences were observed between the short-term and long-term bromocriptine treatment regime with regard to RV and LV improvement or full recovery. However, we observed a trend for higher degree of RV and LV improvement as well as higher likelihood of cardiac recovery after 6 months in the long-term bromocriptine treatment group.Findings from experimental, genetic, clinical and imaging studies over the past two decades have substantially broadened our understanding of both the pathomechanisms as well as the clinical picture of PPCM , 13. In We previously found in a prospective registry of a German PPCM cohort using CMR that 35% of the patients had reduced RV systolic function at initial presentation . This esIt remains to be elucidated whether RV involvement in PPCM constitutes a distinct biventricular subtype with particular pathophysiologic mechanisms affecting the right ventricle or whether RV dysfunction results from impaired LV function. In particular, secondary pulmonary hypertension with subsequent increased RV afterload is a potential mechanism . In manyNotably, in the IPAC cohort a higher percentage of African American patients had reduced RV function compared with Non-African American patients at baseline . MoreoveIn conclusion, the findings of this study reassure that inhibition of prolactin release with bromocriptine is an effective treatment option also for PPCM patients with RV involvement. The study detected a trend for a benefit of prolonged bromocriptine therapy over short-term therapy in increasing RVEF or LVEF in this patient population. This observed trend for higher likelihood of full cardiac recovery encourages to further test the added value of a more intensive bromocriptine treatment to standard heart failure therapy in a larger outcome trial primarily including PPCM patients with biventricular impairment at initial presentation.Below is the link to the electronic supplementary material.Supplementary material 1 (DOC 126 KB)Supplementary material 2 (JPG 137 KB)


Background and objectives: Cardiac magnetic resonance (CMR) imaging is the gold standard method for the detection of ventricular volumes and myocardial edema/scar. Transthoracic echocardiography (TTE) imaging is primarily used in the evaluation of cardiac functions and chamber dimensions. This study aims to investigate whether the chamber diameter measurements are concordant with each other in the same patient group who underwent TTE and CMR. Materials and Methods: The study included 41 patients who underwent TTE and CMR imaging. Ventricular and atrial diameter measurements from TTE-derived standard parasternal long axis and apical four-chamber views and CMR-derived three- and four-chamber views were recorded. The concordance between the two methods was compared using intra-class correlation coefficients (ICC) and Bland–Altman plots. Results: Of the patients, 25 (61%) were male and the mean age was 48.12 ± 16.79. The mean ICC for LVDD between CMR observers was 0.957 (95% CI: 0.918–0.978), while the mean ICC between CMR and TTE measurements were 0.849 (95% CI: 0.709–0.922) and 0.836 (95% CI: 0.684–0.915), respectively. The mean ICC for the right ventricle between CMR observers was 0.985 (95% CI: 0.971–0.992), while the mean ICC between CMR and TTE measurements were 0.869 (95% CI: 0.755–0.930) and 0.892 (95% CI: 0.799–0.942), respectively. Passing–Bablok Regression and Bland–Altman plots indicated high concordance between the two methods. Conclusions: TTE and CMR indicated high concordance in chamber diameter measurements for which the CMR should be considered in patients for whom optimal evaluation with TTE could not be performed due to their limitations. Imaging methods are the most important tools that guide the clinician in the diagnosis and treatment of heart disease . TransthCMR is a non-invasive imaging method which is widely used in the evaluation of cardiac functions because of its excellent temporal and spatial resolution, lack of ionizing radiation, less operator dependency and lack of limitations such as acoustic window problem ,6,7. CMRThe aim of this study is to investigate the imaging data of patients who underwent TTE and CMR with different indications due to known or suspected heart disease and to determine whether the diameter measurement values of all cardiac chambers are in concordance with each other according to both imaging methods.The study was carried out on the basis of retrospective examination of the patients who underwent TTE and CMR between 1 January 2018 and 30 September 2018. A total of 41 patients, four patients with investigation of fibrosis in heart failure, nine patients with evaluation of congenital heart disease and 28 patients evaluated with suspected myocarditis, were included in the study. The echocardiographic data of the cardiac chamber measurements of all patients were obtained from echocardiography reports which were performed by an experienced cardiologist (C) and registered to the hospital information system. Measurements of all patients were performed by the same cardiologist. An experienced radiologist  examined the whole study group. A second radiologist  also examined the same study group. CMR data of cardiac chamber measurements of patients were obtained from the independent examination results performed manually via the Picture Archiving and Communication System (PACS). The mean time between the application of the two imaging modalities was 13.8 ± 6.2 days and the patients with more than 1 month elapse between these two imaging methods were not included in the study. The TTE evaluation in all patients was operated with Vivid 7, GE Vingmed Ultrasound, Horten, Norway (application software version: 6.1.3) using a 2.5–3.5 MHz probe in the left lateral position, parasternal long axes and apical four-chamber images were obtained. To improve image quality, depth, focus position, frame rate and sector size was adjusted. The measurements of the left ventricle were carefully measured at the parasternal long-axis window, perpendicular to the long axis of the left ventricle and at the level of the mitral valve leaflet tips. The end-diastolic and end-systolic frames were identified based on the maximal and minimal left ventricle cavity size. Left atrial anteroposterior diameter measurements were made from the parasternal long axis window, perpendicular to the distance between the aortic sinus level and the left atrium posterior wall. The chamber measurements of the right ventricle and right atrium were performed from the apical four-chamber view window. The basal diameter of the right ventricle was measured at one third of the basal of the right ventricle. The diameter of the atrium was measured at the distance between the inter-atrial septum and the lateral wall. The diameter of cardiac cavities was measured based on the criteria suggested by the American Society of Cardiovascular Imaging and the European Echocardiography Association  Figure A–D. CMR www.turcosa.com.tr) statistical software.The normal distribution hypothesis was tested with the Shapiro–Wilk test. In the evaluation of data, frequency, percentage and mean were used as descriptive statistical methods. In order to evaluate the correlation between TTE and CMR measurements, Pearson’s correlation coefficient and intra-class correlation (ICC) coefficient were calculated. Passing–Bablok regression analysis was performed to evaluate the concordance between TTE and CMR measurements and Bland–Altman plots with 95% limits of agreement (mean difference ± 1.96 standard deviation of the difference) were created for pairs of measurements to evaluate any deviations between observers . The sigp < 0.001 and p = 0.046). There was a significant difference between R1–C for left atrial anteroposterior (LAAP) diameter measurement (p = 0.04). There was a significant difference between R1–C and R2–C for right ventricle (RV) and right atrium (RA) measurements (p < 0.001). Among LVED, LVES and LAAP diameter, RV and RA diameters measured by R1–R2, R1–C, R2–C, when the intraclass correlation coefficients were examined according to the diameter measurements of cardiac chambers, it was seen that there was a good level of agreement between all three observers  and the mean age of the patients was 48.12 ± 16.79. bservers . When Pebservers . Scatterbservers . Moreovebservers , it was The most important findings obtained from this study can be listed as follows: (1) The data for the LVED, LVES and LAAP diameter measurements from the parasternal long axis view obtained with TTE were in concordance with the data from the three-chamber view obtained with CMR, (2) the data for the RV and RA diameter measurement values from the apical four-chamber view obtained with TTE were numerically lower than the data from the four-chamber view obtained with CMR, while the concordance still exists.In clinical practice, the most frequently evaluated parameters with TTE are ventricular systolic and diastolic functions, valve structures and functions, ventricular mass and diameter of the heart chambers . AccuratThe findings of this study should be interpreted with some limitations. In addition to being a retrospective and cross-sectional study, due to the lack of data evaluation according to age and gender, the findings obtained from the study will not reflect the general population. The use of data from a single center and relatively few patients is another limitation. In addition, numerical differences between TTE and CMR, especially in the right heart chambers, may be remarkable. The absence of comparison for these differences can be considered as a limitation. However, it should not be overlooked that the aim of the study was to determine whether there is a general concordance rather than whether there are any numerical differences between the two methods. Lastly, another limitation of the study was that data from a single cardiologist of TTE measurements were used, although data from two different radiologists from CMR measurements were used.As a result, this study revealed that left heart chambers show a high level of concordance between the parasternal long axis in TTE and the three-chamber view in CMR. Of note, concordance between TTE and CMR as demonstrated with statistical analysis also persists in the evaluation of RV chambers. These findings substantiate the clinical efficacy of CMR in clinical decision-making for the diagnosis, treatment as well as follow-up of certain cardiac diseases, and hence; might potentially suggest this modality as an important substitute for TTE particularly in the setting of certain challenges including poor echocardiographic image quality.


Although visualization of heart sounds, known as phonocardiography, provides valuable information on cardiovascular hemodynamics, its use has not been widely encouraged due to the scarcity of information on its interpretation. In the present study, using the intraoperative phonocardiogram recorded by an esophageal stethoscope, we quantitatively evaluated the time and frequency domains of modulation of the heart sounds components and their association with left ventricular contractility and systemic vascular resistance under the effects of various cardiovascular drugs. We analyzed 29 pairs of intraoperative digitalized phonocardiographic signals and their corresponding hemodynamic data before and after cardiovascular drug administration  in 17 patients who underwent liver transplantation. The S1 and S2 components of the heart sounds  were identified and their modulation in time and frequency domains was analyzed. As an index of cardiovascular function, systolic tissue Doppler wave velocity (TDI S’), maximal dP/dt from the arterial waveform, and systemic vascular resistance were simultaneously evaluated. Ephedrine/esmolol and phenylephrine/nicardipine primarily affected the S1 and S2 components of the heart sounds, respectively. This result implies that the intraoperative phonocardiogram may have the potential to be useful in detecting the changes in contractility and afterload that commonly occur in patients receiving anesthesia. In an era of constant need for noninvasive hemodynamic assessment, phonocardiography has the potential for use as a novel and informative tool for monitoring of hemodynamic function. Since the invention of the stethoscope by Rene Laennec in 1816, auscultation of heart sounds has been widely used in the diagnosis of various diseases, particularly in cardiology. In the field of clinical anesthesia, the esophageal stethoscope has been used for more than 60 years to listen to heart sounds continuously during surgery [With the recent development of signal processing technology, digitalized analysis of heart sounds became available. A graphic recording of heart sounds, phonocardiography, enables more objective and quantitative analysis and interpretation. Phonocardiography provides valuable information about the function and integrity of the heart valves and about the hemodynamics of the heart, and has great potential as an aid to the diagnosis of various heart diseases ,3,4. HeaThis observational study was approved by the Institutional Review Board of Asan Medical Center (2014-0357). After obtaining informed consent from each patient, we prospectively recruited patients who underwent living-donor liver transplantation consecutively with concomitant monitoring of intraoperative transesophageal echocardiography as a routine monitoring, and analyzed the recorded signal data in a retrospective fashion. In the current study, we included patients who were given bolus doses of cardiovascular drugs such as ephedrine, esmolol, phenylephrine, or nicardipine, as a routine treatment of hemodynamic instability during liver transplantation from our database. Patients with arrhythmia, valvular heart disease, heart failure with an ejection fraction <40%, or pulmonary hypertension were excluded.All patients received standardized anesthetic care according to the protocols of our institution, as previously described ,9,10,11.The patient’s hemodynamic state was assessed by an attending anesthesiologist, who was unaware of this study, whenever hemodynamic instability was observed. The decision to administer a bolus dose of cardiovascular drug was taken by the attending anesthesiologist based on the patient’s hemodynamic state. If the patients needed fluid replacement or continuous drug infusion, the attending anesthesiologist administered treatment as appropriate according to our institutional protocol. A skillful independent anesthesiologist assessed ventricular contractility before and after administration of the cardiovascular drugs. To assess left ventricular contractility, systolic tissue Doppler wave velocity (S’) of the lateral mitral annulus was measured using transesophageal echocardiography . The maxFor the offline analysis, a pair of heart sound 20-second interval windows synchronized with vital signs were collected at two minutes before and after drug administration. For each obtained 20-second window of heart sound signal, the average amplitudes of S1 and S2 heart sound were calculated by using the Hilbert transformation , which iPower spectrum was also generated using fast Fourier transformation with a Hamming window. Signal processing was conducted using the CALC package of Advanced CODAS software , Matlab , Python packages, and DADiSP  ,17.r2). The p-values < 0.05 were considered significant. All statistical data analyses were performed using SPSS version 22  and R software version 3.3.2 (http://www.r-project.org).Values are expressed as numbers (percentages), mean ± standard deviation, or median (interquartile range) according to the normality of the data. The paired t test or the signed-rank test was used for comparison of the heart sound signal and hemodynamic variables before and after drug administration. The relationship between the heart sounds and the hemodynamic variables were evaluated using Pearson’s correlation coefficient , esmolol (n = 11), phenylephrine (n = 7), and nicardipine (n = 2). Duplicated patients were included only when a one hour or longer wash out period between drug administrations was guaranteed.We identified twenty-nine fully-recorded episodes of cardiovascular drug administration from the 17 selected patients. The cardiovascular drugs used were ephedrine  and dP/dt . Percentr2 = 0.285, p = 0.013, In contrast, phenylephrine and nicardipine administration mainly affected the amplitude of the S2 component . PercentWe had two cases of nicardipine administration, but concomitant recording of the echocardiogram was unavailable. The effects of nicardipine administration on the S2 heart sound and the hemodynamics appear to be opposite to those of phenylephrine, although the number of cases was not enough for statistical analysis. Both cases of nicardipine administration showed a decrease in S2 heart sound amplitude (−14.2% with respect to baseline) along with a fall in systolic blood pressure (−27.4% with respect to baseline) and systemic vascular resistance (−43.5% with respect to baseline).p = 0.013) and esmolol , systolic arterial pressure waveforms (dP/dtmax), and Swan–Ganz monitors (SVR) as standard references. Our results suggest that digitalized heart sound analysis may have the potential to discriminate between different physiological mechanisms causing hemodynamic malfunction, for example, in the differential diagnosis of hypotension due to reduced cardiac contractility or reduced SVR.p = 0.012), while esmolol attenuated the S1 amplitude to −15.3% from the baseline (p < 0.001). These changes are consistently accompanied with TDI S’ and femoral dP/dtmax changes, and were linearly correlated with percentage changes of TDI S’  and dP/dtmax . This effect can be explained by the fact that esmolol is a β1-selective adrenoceptor antagonist and, therefore, by blocking cardiac β-receptors, would be expected to have a negative inotropic effect, thus reducing the force of cardiac contraction. Ephedrine is an adrenoceptor agonist that acts on both α and β adrenergic receptors at the post-ganglionic neuron/effector junction, and also facilitates the release of norepinephrine (NE) from the synaptic vesicles of this neuron. Therefore, both its direct action on β1 receptors in the sino-atrial node (resulting in positive chronotropic and inotropic effects), and its indirect sympathomimetic effect via the release of NE would explain this augmentation of the amplitude of S1. Its α-agonist effects would be expected to cause vasoconstriction with an effect on the S2 component similar to that of phenylephrine .Our results suggest that cardiac contractility changes during the use of ephedrine or esmolol mainly affect the S1 heart sound, but not S2. Although we do not have the exact explanation for these findings, we can review and speculate on the underlying physiology. During the cardiac cycle, the first sound (S1) is mainly generated by the closing of the atrioventricular valves [In this study, we used femoral dP/dtmax and TDI S’ as representative measurements of cardiac contractility. Our current data showed that the changes of dP/dt and the changes of TDI S’ also correlated. Although left ventricular (LV) dP/dtmax is used as a variable for assessment of LV contractile function, it is not feasible in the usual clinical setting. The dP/dt is not a gold standard method for measuring the LV contractility, but it is also true that dP/dt is considered to be one of the most accurate methods , especiap = 0.016), along with systolic blood pressure (p = 0.014) and systemic vascular resistance (p = 0.007). Percentage changes of amplitude of the S2 heart sound were linearly correlated with percentage changes in systemic vascular resistance (p = 0.013). Interestingly, the amplitude of the S1 heart sound was not affected by administration of phenylephrine (p = 0.722). We had two cases of nicardipine administration; however, concomitant recording of the echocardiogram was unavailable and the number of cases was not sufficient for statistical analysis. The effects of nicardipine administration on the S2 heart sound and hemodynamics appear to be opposite to those of phenylephrine administration. We regret that we were not able to enroll more cases of nicardipine usage. However, our study protocol was principally based on routine patient care and most cases showed low SVR during liver transplant surgery. It is unethical to use nicardipine if it is not indicated clinically. Although we refrained from making any inferences from this deficient data, certain predictions as to the likely result can be made from a knowledge of the mechanism of action of nicardipine. It is a dihydropyridine calcium channel blocker (of the type that have a specificity for L-type Ca++ channels). Its effects include vasodilatation due to inhibition of the contraction of vascular smooth muscle, which might result in a reduction of amplitude of the S2 component as was observed in our two cases, and a small (less predictable) positive inotropic effect due to increased sympathetic tone as a baroreceptor reflex to the vasodilatory drop in blood pressure. The predicted effect of this on the heart sounds would be a modest increase in the amplitude of S1.In our study, changes in SVR seemed to be closely associated with the S2 heart sound, but not with S1. Physiologically, the second sound (S2) represents the end of systole and the beginning of diastole, and is heard at the time of closing of the aortic and pulmonary valves. S2 is probably the result of oscillations in the cardiovascular system caused by deceleration and reversal of flow into the pulmonary artery and the aorta. Therefore, it is plausible that changes in afterload would affect the amplitude of S2 rather than S1. In our study, phenylephrine and nicardipine administration significantly affected the amplitude of S2, but not that of S1. Phenylephrine significantly augmented the amplitude of the S2 heart sound (Estimation of and maintenance of an adequate level of SVR is a key requirement for hemodynamic management of surgical patients. Low SVR is known to be a frequent cause of low BP during surgery . The phaPhonocardiography has possibilities for detecting hemodynamic and pulmonary deterioration during the anesthesia. Cardiovascular depression from deep anesthesia might be found by phonocardiography, as the phonocardiographic sound may be muffled because of decreased contractility. The lung sound, which is also detected by esophageal stethoscope along with the heart sound, could be a valuable monitoring tool for the respiratory system during anesthesia . Thus, mThis report is the first trial to investigate and interpret the effects of various cardiovascular drugs on intraoperative heart sounds and their comparison with standard reference data. Therefore, a careful approach is required in interpreting our data, and the limitations of this novel analysis must be taken into consideration. Firstly, the amplitude the of S1 and S2 components is mainly dependent on the depth of the esophageal stethoscope, for the obvious reason that this parameter will be determined by the stethoscope’s distance from the relevant cardiac chambers/valves, where the sounds originate. For example, the amplitude is maximized when the probe of the esophageal stethoscope is located at 28–30 cm from the incisor for an average adult. However, there are reciprocal relationships between S1 and S2 amplitudes and the depth of the esophageal stethoscope. Although we tried to fix the depth of the esophageal stethoscope to the best of our ability in this study, the absolute value of S1 and S2 amplitude might have been influenced by this factor. Therefore, relative amplitude appears to be more important and easier to interpret than absolute amplitude. Secondly, we did not accurately titrate the dose of drugs based on the clinical response, and did not evenly distribute patients to each group. Furthermore, data for nicardipine was available for only two cases, and this was without echocardiographic measurement. This bias was inevitable and mainly attributed to the fact that the study protocol was based on routine clinical practice. Thirdly, although we used Hilbert transformation to detect peak points of S1 and S2 and calculated their amplitudes, this was not validated for phonocardiographic signal analysis. Although we used band-pass filters, which can significantly reduce noise, such processing can also induce signal distortion. In addition, instead of amplitude after Hilbert transformation, other sound parameters such as loudness or pitch could have been selected for comparison. Therefore, the different effects between signal filters/processing should be cautiously evaluated in any further studies. Lastly, the patient population of the present study was limited to cirrhotic patients undergoing liver transplantation. Patients with end-stage liver disease usually show altered hemodynamic characteristics such as low SVR and underlying cirrhotic cardiomyopathy ,26. MoreIn conclusion, the S1 heart sound was mainly modulated by ephedrine/esmolol, and the S2 sound was mainly modified by phenylephrine/nicardipine, but not vice versa. These results suggest that intraoperative phonocardiography may have the potential to aid in the assessment of changes in contractility and afterload, respectively, in patients undergoing anesthesia. In the current era of constant need for non-invasive hemodynamic assessment, phonocardiography might prove to be a promising tool for novel and informative monitoring of hemodynamic status during major surgery.