S′) < 10 cm/s, 1 point; right ventricular fractional area change (RVFAC) < 35%, 1 point; and right ventricular myocardial performance index (RV-MPI) > 0.4, 1 point. TAPSE, S′, RVFAC, and RV-MPI was 18.7 ± 4.8 mm, 11.9 ± 3.1 cm/s, 33.5 ± 13.9%, and 0.39 ± 0.2, respectively. The RV dysfunction score was associated with symptom [WHO functional class (p = 0.026)], hemodynamics , exercise capacity , and plasma BNP level (p = 0.005). This RV dysfunction score using the four RV echocardiographic parameters could be a simple and useful scoring system to evaluate prognostic factors in patients with CTEPH.Right ventricular (RV) function is associated with prognosis in chronic thromboembolic pulmonary hypertension (CTEPH). This study aimed to establish an RV dysfunction score using RV echocardiographic parameters to clarify the clinical characteristics in patients with CTEPH and to compare RV dysfunction score with parameters such as World Health Organization (WHO) functional class, hemodynamics, exercise capacity, and plasma BNP level. We enrolled 35 inpatients with CTEPH . We constructed ‘an RV dysfunction score’ calculated as the summation of each point awarded for the presence of four parameters: tricuspid annular plane systolic excursion (TAPSE) < 16 mm, 1 point; tissue Doppler-derived tricuspid lateral annular systolic velocity (The online version of this article (10.1007/s00380-018-1168-7) contains supplementary material, which is available to authorized users. S′), right ventricular fractional area change (RVFAC), and right ventricular myocardial performance index (RV-MPI) , and plasma brain natriuretic peptide (BNP) level used for risk assessment in patents with CTEPH.This study aimed to establish an RV dysfunction score using the four RV echocardiographic parameters  of ≥ 25 mmHg and a pulmonary arterial wedge pressure (PAWP) of < 15 mmHg by right heart catheterization (RHC), ventilation-perfusion lung scintigraphy, computerized tomography, and/or pulmonary angiography after at least 3 months anticoagulant treatment. Pregnancy, hypersensitivities to the contrast medium, and renal dysfunction were excluded. This study was approved by the human research ethics committees of Nagoya University Hospital (no. 2014-0332), and all patients gave written informed consent.S′ was measured. The percentage RVFAC was defined as (end diastolic area – end systolic area)/end diastolic area × 100. RV-MPI was defined as the ratio of isovolumic time divided by ejection time.Two-dimensional, M-mode, and Doppler echocardiographic images were acquired  and examined in accordance with the ASE guidelines . Patient2) and arterial oxygen saturation (SaO2) were measured in blood drawn from the main pulmonary artery and radial artery, respectively. Cardiac output (CO) was calculated by using the Fick method, and pulmonary vascular resistance (PVR) was calculated by using the standard formula: PVR = (mean PAP − mean PAWP)/CO. Cardiac index (CI) was calculated by using the formula: CI = CO/body surface area.All patients underwent RHC via the right internal jugular vein with a 6-French Thermodilution catheter  to obtain the PAP, PAWP, RV pressure (RVP), and right atrial pressure (RAP). Mixed venous oxygen saturation (SvO2) was monitored by saturation monitoring for the safety.The measurement of 6-min walk distance (6MWD) was performed in all but one patients enrolled in this study. Each patient was instructed to walk at their own pace. The physiotherapist supervised the test, telling the patient the elapsed time every 1 min. Although the patient was allowed to stop and take a rest freely, all patients continued to walk during the test. No patients were terminated prematurely by the test administrator, and no complications occurred. Dyspnea during the test was checked with the modified Borg dyspnea score. Before and during the 6MWT, the peripheral capillary oxygen saturation (SpO2), carbon dioxide output (VCO2), and the minute ventilation (VE) were continuously measured by a fixed cardio-pulmonary exercise system through a tightly fitted facemask. The CPET was safely performed without any problem such as syncope, arrhythmia, or worsening of right heart failure.Cardiopulmonary exercise testing (CPET) was performed in all patients in an erect position on an electronically braked cycle ergometer with breath-by-breath measurements by using an Ergospirometry Oxycon Pro . The exercise protocol consisted of 3 min of rest and 3 min of unloaded cycling, followed by a 10-W/min ramp-incremental protocol. Parameters including oxygen consumption  using the cut-off value recommended by ASE guidelines [n = 6), score 1 (n = 13), score 2 (n = 11), and score 3/4 (n = 5). Higher score indicates worse RV function.The RV dysfunction score was calculated as the summation of points awarded for the presence of four parameters . Baseline characteristics were compared using the Kruskal–Wallis test for continuous variables and the 2, and 6.0 ± 3.0 mmHg, respectively. All patients were prescribed anticoagulation, such as warfarin or direct oral anticoagulants. There were no statistically significant differences between four groups in the laboratory findings and pericardial effusion.Table 2) according to the RV dysfunction score. The mean PAP, CI, PVR, and SvO2 were significantly worsening as the RV dysfunction score increased . The RAP showed a considerable trend toward significance (p = 0.062).Figure 2, and VE/VCO2 slope), symptom , and plasma BNP level according to RV dysfunction score. All parameters showed significant deteriorating trend as the RV function score increased .Figure S′ (≥ 10 vs. < 10), RVFAC (≥ 35 vs. < 35), and RV-MPI (≤ 0.4 vs. > 0.4). Of these parameters, the correlations between RV-MPI/RVFAC and hemodynamics was stronger than those between TAPSE/S′ and hemodynamics. Especially, RVFAC (≥ 35 vs. < 35) showed the strongest correlation with hemodynamics . RVFAC also tends to show stronger correlation with exercise capacity and laboratory findings than the other parameters. Since there is a possibility that riociguat positively affected RV function and hemodynamics, sub-group analysis was conducted between the patients with riociguat and without riociguat (Supplementary Table 1). The result showed no significant difference between these two groups. Therefore, we concluded that treating two groups of patients collectively was appraisable. Table S′, and between RVFAC and RV-MPI .Table S′ < 10 cm/s, RVFAC < 35%, and RV-MPI > 0.4) was useful for risk assessment in CTEPH patients in terms of symptoms , hemodynamics, exercise capacity (6MWT and CPET) and plasma BNP level. Patients with a higher RV dysfunction score had higher BNP levels, more impaired exercise capacity, and worse hemodynamics.In the present study, we demonstrated that our simple RV dysfunction score using four important RV echocardiographic parameters  assessed by MRI in patients with CTEPH . RV-MPI S′ did not show strong correlations with hemodynamics and exercise capacity. Kind et al. reported that transverse measurement rather than longitudinal assessment, such as TAPSE and S′, reflects RVEF in pulmonary hypertension [S′ could be affected by RV enlargement and clockwise rotation of the apex of the heart [S′. But, actually TAPSE showed significant correlation with 6MWD  in our study (data not shown). There is also another report that resting TAPSE and S′ also showed moderate correlations with peakVO2 [S′ < 10.5 cm/s raise suspicion for worse response to vasodilators in patients with CTD-PAH [S′ are used for the evaluation of the RV longitudinal movement, there are few reports clearly representing the difference between TAPSE and S′ in patients with CTEPH. Indeed, TAPSE is the index of distance of RV longitudinal movement, while S′ is that of speed of RV longitudinal movement. Considering relatively low correlation coefficient between TAPSE and S′ shown in Table r = 0.603), we finally proposed to evaluate comprehensive RV function by adding both TAPSE and S′ into RV dysfunction score in our study.In contrast, TAPSE and rtension , In addihe heart . Therefo peakVO2 , and RV  CTD-PAH . AlthougThe 2015 ESC/ERS guidelines recommended the comprehensive prognostic evaluation and risk assessment for PAH patients since the single variable provides insufficient prognostic information . HoweverThe strength of the RV dysfunction score is that it can evaluate the patient’s status non-invasively and comprehensively. It could be useful not only for assessing RV function during the course of CTEPH treatment but also for predicting CTEPH prognosis.Our study had several limitations. First, this study was single-center study and the sample size was relatively small. Because of few clinical events, we could not examine a relationship between the RV dysfunction score and prognosis in our cohort. Second, we have not determined whether this RV dysfunction score is suitable for patients with other types of pulmonary hypertension. Third, as intra-observer variability was not assessed, and the reproducibility of RV echocardiographic parameters could not be evaluated. Fourth, as we did not correct weighting, we could not prove each of the four RV echocardiographic parameters had equal value. Finally, we did not measure speckle-tracking strain, which has been used recently as a useful index for the assessment of RV function –35, RV dS′ < 10 cm/s, RVFAC < 35%, and RV-MPI > 0.4) in patients with CTEPH and demonstrated that the RV dysfunction score represents patients' characteristics on admission and hemodynamics. This RV dysfunction score could be a simple and useful scoring system providing a good estimation for hemodynamics when treating patients with CTEPH before catheterization.In conclusion, we proposed an RV dysfunction score using the four RV echocardiographic parameters Below is the link to the electronic supplementary material.


Myocardial energetic efficiency (MEE), is a strong predictor of CV events in hypertensive patient and is reduced in patients with diabetes and metabolic syndrome. We hypothesized that severity of insulin resistance (by HOMA-IR) negatively influences MEE in participants from the Strong Heart Study (SHS).2 consumption, which can be simplified as SV/HR ratio and expressed in ml/sec. Due to the strong correlation, MEE was normalized by left ventricular (LV) mass (MEEi).We selected non-diabetic participants  free of cardiovascular (CV) disease, by merging two cohorts . MEE was estimated as stroke work (SW = systolic blood pressure [SBP] × stroke volume [SV])/“double product” of SBP × heart rate (HR), as an estimate of OLinear trend analyses showed that with increasing quartiles of HOMA-IR patients were older, more likely to be women, obese and hypertensive, with a trend toward a worse lipid profile , progressive increase in LV mass index, stroke index and cardiac index and decline of wall mechanics . In multivariable regression, after adjusting for confounders, and including a kinship coefficient to correct for relatedness, MEEi was negatively associated with HOMA-IR, independently of significant associations with age, sex, blood pressure, lipid profile and central obesity .Severity of insulin resistance has significant and independent negative impact on myocardial mechano-energetic efficiency in nondiabetic individual from a population study of American Indians.Trial registration number NCT00005134, Name of registry: Strong Heart Study, URL of registry: https://clinicaltrials.gov/ct2/show/NCT00005134, Date of registration: May 25, 2000, Date of enrolment of the first participant to the trial: September 1988The online version of this article (10.1186/s12933-019-0862-9) contains supplementary material, which is available to authorized users. Left ventricular (LV) work can be represented dimensionally by the force needed to eject blood  into the aorta, and estimated as stroke work (SW), the product of peak-systolic pressure times SV. Cuff systolic blood pressure (SBP) may be used as a surrogate of peak-systolic pressure, under the assumption that the kinetic energy is negligible at least in resting conditions. Thus, at rest, SW may be effectively estimated using fully non-invasive methods.2) and LV structure and function [Energy to support cardiac work is provided almost exclusively by aerobic oxidation of substrate, with close coupling between myocardial oxygen consumption , which has been prognostically validated , 5. Low Accordingly, in this analysis, we tested the hypothesis that MEEi progressively deteriorates for increasing degrees of insulin resistance.2. Arterial hypertension was defined by BP ≥ 140/90 mmHg or current antihypertensive treatment.We selected non diabetic participants (i.e. no history of diabetes and plasma glucose < 126 mg/dl) from the Strong Heart Study (SHS) initial cohort (2nd exam) and the Strong Heart Family Study (SHFS) cohort , with available data on fasting glucose and fasting insulin levels, and free of prevalent CV disease, as already done in a previous study . DetaileFasting plasma glucose, lipid profile and other laboratory variables were measured by standard methods, as previously reported , 9, 11. 2.7) were estimated [2 was approximated using the “double product” of heart rate (HR) times SBP. SW was estimated as SBP × SV. Accordingly, MEE is the ratio between the SW and MVO2. Thus:Echocardiograms were performed using phased-array, commercially available echocardiographs, with M-mode, two-dimensional and Doppler capabilities, and read off line using working stations equipped with frame-grabber to measure on stop-frame images, as previously reported in detail . LV massstimated , 14. Relstimated . Stroke stimated . Cardiacstimated . Ejectiostimated . To estiformance .The population sample was divided into quartiles of HOMA-IR and exploratory statistics were performed to analyse the linear trend among the different degrees of insulin resistance for age, sex, heart rate, blood pressure, BMI, risk profile , and LV structural and functional parameters . ANCOVA was used to study the correlation of MEEi with HOMA-IR, adjusting for age, sex, obesity and hypertension. Because in this population, including members of the SHFS cohort, the level of family relatedness could be significant , we alsoThe study population comprised 3128 non-diabetic participants . Table Whereas no effect was observed in ejection fraction, increasing in HOMA-IR was associated with progressive increase in LV mass index, stroke index and cardiac index and decline of midwall shortening  Fig. .Fig. 1LVIn sequential multivariable regression models, the correlation of MEEi with HOMA-IR was adjusted for many potential covariates Table . First, This study demonstrates that in non-diabetic participants of the SHS cohort with normal ejection fraction and free of prevalent CV disease, insulin resistance is a significant contributor of the variance of myocardial mechano-energetic efficiency per gram of LV mass. The effect of insulin resistance could be demonstrated to be independent of major CV risk factors, including hypertension, lipid profile and central obesity, all factors linked to metabolic syndrome that could mediate the direct relation between insulin resistance and myocardial energetic efficiency . This is2. In contrast, one molecule of glucose produces only 31 ATPs but using only 12 atoms of O2. Thus, the ratio of produced ATP/MVO2 is higher with glucose (P/O = 2.58) than with fatty acids (P/O = 2.28), which produces a redundant number of ATP molecules, a source of energy that is mainly dissipated as heat [In a normal myocardium, 60–70% of energy is produced by fatty acid oxidation, while only 30–40% of energy is produced by glucose-pyruvate oxidation. There are major differences between the two pathways . One mol as heat , 23.Accordingly, myocardial mechano-energetic efficiency is much higher when utilizing glucose than with fatty acids. In the diseased heart, there is in fact a progressive shift toward more glucose utilization up to a near total utilization in heart failure, to realize the most efficient energetic mechanisms in conditions of distress . AccordiTaken together, our findings support the assumption that mechanisms of production and delivery of energy play substantial role in the evolution of at least some clinical manifestation of overt CV disease.2 [2 is devoted to the development of isovolumic tension that alters geometry of elastic elements before ejection. The isovolumic activity, therefore, do not develop any real physical work, while dissipating energy. This part of energy waste increases with increasing heart rate, mainly due to the increased frequency of isovolumic contraction, while it is reduced if cardiac output is sustained by stroke volume. With the energetic sparing obtained by increasing stroke volume, if aortic pressure increases, end-systolic wall tension also increases, and energy dissipation also increases. For these reasons, product of heart rate by systolic pressure is a potent and reliable predictor of MVO2 [2 with the double product might be imprecise, especially in conditions of acute hemodynamic manipulations [Compared to our indirect approach, a direct measure of myocardial metabolism would be desirable. However, direct detection of myocardial energetic metabolism is not feasible on epidemiological scale. The approach we use to estimate myocardial mechano-energetic efficiency has a strong rationale. Systolic work at each cardiac beat (stroke work) is represented as the area of the pressure–volume loop Fig. . As can 2 , 32. A s of MVO2 . Despiteulations , 35, butulations .Fig. 3Pr2 used [In our analysis, MEEi progressively declines with increasing levels of insulin-resistance, a relation that is maintained also after multiple adjustments for potential confounders. This result was expected. We had already seen that in the treated hypertensive patients of the Campania Salute Network registry , metabol2 used –23, cons2 used , providi2 consumption without a corresponding increased LV pump performance, therefore decreasing myocardial energetic efficiency.There is a large number of studies demonstrating a link between insulin resistance and non-ischemic cardiomyopathy or even heart failure , 40. In Also, consistent with our findings, insulin resistance has also been reported to be associated with other adverse characteristics of CV system, including diastolic dysfunction  and incrThe present study demonstrated that myocardial energetic efficiency is affected by the level of insulin resistance in non-diabetic participants from the SHS. Patients with high insulin-resistance have low amount of blood, ejected at each systole, per gram of LV mass, independently of common confounders such as hypertension, waist circumference and markers of inflammation.Additional file 1: Table S1. LV geometry, systolic function and performance in quartiles of HOMA-IR.


Early risk stratification after ST-segment–elevation myocardial infarction (STEMI) is of major clinical importance. Strain quantifies myocardial deformation and can demonstrate abnormal global and segmental myocardial function in acute ischaemia. Native T1-mapping allows assessment of the severity of acute ischemic injury, however its clinical applicability early post MI is limited by the complex dynamic changes happening in the myocardium post MI. We aimed to explore relationship between T1-mapping and feature tracking imaging, to establish whether combined analysis of these parameters could predict recovery after STEMI. 96 STEMI patients (aged 60 ± 11) prospectively recruited in the Oxford Acute Myocardial Infarction (OxAMI) study underwent 3T-CMR scans acutely (within 53 ± 32 h from primary percutaneous coronary intervention) and at 6 months (6M). The imaging protocol included: cine, ShMOLLI T1-mapping and late gadolinium enhancement (LGE). Segments were divided in the infarct, adjacent and remote zones based on the presence of LGE. Peak circumferential (Ecc) and radial (Err) strain was assessed using cvi42 software. Acute segmental strain correlated with segmental T1-mapping values  and with LGE segmental injury . Moreover, acute segmental T1 and strain predicted segmental LGE transmurality on 6M scans . Multiple regression analysis confirmed combined analysis of global Ecc and T1-mapping was significantly better than either method alone in predicting final infarct size at 6M . This novel CMR method combining T1-mapping and feature tracking analysis of acute CMR scans predicts LGE transmurality and infarct size at 6M following STEMI. Myocardial infarct (MI) size is a major determinant of the left ventricular (LV) dysfunction and long term remodelling in patients post ST-segment–elevation myocardial infarction (STEMI) . AlthougBy allowing quantitative assessment of the severity of the ischemic injury on a continuous scale, CMR mapping techniques allow accurate characterisation of the composition and viability of the myocardium after MI –12 provi96 STEMI patients who underwent PPCI were prospectively enrolled in the study at the John Radcliffe Hospital as part of the OxAMI Study. This was a pre-specified study within the OxAMI research programme. Patients were eligible if the onset of symptoms had been within 12 h before PPCI and if they had ST-segment elevation of at least 0.1 mV in ≥ 2 contiguous limb leads or at least 0.2 mV ≥ 2 contiguous precordial leads. Patients with previous MI, previous revascularization procedure (coronary artery bypass grafts or PCI), severe heart valve disease, known cardiomyopathy, or hemodynamic instability lasting ≥ 12 h after revascularization were excluded. Further exclusion criteria were contraindications to CMR, including implanted pacemakers, defibrillators, or other metallic implanted devices and claustrophobia. Acute clinical management was at the discretion of the responsible physician, with the intention to reflect contemporary practice and guidelines. The study protocol was approved by the local ethics committee, and all patients gave written informed consent.Patients underwent 3 T CMR scan  at 2 time points: acutely (within 53 ± 32 h post PPCI) and at 6 months (6M). Matching short axis slices covering the LV were acquired using an established CMR protocol including: cine, native T1-mapping using the Shortened Modified Look-Locker Inversion recovery (ShMOLLI), and LGE as described in the Table Anonymised images were analysed using cvi42 software  by two experienced operators  blinded to CMR measurements of the same patient across two time points and included LV volumes, quantification of LV% oedema on T1 maps , LV% necSegmental analysis was performed on the short-axis (SA) images Fig. . For allCvi42 software was used to assess LGE transmurality (Tissue characterisation: LGE module). Briefly, contours were drawn manually around LV endo- and epicardium. The LGE signal intensity threshold for quantification of necrosis was set at five standard deviations (SD) above the reference ROI in the remote unaffected myocardium , 28. MyoStatistical analyses were performed using IBM SPSS Statistics . Continuous data are expressed as mean ± SD except where otherwise specified. Categorical variable was expressed as n%. The normality of the data was assessed using the Shapiro–Wilk test or the Kolmogorov–Smirnov test depending on the size of samples tested. Those variables that did not follow a normal distribution are presented as medians with interquartile range (median (IQR)). Comparisons between groups were performed with t-test or one-way ANOVA where normality was met or with the non-parametric Kruskal–Wallis H. Test when data normality was violated . Correlation was expressed as Pearson or Spearman correlation coefficient. To account for the fact that segmental T1 values and segmental peak strain analysis could not be treated as independent samples, the following approach was utilised: correlation coefficient values from the segmental analysis of two imaging biomarkers was first derived for each patient, then transformed with the Fisher’s z’ transformation that converts Pearson’s r’s to the normally distributed variable z and subsequently analysed by t-test . CASTS % vs. Errremote = 35 (23)%, p < 0.01; Eccinfarct = − 10 (9)% vs. Eccremote = − 20 (9)%, p < 0.01) (Table adjacent = − 20 (8)% vs. Eccremote zone − 21 (7)%; p = 0.07). Err and Ecc values varied significantly between segments grouped by LGE transmurality  Errty Table .Table In order to assess whether acute myocardial deformation in addition to myocardial composition, as assessed by T1 values, predict the 6M peak LGE segmental transmurality, we performed a multiple regression analysis including acute segmental T1, Err and Ecc values as independent variables. When combined these variables significantly predicted 6M segmental LGE transmurality . Furthermore, we analysed the contribution of each of the independent variables to the prediction of the 6M peak LGE segmental transmurality. When T1 and Ecc values were used together both variables significantly improved the prediction of final segmental LGE transmurality (p < 0.001 for each of them), however, Err did not add to the prediction of 6M segmental LGE transmurality (Err p = 0.662). Thus, in further analyses we used T1-mapping combined with Ecc only.In view of the fact, that global rather than segmental stain has been previously shown to predict cardiac remodelling after STEMI , we wantIn patients with acute MI, novel CMR imaging markers derived from either tissue characterisations mapping techniques or FTI methods have been shown to have incremental prognostic value compared to standard LGE infarct size and EF , 15, 23.Whilst peak segmental strain and native T1-mapping analysis reliably identifies infarct and remote zones, in areas adjacent to the ischemic myocardium, circumferential strain measures did not significantly differ from remote myocardium despite of the high T1 values. This suggests that native T1-mapping and peak circumferential strain analysis combined is able to distinguish between infarcted, irreversibly damaged segments and peri-infarct zones that have a high chance to recover.Moreover, we observed significant prolongation of the native T1 values in 20% of the non-ischaemic zones and their recovery on the follow-up scans. Significantly, all these segments had normal values of circumferential strain. This observation is particularly potent in light of gadolinium-free T1-mapping techniques potentially replacing contrast methods altogether. In our study, segments were divided in the infarct, adjacent and remote zones based on the presence of LGE. Thus, if one would rely exclusively on the analysis of segments of the native T1 values, these remote segments with increased T1-mapping values might get wrongly labeled as infarcted. Conversely, the addition of circumferential strain allows us to accurately identify these segments. This is particularly true when assessing zones adjacent to the infarct. Similar observations that were previously reported by Carrick et al.  and by RThe additive value of the combined analysis of segmental native T1 mapping and tissue tracking is somewhat smaller than anticipated. This could be explained by the fact that actually both imaging biomarkers measure the same process, namely acute injury caused by inflammation and oedema of the myocardium. Thus, changes in the tissue characteristic will influence changes in the tissue deformation measured by the peak strain. This observation is supported by our findings that show significant correlation between the percentage of global oedema and global strain.Another important limitation of our study is a significant drop out in the follow-up CMR scans. 59 out of 96 recruited subjects returned for the 6M follow up scans. We decided to include all recruited patients in our study but we acknowledge the analysis of the predictive value of the combined analysis of global strain and T1-mapping in the assessment of 6M infarct size was performed on those subjects, which underwent full study protocol including 6M scans.This novel CMR method combining T1-mapping and strain analysis of acute CMR scans improves the prediction of irreversible ischaemic injury following STEMI. Further studies using alternative mapping modalities and investigating the longitudinal changes over the early hours post MI, will be needed to establish a combined protocol of native T1 mapping and feature tracking assessment as an alternative to the standard LGE method, limiting the CMR protocol to non-contrast acquisitions.


After more than a decade of relatively modest advancements, heart failure therapeutic development has accelerated, with the PARADIGM-HF trial and the SHIFT trial demonstrated significant reductions in cardiovascular death and heart failure hospitalization for sacubitril-valsartan and in heart failure hospitalization alone for ivabradine. Several heart failure therapies have since received or stand on the verge of market approval and promise substantive advances in the treatment of chronic heart failure. Some of these improve clinical outcomes, whereas others improve functional or patient-reported outcomes. In light of these rapid advances in the care of adults living with chronic heart failure, in this review we seek to update the general practitioner on novel heart failure therapies. Specifically, we will review recent data on the implementation of sacubitril-valsartan, treatment of functional mitral regurgitation, sodium-glucose co-transporter-2 (SGLT-2) inhibitor therapy, agents for transthyretin amyloid cardiomyopathy, treatment of iron deficiency in heart failure, and the use of biomarkers or remote hemodynamic monitoring to guide heart failure therapy. After a decade without successful development of novel heart failure therapeutics, the PARADIGM-HF trial and the SHIFT trial demonstrated significant reductions in cardiovascular death and heart failure hospitalization for sacubitril-valsartan and in heart failure hospitalization alone for ivabradine. Since the market introduction of these two therapies, several heart failure therapies have received or stand on the verge of market approval. In light of the rapid advances in the care of adults living with chronic heart failure, we have sought to update the general practitioner on heart failure therapies approved during this wave of successful drug development.1. All patients received sacubitril-valsartan 24/26 mg twice daily for 5 days during an open-label, run-in period followed by randomization and two additional treatment periods. At randomization, patients in the conservative arm continued sacubitril-valsartan at 24/26 mg twice daily whereas patients in the condensed arm were titrated to 49/51 mg twice daily. After 2 weeks, the conservative arm increased to 49/51 mg twice daily and the condensed arm increased to the maximal dose of 97/103 mg twice daily. The condensed arm then continued the maximal 97/103 mg twice daily for the remaining 9 weeks of the study, whereas the conservative arm continued the 49/51 mg twice-daily regimen for 3 weeks before increasing to the maximal 97/103 mg twice daily for 6 weeks. In aggregate, the condensed arm reached the maximal dose with one fewer visit than the conservative arm and increased from 24/26 mg to 49/51 mg 2 weeks earlier than the conservative arm and from 49/51 mg to 97/103 mg 3 weeks earlier than the conservative arm.Two clinical trials have tested novel strategies for the safe and effective implementation of sacubitril-valsartan in 498 patients with heart failure and a reduced ejection fraction. The TITRATION study compared the safety and efficacy of conservative and condensed up-titration schedules for sacubitril-valsartan in ambulatory patientsP = 0.57) and systolic blood pressure less than 95 mm Hg  was not significantly different between the conservative and condensed arms. Serum potassium of more than 5.5 mmol/L occurred in 7.3% of condensed and 4% of conservative patients (P = 0.10). There was no significant difference in renal dysfunction between the two arms . Adverse effects occurred most frequently in patients who switched to sacubitril-valsartan from a low dose of an angiotensin-converting enzyme inhibitor  or angiotensin receptor blocker  and those who had baseline systolic blood pressure of 100 to 110 mm Hg. Less than one fifth of patients with heart failure reach target doses of renin–angiotensin–aldosterone inhibitors.The proportion of patients experiencing any hypotension  from baseline to week 8 was significantly greater in the sacubitril-valsartan group than the enalapril group . Sacubitril-valsartan had no effect on a secondary 7-point composite clinical endpoint but was associated with a reduced risk of rehospitalization for heart failure . Of note, the trial protocol aimed to achieve maximal sacubitril-valsartan doses within 1 week if tolerated. Slightly more patients experienced worsening renal function (13.6% vs. 14.7%), hyperkalemia (11.6% vs. 9.3%), and symptomatic hypotension (15.0% vs. 12.7%) but these differences did not reach statistical significance.The randomized, double-blind PIONEER-HF trial compared in-hospital initiation of sacubitril-valsartan to initiation or enalapril among 881 patients with stabilized decompensated heart failure2).These important trials provide clinicians with structured protocols  to maxim3. In addition to a left ventricular ejection fraction (LVEF) of at least 45%, patients were required to have additional objective criteria of heart failure, including an elevated natriuretic peptide level, structural heart disease , and diuretic use. Patients were ineligible if they had a previous LVEF of less than 40%. After a single-blind run-in phase, 4796 patients were randomly assigned to sacubitril-valsartan (target dose of 97/103 mg twice daily) or valsartan (target dose of 160 mg twice daily) and followed for a median of 35 (interquartile range of 30 to 41) months.The PARAGON-HF trial tested the hypothesis that sacubitril-valsartan lowers the rate of a composite outcome of total heart failure hospitalizations and cardiovascular death compared with valsartan alone in patients with heart failure and preserved ejection fractionP = 0.06) but did not achieve statistical significance. Randomization to sacubitril-valsartan was associated with a smaller total number of heart failure hospitalizations  but no difference in death due to cardiovascular causes  or due to any cause (342 [14.1%] vs. 349 [14.6%]). Although New York Heart Association functional class remains unchanged at 8 months in most patients, more sacubitril-valsartan patients than valsartan patients appeared to have investigator-assessed improvements in functional class . Hypotension with systolic blood pressure of less than 100 mm Hg and elevations in serum creatinine of at least 2.0 mg/dL occurred less frequently in the sacubitril-valsartan arm, whereas angioedema occurred more frequently in the sacubitril-valsartan arm . The investigators concluded that sacubitril-valsartan did not reduce the rate of a composite outcome of total heart failure hospitalizations and cardiovascular deaths compared with valsartan in patients with heart failure and preserved ejection fraction. Furthermore, any potential beneficial treatment effect appeared restricted to heart failure hospitalization and not cardiovascular mortality. The use of valsartan as an active comparator was consistent with most participants’ pre-enrollment treatment regimens but may have diminished any potential between-group differences.The number of composite heart failure hospitalizations or cardiovascular deaths was nominally lower in the sacubitril-valsartan arm than in the valsartan arm  but not those with an ejection fraction above the median of 57%  and among women  but not men . Although the results of pre-specified subgroup analyses in an overall neutral trial must be considered with caution, the intriguing interactions by LVEF and gender may prove to be significant for several reasons. Patients who have a preserved but modestly depressed ejection fraction may be phenotypically more similar to those with a markedly reduced than robustly preserved ejection fraction10. The MitraClip is a percutaneous device that reduces mitral regurgitation severity by facilitating approximation of the anterior and posterior mitral valve leaflets11. The efficacy and safety of mitral valve repair with the MitraClip were studied in two clinical trials with similar designs.Although secondary mitral regurgitation due to left ventricular dysfunction confers an increased risk of hospitalization and death, treatment options remain limited as surgical repair or replacement does not improve clinical outcomes13. Although both trials enrolled patients with at least moderate to severe regurgitation, COAPT targeted a population of patients with a larger effective orifice regurgitant area (≥30 vs. ≥20 mm2) or a larger regurgitant volume (>45 vs. >30 mL) and less severe left ventricular dysfunction (LVEF 20 to 50% vs. 15 to 40% and left ventricular end-systolic diameter of not more than 70 mL in COAPT vs. no restriction in MITRA-FR). Thus, the contribution of mitral regurgitation to heart failure symptoms relative to myocardial dysfunction may have been greater in COAPT than MITRA-FR. In addition, COAPT patients were enrolled after optimization of guideline-directed medical therapy.MITRA-FR (N = 304) and COAPT (N = 614) were randomized comparisons of mitral valve repair with the MitraClip plus guideline-directed medical therapy versus guideline-directed medical therapy aloneP = 0.53). In contrast, in the COAPT trial, mitral valve repair with the MitraClip significantly reduced the risk of the primary endpoint of heart failure hospitalization at 24 months  and the composite of all-cause death or heart failure hospitalization (P <0.001).In MITRA-FR, mitral valve repair with the MitraClip had no significant effect on the primary endpoint of all-cause death or heart failure hospitalization at 12 months  and regurgitant volume  than those randomly assigned to valsartan. One (2%) death and three (5%) heart failure events occurred in the sacubitril-valsartan group versus zero and five (9%) in the valsartan group (P >0.49 for each).Pharmacologic treatment with sacubitril-valsartan may also reduce mitral valve regurgitation, although the effects on clinical outcomes remain unclear. In the PRIME trial, patients with heart failure and mitral valve regurgitation who were randomly assigned to sacubitril-valsartan had significantly greater reductions in effective orifice regurgitant area  is twofold greater than that of patients without T2DM15. SGLT-2 inhibitors therefore lower blood glucose concentrations by enhancing glucosuria. SGLT-2 inhibition also induces durable weight loss (primarily a reduction in fat mass and not in lean mass) and lowers blood pressure16.About 90% of tubular glucose reabsorption occurs through the tubular sodium-glucose co-transporter-2 (SGLT-2)19. Whereas the beneficial effects of empagliflozin were consistent between patients with and without a history of heart failure at baseline20, canagliflozin and dapagliflozin demonstrated larger effect sizes in patients with a history of heart failure23.Secondary and post-hoc analyses of three clinical trials provide strong evidence that SGLT-2 inhibitors modulate heart failure outcomes in patients with T2DM. Three SGLT-2 inhibitors  significantly reduce the composite of heart failure hospitalization or cardiovascular death25. The molecular mechanisms through which SGLT-2 inhibition may modulate cardiac structure and function remain under investigation. Hypothesized mechanisms include altered myocardial metabolism and energetics, glucosuria-induced diuresis without concomitant renin–angiotensin–aldosterone system activation, and inhibition of the myocardial sodium-hydrogen transporter10.Small observational studies suggest that treatment of T2DM (with or without heart failure) with SGLT-2 inhibitors improves left ventricular filling pressure, as measured by E/e′ ratio and left atrial volume index26. This trial randomly assigned 4744 patients with symptomatic heart failure and an ejection fraction of less than 40% to receive dapagliflozin 10 mg once daily or placebo, in addition to background heart failure therapy. The primary endpoint was hospitalization or urgent visit for heart failure or cardiovascular death. Most patients (58%) did not have a history of diabetes mellitus at baseline. The mean LVEF and the median NT-proBNP level at baseline were approximately 31 ± 7% and 1400 (857 to 2650) pg/mL, respectively. Use of guideline-directed medical therapy was high, including angiotensin-converting enzyme inhibitor (56%), angiotensin receptor blocker (27%) or sacubitril-valsartan (11%), a beta-blocker (96%), and mineralocorticoid receptor antagonist (71%).Most recently, the DAPA-HF trial extended the benefits of SGLT-2 inhibitors from patients with T2DM to heart failure with reduced LVEF patients without T2DMP <0.001). Dapagliflozin also reduced the incidence of each of the individual components of the primary outcome. Furthermore, the benefits of dapagliflozin did not significantly differ between patients with  and without  T2DM at baseline (P interaction = not reported). As expected, hypoglycemia requiring intervention occurred infrequently (4/2368 [0.2%]) in the dapagliflozin arm. There were no significant differences in amputations, diabetic ketoacidosis, or renal adverse events. These exciting results have re-positioned SGLT-2 inhibitors as a complete cardiometabolic, rather than glucose-lowering, therapy.After a median follow-up duration of 18.2 months, patients randomly assigned to dapagliflozin experienced significantly fewer primary composite events than those randomly assigned to placebo  of tafamidis patients were living compared with 57% (n = 101) of placebo patients at 32 months . Cardiovascular hospitalization occurred in 138 tafamidis patients  compared with 107 placebo patients  .Tafamidis is a synthetic small molecule that binds to the thyroxine-binding sites on transthyretinThe effects of tafamidis were consistent across transthyretin genotypes (for those with hereditary transthyretin amyloid cardiomyopathy) and both the 80 mg and 20 mg tafamidis doses. Delayed worsening heart failure symptoms and declining exercise capacity were observed in the tafamidis arms as early as 6 months, whereas the mortality benefit emerged after 18 months. ATTR-ACT was not powered to detect statistically significant improvements in left ventricular structure and function, although favorable trends were observed in left ventricular wall thickness and left ventricular global longitudinal strain. The incidence of serious adverse events was not significantly different between tafamidis and placebo.31 encapsulated within a liposome that targets a conserved sequence in the 3′ untranslated region of wild-type and mutant transthyretin mRNA, thereby suppressing gene expression via the RNA-induced silencing complex32. Patisiran 0.3 mg/kg every 3 weeks decreased serum transthyretin levels by 81% and improved neuropathy, as measured by the modified Neuropathy Impairment Score + 7 in 225 patients with hereditary transthyretin amyloidosis enrolled in the randomized, double-blind, placebo-controlled APOLLO study (N = 225)33.Patisiran is a small, interfering RNA35. Mean left ventricular wall thickness  and left ventricular end-diastolic volume  each decreased to a greater extent in the patisiran arm compared with placebo at 18 months. Patisiran improved left ventricular absolute global longitudinal strain by 1.4%  versus placebo. Absolute basal, midwall and apical longitudinal strains also improved with patisiran treatment with basal longitudinal strain reaching statistical significance. In an exploratory post-hoc analysis of clinical outcomes, patisiran was associated with a trend toward lower risk of cardiac death or hospitalization compared with placebo .Transthoracic two-dimensional echocardiography was performed in 126 (56%) APOLLO patients with left ventricular wall thickness of at least 13 mm and no history of aortic valve disease or hypertensionTafamidis was approved by the US Food and Drug Administration for the treatment of wild-type or hereditary transthyretin-mediated amyloid cardiomyopathy in 2019, whereas patisiran was approved for the treatment of hereditary transthyretin amyloid polyneuropathy, but not amyloid cardiomyopathy, in 2018. Both agents have a considerable cost of tens or hundreds of thousands of dollars annually. Thus, patisiran is unlikely to be covered by payers for the treatment of amyloid cardiomyopathy and tafamidis is unlikely to be covered for the treatment of polyneuropathy. Tafamidis is the preferred agent for patients with amyloid cardiomyopathy.36, and a second transthyretin tetramer stabilizer, AG1037, on cardiac structure and function in adults with transthyretin amyloid cardiomyopathy are unclear.The effects of a second RNA therapeutic, inotersen40 and is associated with poor prognosis41, impaired exercise capacity and skeletal muscle function43, and worse quality of life44. Patients with heart failure have decreased myocardial iron content45, and iron-deficient cardiomyocytes have impaired contractility46 and mitochondrial dysfunction48. Iron repletion with intravenous iron improves quality of life and may prevent heart failure hospitalizations in patients with heart failure and iron deficiency, irrespective of anemia status50. In 2017, three clinical trials addressed important unanswered questions related to iron repletion in adults with heart failure, namely the effect of iron repletion on exercise capacity as measured by peak oxygen consumption50, the effect of iron repletion on peripheral skeletal muscle function51, and the role of oral iron supplements in patients with heart failure and iron deficiency52.Depending upon the definition, iron deficiency (with or without anemia) affects up to 50% of adults with chronic heart failure49. At 24 weeks, peak oxygen consumption decreased to a greater extent in the usual care arm than the ferric carboxymaltose arm . There were no between-group differences in ventilatory efficiency, as measured by the slope of the carbon dioxide–minute ventilation relationship, or treatment effect differences between patients with and without concomitant anemia.EFFECT-HF randomly assigned 172 adults with symptomatic heart failure with reduced ejection fraction and iron deficiency (defined as serum ferritin of less than 100 ng/mL or serum ferritin 100 to 300 ng/mL with a transferrin saturation of less than 20%) to receive ferric carboxymaltose, dose-adjusted to target hemoglobin, ferritin, and transferrin saturation levels, or usual care for 24 weeks8. EFFECT-HF was not included in the focused guideline update.Thus, EFFECT-HF was the first trial to demonstrate an improvement in exercise capacity using gas-exchange variables rather than the 6-minute walk test. In their joint 2017 focused update of the Guideline for the Management of Heart Failure, the American College of Cardiology Foundation and the American Heart Association gave intravenous iron replacement to improve function status and quality of life a weak recommendation (IIb) based upon moderate-quality evidence (B-R)12 levels51. Patients randomly received iron isomaltoside  or matching placebo. The primary endpoint was phosphocreatine recovery half-time on dynamic 31P magnetic resonance spectroscopy during submaximal exercise, where a shorter half-life indicates faster phosphocreatine recovery and improved mitochondrial oxidative function.FERRIC-HF was a randomized, double-blind, placebo-controlled clinical trial of 40 patients with symptomatic heart failure with reduced ejection fraction, iron deficiency (defined as serum ferritin of less than 100 ng/mL or serum ferritin 100 to 300 ng/mL with a transferrin saturation of less than 20%), and normal folate and vitamin BP = 0.006) shorter in the iron isomaltoside group than the placebo group. Iron isomaltoside also improved adenosine diphosphate recovery half-time but had no effect on resting or end-exercise phosphocreatine or adenosine diphosphate half-time. This study provides important mechanistic insight into the pleiotropic effects of iron repletion in heart failure.At 2 weeks, phosphocreatine half-time was −6.8 seconds  and transferrin saturation .In IRONOUT HF, 225 patients with symptomatic heart failure with reduced ejection fraction and iron deficiency (defined as serum ferritin of less than 100 ng/mL or serum ferritin 100 to 300 ng/mL with a transferrin saturation of less than 20%) were randomly assigned to receive iron polysaccharide 150 mg twice daily for 16 weeks53.Future studies should determine whether different oral iron regimens can replete iron stores in patients with heart failure. Studies of women with anemia suggest that frequent oral iron administration induces an increase in hepcidin levels and that less frequent oral supplementation  paradoxically may improve iron repletion19. Yet the value of natriuretic peptide–guided heart failure management remains unclear. A meta-analysis of 2000 participants across 11 clinical trials demonstrated significant reductions in all-cause mortality , heart failure hospitalization , and cardiovascular hospitalization  with natriuretic peptide–guided heart failure management54. In contrast, the GUIDE-IT trial (N = 894) found no difference in time to first heart failure hospitalization or cardiovascular death between patients randomly assigned to an NT-proBNP–guided strategy and usual care55.The natriuretic peptide B-type natriuretic peptide (BNP) and its congener N-terminal-proBNP (NT-proBNP) provide considerable diagnostic and prognostic value in heart failure56. While NT-proBNP–guided therapy was associated with reduced second all-cause hospitalizations, there was no effect on the second heart failure hospitalization. In the subgroup of patients younger than 75 years, guided therapy was associated with reduced first and second all-cause and heart failure hospitalizations. Current guidelines do not recommend natriuretic peptide–guided therapy58.An exploratory, post-hoc analysis of the neutral TIME-CHF trial used the gap-time method to compare NT-proBNP–guided therapy with usual care to account for recurrent eventsCarbohydrate antigen 125 is a glycoprotein associated with prognosis in acute heart failure. In a multicenter clinical trial of 380 patients, carbohydrate antigen 125–guided therapy significantly reduced the composite of death or heart failure hospitalization at 1 year. Replication of these results would provide compelling support for carbohydrate antigen 125–guided therapy.60. Recent analyses have provided additional insights into the efficacy and safety of remote hemodynamic monitoring. First, the findings of the CHAMPION trial have been replicated in two separate analysis of routinely collected clinical data62. Second, review of medication titration patterns during the CHAMPION trial has demonstrated that diuretic adjustments and (among patients with heart failure and a reduced ejection fraction) guideline-directed medical therapy adjustments contributed to the reduced hospitalization rates64. Third, individual practices have begun to report their experience with the implementation and maintenance of a remote hemodynamic monitoring program67. These practice-based insights will prove useful as additional remote monitoring devices reach the market. Last, comparative effectiveness studies suggest that remote hemodynamic monitoring meets currently accepted thresholds for cost-effectiveness but the overall budget impact may be difficult to absorb69. Ongoing research is investigating the role of remote hemodynamic monitoring in patients with mechanical circulatory support devices and the effects of novel heart failure therapies on pulmonary artery pressure72.Titration of guideline-recommended medical therapy to a target pulmonary artery diastolic pressure, estimated using an implantable hemodynamic monitor, reduces heart failure hospitalizations by 28% in patients with reduced and preserved ejection fractionAfter more than a decade of relatively modest advancements, heart failure therapeutic development has accelerated and led to several advances in the treatment of chronic heart failure. Some of these new technologies improved clinical outcomes, whereas others improve functional or patient-reported outcomes.


We investigated the predictive value of the combination of two different types of examinations, LGE on CMR and WR by 123I-MIBG scintigraphy for outcomes in DCM compared with LGE alone. One-hundred forty-eight DCM patients underwent CMR and 123I-MIBG scintigraphy. Patients were divided into 4 groups according to the presence or absence of LGE and WR cut-off value of 45% for predicting prognosis based on receiver operating characteristic curve analysis. Cardiac deaths, re-hospitalization for heart failure, implantation of a left ventricular assist device, and life-threatening ventricular arrhythmias were defined as clinical events. Forty-two DCM patients reached the clinical events during the median follow-up for 9.1 years .Multivariable Cox regression analysis identified WR≥45%+LGE positive group as an independent predictor of cardiac events . Notably, there was no significance in the cardiac event-free survival rate between the WR<45%+LGE positive and WR≥45%+LGE negative groups (p = 0.89). The combination of WR by 123I-MIBG scintigraphy and LGE on CMR, which evaluate different type of cardiac deterioration, serves as a stronger predictor of long-term outcomes in DCM patients than LGE alone.Late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is limited in its ability to detect diffuse interstitial fibrosis, which is commonly found in idiopathic dilated cardiomyopathy (DCM). On the other hand, Washout rate (WR) by cardiac  Cardiac magnetic resonance (CMR) is well established as the reference imaging method for the assessment of cardiac anatomy and function . The lat123I-metaiodobenzylguanidine (123I-MIBG), an analogue of norepinephrine, is a useful tool for detecting abnormal cardiac sympathetic nervous activity in heart failure (HF) patients , or implanted devices such as pacemakers and/or defibrillators), neuro-degenerative diseases such as Parkinson disease and dementia with Lewy bodies, and receiving reserpine or tricyclic antidepressants. The remaining 158 DCM patients underwent CMR and 123I-MIBG scintigraphy  functional class, serum creatinine level, plasma B-type natriuretic peptide (BNP) level, and prescribed medication for HF. The study conformed with the principles outlined in the Declaration of Helsinki. This study was approved by the research ethics committee of Himeji Cardiovascular Center and carried out in accordance with approved guidelines. For this analysis of clinically acquired data, the institutional review board waived the need for patients’ written informed consent.We conducted a longitudinal study in a cohort of consecutive 470 DCM patients who were referred to Himeji Cardiovascular Center with HF at their initial visit between January 2005 and December 2014. Patients were excluded before entry if they had had any of the following: Contraindications to CMR  and a standardized protocol. Cine images were acquired with a steady-state, free-precession sequence in long-axis planes and contiguous short-axis slices from the atrioventricular ring to the apex, as previously described . Ten min123I-MIBG, the delayed heart to mediastinum ratio (H/M) and washout rate (WR) were calculated as described in a previous study [A complete imaging protocol included planar and SPECT images obtained at 15 min (early) and 3 hours (delayed) after intravenous injection of 111 MBq (3 mCi) at rest. For the gamma camera, PRISM-IRIX , with 3 heads, attached to a low-energy, high-resolution collimator, and then stored in 256×256 matrix. The data were analyzed by two independent observers blinded to patients’ clinical conditions. On anterior planar images, regions of interest (ROIs) were drawn manually over the whole heart (H) and upper mediastinum (M) was used as the reference background. For the quantitative analysis of us study .Comprehensive transthoracic echocardiography was performed by highly experienced research sonographers by using commercially available Aplio .Two-dimensional and color Doppler echocardiography were performed in standard parasternal and apical views. LV end-diastolic volume (EDV), end-systolic volume (ESV), and LV ejection fraction (EF) were measured using a modified Simpson method.All patients were followed for nonfatal events by outpatient clinic or telephone and by medical record review. Cardiac deaths, re-hospitalization for HF, implantation of an LV assist device, and life-threatening ventricular arrhythmia events were defined as cardiac events building the composite end points. Life threatening arrhythmias were defined as ventricular fibrillation (VF) and sustained ventricular tachycardia (VT), which lasted more than 30 seconds, at R–R intervals of ≤ 400 milliseconds.2 test. Continuous variables were compared using a one-way analysis of variance with Bonferroni correction or the Steel–Dwass test for multiple unadjusted comparisons when appropriate after the assessment of normal distribution. Data from the findings of 123I-MIBG scintigraphy between the presence and absence of LGE were compared by using the Wilcoxon–Mann–Whitney test. WR by 123I-MIBG scintigraphy cut-off values were determined based on receiver operating characteristics (ROC) analysis. Univariate and multivariate Cox proportional hazards models were performed to adjust for differences in baseline characteristics or pertinent covariates on outcomes. Multivariable Cox regression analysis was performed using covariates that significantly predicted adverse cardiac events in univariate analysis. Event-free survival curves were drawn according to the Kaplan-Meier method, and the comparison among curves was carried out by the log-rank test. Two-tailed p values of <0.05 were considered statistically significant. MedCalc Version 12.7.8  was used for all analyses.Data are expressed as mean ± standard deviation for continuous variables, and median and interquartile range for non-normally distributed continuous variables. Categorical variables were compared using the xOf 158 DCM patients, 8 with inappropriate CMR images and 2 who were lost to follow-up were excluded, resulting in a final cohort of 148 patients . Cardiac123I-MIBG scintigraphic findings, such as delayed H/M and WR, and the presence or absence of LGE is shown in The relationship between cardiac Of 148 DCM patients, 42 patients experienced cardiac events. Among the 4 groups, 30 (48%) of the 63 WR ≥45%+LGE positive patients experienced cardiac events. On the other hand, 5 (14%) of the 37 WR<45%+LGE positive patients and 6 (20%) of the 31 WR≥45%+LGE negative patients experienced them. Only 1 (5%) of the 18 WR<45% +LGE negative patients experienced a cardiac event. Kaplan-Meier analysis demonstrated that WR≥45% and the LGE positive patients were significantly associated with cardiac events, respectively . On a st123I-MIBG scintigraphy, such as delayed H/M and WR are not associated with the LGE status. (Ⅱ) The combination of WR by 123I-MIBG scintigraphy and LGE on CMR in DCM patients is a relevant prognostic marker of long-term cardiac events compared with either the presence of LGE or WR by 123I-MIBG scintigraphy alone. This study is the first clinical study to demonstrate that the combination of WR by 123I-MIBG scintigraphy and LGE on CMR serves as a strong predictor of very long-term outcomes in DCM patients.The main results are as follows: (Ⅰ) The findings of 123I-MIBG scintigraphy. 123I-MIBG scintigraphy showed myocardial uptake, storage and release mechanisms similar to those of plasma norepinephrine in the cardiac sympathetic nerve terminal. It had properties that allow its use for the noninvasive monitoring of the characteristics of cardiac sympathetic nervous function and of the myocardial β-adrenergic receptor signaling pathway, those were not detected by evaluation of myocardial properties, such as LGE on CMR [Detection of myocardial fibrosis was useful for the risk stratification of DCM patients, because increasing amount of fibrosis was associated with increased LV stiffness and reduced LV relaxation, and resulted in systolic dysfunction . In the E on CMR –24.123I-MIBG scintigraphy [123I-MIBG scintigraphy provides more detailed risk stratification in DCM patients than LGE on CMR alone.In the HF status, the rein-angiotensin-aldosterone system was activated and the angiotensinⅡinduced expression of plasma connective tissue growth factor (CTGF) which was a cytokine that played a key role in the prognosis fibrosis, and expression of transforming growth factor-β(TGF-β) which caused cardiac fibrosis ,26. Moretigraphy ,28. In ttigraphy  both gro123I-MIBG scintigraphy, where the first 3-year survival curve with WR≥50% showed frequent cardiac events, but very few events during the rest of the follow-up periods [123I-MIBG scintigraphy, however in their study, only 24 (28%) patients received them. Compared with their study, almost all the patients receives adequate optimal medical therapy at the time of undergoing 123I-MIBG scintigraphy in our study, so we obtained more comprehensive information for assessing the risk of cardiac events.Momose et al. reported a 10-year long-term prognostic evaluation in DCM patients by  periods . However123I-MIBG scintigraphy could not be included in this study; thus, our conclusions might not be extrapolated to all DCM patients. Furthermore we did not assess LGE quantification and T1 mapping, because there is no current consensus on these techniques in DCM patients [This study is limited by the fact that it was a single center, retrospective study and had a small number of events, which might diminish the power of the drawn statistical inference. An additional limitation is that inappropriate cases of LGE on CMR and of 123I-MIBG scintigraphy and LGE on CMR, which have different properties, might be useful to stratify the future cardiac events than LGE on CMR alone.In DCM patients, the combination of WR by


Reliability of myocardial blood flow (MBF) quantification in myocardial perfusion imaging (MPI) using PET can majorly be affected by the occurrence of myocardial creep when using pharmacologically induced stress. In this paper, we provide instructions on how to detect and correct for myocardial creep. For example, in each time frame of the PET images the myocardium contour and the observed activity have to be compared to check for misalignments. In addition, we provide an overview of the functionality of commonly used software packages to perform this quality control step as not all software packages currently provide this functionality. Furthermore, important clinical considerations to obtain accurate MBF measurements are given. Myocardial blood flow (MBF) quantification in myocardial perfusion imaging (MPI) using Rubidium-82 (Rb-82) PET provides valuable information about the extent and functional importance of possible stenosis.4In our recent study, we observed a myocardial creep during regadenoson-induced stress in 52% of the 104 consecutively included patients.Several steps have to be performed prior to quantification of MBF: (1) dynamic PET acquisition; (2) image reconstruction of the PET data; (3) segmentation of the myocardium contour; (4) derivation of time-activity curves (TACs) of the myocardium and the left ventricle (LV); (5) quality control; and (6) compartmental analyses.7The first step starts with a PET acquisition of typically 7 minutes for both the rest and stress scans directly after Rb-82 administration. Typically, a low-dose CT scan is added to provide an attenuation map of the chest to allow attenuation correction. Next, the PET images are reconstructed in several time frames (step 2) where the first-pass phase or blood-pool phase is generally sampled with small frame durations of five to ten seconds to assure sufficient temporal resolution and prevent under-sampling of the LV TAC.10Subsequently, a myocardium contour is drawn, based on all data acquired during the tissue phase where a steady state is reached, i.e., data acquired >2:15 minutes after Rb-82 administration (step 3),8To obtain reliable MBF measurements, a quality control (step 5) has to be performed which covers the detection and correction of myocardial creep. We previously defined myocardial creep as a gradual decreasing misalignment of the myocardium contour with the activity present in the ventricle and/or myocardium primarily in the inferior direction.4As it is essential to check and correct for myocardial creep,The detection and correction procedure consists of seven steps, as shown in Figure If myocardial creep is present, it can be corrected for by estimating the misalignment in the x-, y- and z-direction for each time frame in which myocardial creep is visible (F). This geometrical translation can be used to realign the observed activity to the myocardium contour by, for example, changing the initial coordinates in the DICOM header of the PET data for each of the time frames containing myocardial creep. The calculation of the TACs then has to be repeated to calculate reliable MBFs (G).It is possible to perform the detection and correction steps in some commercially available software, for example in Corridor4DM v2016. This software automatically derives an image reconstruction of the acquired PET data between 2:30 and 6:00 minutes after Rb-82 administration. After assigning the three cardiac axes, a myocardium contour is automatically drawn in the PET image which can manually be optimized if needed. Next, the user has to manually position a ROI at the center of the mitral valve. This ROI is used to estimate the activity concentration in the LV, as illustrated in Figure Corridor4DM has the option to scroll through the time frames which makes it possible to detect myocardial creep, as shown in Figure Besides detecting myocardial creep, Corridor4DM also provides the possibility to correct for this movement by manually realigning the myocardium contour with the activity for each individual time frame, as shown in Figure As myocardial creep may hamper diagnostic interpretation, accurate detection and correction of myocardial creep are necessary for reliable MBF quantification. Although the detection is most of the time straightforward, correction can be complicated and is not always feasible in the clinical routine due to missing functionality of the used software. From the latest versions of four commonly known and used commercially software packages to quantify MBF using Rb-82 PET, Corridor4DM and QPET (Cedars-Sinai) have the ability to visually evaluate the detection and correction of myocardial creep. SyngoMBF  provides the functionality to automatically detect and correct for motion, such as myocardial creep, but does not provide insight in the accuracy of the correction. Moreover, it is not possible to manually adjust this correction. Lastly, FlowQuant (University of Ottawa Heart Institute) currently does not have a feature for detection and correction of myocardial creep.Measurements of MBF using Rb-82 PET are affected by many methodological factors such as differences in equipment, acquisition and reconstruction settings, processing software, tracer infusion, temporal sampling, and compartmental analyses.Although we focused on Rb-82 PET, it is likely that myocardial creep occurs in a similar way using other PET tracers such as Oxygen-15 water and Nitrogen-13 ammonia. Therefore, detection and correction should always be performed in quantitative PET MPI studies, independent of the tracer.Physicians should always check for accurate myocardial creep correction before clinical interpretation. This can be performed by inspecting the TAC for an elevated peak of the RCA during the first-pass phase in comparison to the LAD and LCX as shown in Figure In conclusion, adequate detection and correction of myocardial creep are crucial for reliable MBF quantification. To adequately perform the required quality control, it is not only important that software packages provide the possibility to detect and correct myocardial creep, but also that users can visually inspect and evaluate these steps. Hence, vendors should provide this functionality or adapt their software accordingly.