Heart failure is a systemic syndrome caused by multiple pathological factors. Current treatments do not have satisfactory outcomes. Several basic studies have revealed the protective effect of trimetazidine on the heart, not only by metabolism modulation but also by relieving myocardial apoptosis, fibrosis, autophagy, and inflammation. Clinical studies have consistently indicated that trimetazidine acts as an adjunct to conventional treatments and improves the symptoms of heart failure. This review summarizes the basic pathological changes in the myocardium, with an emphasis on the alteration of cardiac metabolism in the development of heart failure. The clinical application of trimetazidine in heart failure and the mechanism of its protective effects on the myocardium are carefully discussed, as well as its main adverse effects. The intention of this review is to highlight this treatment as an effective alternative against heart failure and provide additional perspectives for future studies. Cardiovascular disease is one of the most harmful diseases to human health, and heart failure represents the final clinical manifestation of all chronic cardiovascular diseases . AlthougIn Europe, trimetazidine has been used for the treatment of angina pectoris for more than 40 years. In 2000, trimetazidine was shown to directly improve myocardial metabolism by modulating beta oxidation, rather than by indirectly improving the hemodynamics . In the In heart failure, the cardiac contractile function decreases greatly, and the heart is unable to pump enough blood into the artery, resulting in ischemia and hypoxia, venous reflux obstruction, dyspnea, edema, and limb cyanosis. The burden of heart failure has increased to an estimated 23 million people. The incidence of heart failure for all ages is 2%–3% (3%–4% for people over 45 years old and 10% for people over 70 years old) .A variety of external stimuli can promote the development of heart failure, including ischemia/hypoxia, pressure overload, and volume overload . A serieCardiac hypertrophy is characterized by an increased cross-sectional area of cardiomyocytes and enhanced protein synthesis, which is the most obvious and important change in myocardium under pressure or volume overload . In a stIn addition to alterations in cardiomyocytes, myocardial interstitial fibrosis is another important pathological change in heart failure . MyocardThe energy required by myocardial tissue is mainly provided by aerobic oxidation of fatty acids, supplemented by glucose, ketone bodies, amino acids, and lactic acid . AlthougMore than 90% of the ATP in the heart is produced by aerobic oxidation. As mentioned above, in the case of heart failure, the energy supply is insufficient, so the heart preferentially chooses glucose, which leads to more efficient oxidation. Trimetazidine has been shown to reduce the rate of aerobic oxidation of fatty acids by inhibiting the mitochondrial long-chain 3-ketoacyl-CoA thiolytic enzyme, which is a key enzyme of long-chain fatty acid beta oxidation that catalyzes the last step of the fatty acid beta-oxidation cycle; this process indirectly increases the activity of pyruvate dehydrogenase, the rate-limiting enzyme of aerobic oxidation of glucose  Figure . The eviGlycolysis only takes place in the cytoplasm before glucose is fully oxidized in the mitochondria. Glycolysis produces pyruvate together with hydrogen ions; if excess pyruvate cannot successfully enter the mitochondria for oxidation, it will be reduced to lactic acid in the cytoplasm. During heart failure, glycolysis is enhanced, and consequently, hydrogen ions and lactic acid are increased. Indeed, previous clinical studies have shown that the level of plasma lactic acid in patients with heart failure is much higher than that in healthy people . The levTaken together, the positive effects of trimetazidine on energy metabolism for heart failure is three-fold: First, it reduces the fatty acid metabolism by inhibiting the enzyme long-chain 3-ketoacyl-CoA thiolytic; second, it increases glucose metabolism by increasing the rate-limiting enzyme activity of glucose aerobic oxidation; and third, it inhibits excessive glycolysis and reduces the levels of hydrogen ions and lactic acid in the cytoplasm.Cardiomyocyte apoptosis is a key factor that determines the transformation from compensation to decompensation. In a model of coronary artery microembolization-induced heart failure, trimetazidine significantly prevented cardiomyocyte apoptosis . In addiin vivo, the heart benefits from the inhibition of excessive autophagy following the activation of the Akt/mTOR signaling pathway by trimetazidine (Autophagy degrades longevity proteins and damaged or excessive organelles through lysosome-mediated pathways . Trimetatazidine .Connective tissue growth factor (CTGF) is a key molecule in myocardial interstitial fibrosis, which induces fibroblasts to proliferate and secrete extracellular matrix . InteresThe improvement of myocardial interstitial fibrosis increased the efficiency of oxygen utilization by cardiomyocytes, alleviates the impaired contractility and compliance of the myocardium, and improves the symptoms of heart failure. The function of trimetazidine in myocardial fibrosis suggests that the protective effects of trimetazidine on the heart may not only depend on cardiomyocytes; therefore, the effects on non-cardiomyocytes and extracellular remodeling need to be explored further.Heart failure evokes inflammation, and TNF-α, IL-6, IL-18, and atrial natriuretic peptide (ANP) can be induced in pressure overload-induced heart failure. In contrast, the release of cardiac cytokines deteriorate heart function and induce heart failure . TrimetaThe recommendation for the utilization of trimetazidine in stable coronary syndrome is at the IIa level . The 201p < 0.01) (p < 0.01). Ischemic heart disease is an important cause of heart failure, and clinical studies have also shown that trimetazidine has a significant protective effect against chronic ischemic heart failure. A meta-analysis  showed that trimetazidine dramatically increased the ejection fraction of patients with heart failure  . FurtherPrevious clinical studies have shown that the treatment time for trimetazidine ranges from 1 to 48 months. The improvement of the ejection fraction (EF) value of the heart is not obvious in short-term treatment (≤6 months). A previous study of 19 patients with heart failure with EF values less than 40% who received trimetazidine for 1 month showed no significant difference in cardiac function compared to the placebo group . SubsequUnlike short-term treatment, trimetazidine has been shown to improve heart function in chronic treatment for more than 1 year. In a trial of 55 people with heart failure with an EF value of less than 45%, the trimetazidine group showed a significant improvement in EF value compared to the placebo group  after receiving trimetazidine 60 mg daily for 13 months . FurtherHowever, it is worth noting that the population samples included in the current clinical studies on trimetazidine are very small, and there is a probability of overestimating the clinical benefit. Second, the follow-up time was relatively short; only one study lasted 48 months, and most lasted 3–6 months. In addition, the side effects of trimetazidine have not been thoroughly evaluated. Therefore, large-scale, prospectively designed, randomized, double-blinded trials are still required to verify the cardiac benefits of trimetazidine and evaluate its adverse effects .In addition to improving the EF value, trimetazidine can also improve arrhythmia by reducing heart rate variability and shortening the QTc interval . In addip < 0.01), as well as significantly improve the exercise ability of patients   . Further < 0.05) . Trimeta < 0.05) . In addi < 0.05) . Therefop < 0.01)  . In a ra < 0.01) . Therefo < 0.01) . One exp < 0.01)  and impr < 0.01) . However < 0.01) , while tClinical pharmacological studies suggest that although common adverse reactions of trimetazidine can be found occasionally, such as gastrointestinal discomfort, nausea and vomiting, and rarely reported thrombocytopenia, agranulocytosis, and liver dysfunction , these aUntil now, heart failure has been a huge challenge for cardiovascular doctors. Myocardial hypertrophy, apoptosis, myocardial interstitial fibrosis, and myocardial metabolic remodeling are all important pathological factors leading to heart failure. There are a variety of medicines used for the treatment of heart failure, among them, trimetazidine has a unique position in cardiovascular therapy because of its ability to optimize energy metabolism . TrimetaMany basic studies have confirmed that trimetazidine has positive effects, including against myocardial fibrosis and apoptosis, as well as anti-inflammatory effects. Double-blind controlled trials have demonstrated the effectiveness of trimetazidine in ischemic and diabetic heart failure, but whether trimetazidine has a good protective effect on other types of heart failure with decreased ejection fractions remains unknown. In addition, the effect of trimetazidine on heart failure is not limited to cardiomyocytes, and clinical studies have found that trimetazidine also improves EDR  and reduHeart failure with preserved ejection fraction accounts for a large proportion of patients with heart failure , and itswww.editage.cn) for English language editing.HS designed and drafted the manuscripts; YP, NZ, WH, and DW critically revised the entire manuscript; and all authors approved the entire submitted and final versions. We would like to thank Editage .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Figure 1) and the fixed-open pulmonary valve to which PR was attributable . Aortic regurgitation is among causes of post-LVAD heart failure; the contributing factors are inadequate LV unloading, permanently closed AV, commissural fusion, changes in valve leaflets, systemic hypertension, and support period.,A 29-year-old woman with idiopathic dilated cardiomyopathy was implanted with durable left ventricular assist device  as a bridge-to-transplantation. She repeatedly experienced heart failure hospitalization due to aortic regurgitation (AR) and right ventricular (RV) dysfunction since 2 years post-LVAD. The heart failure symptoms got refractory three and half years post-LVAD. Echocardiography demonstrated severe AR Figure S1European Heart Journal - Case Reports online.Consent: The Informed consent for submission and publication was obtained from the parents of the patient because she was deceased.Funding: This study was supported by the JSPS KAKENHI grant 19K17567 to T.H.Conflict of interest: none declared.ytaa406_Supplementary_DataClick here for additional data file.


Cardiac MR (CMR) is the imaging modality with the best potential to characterise the myocardial effects of anthracycline therapy in the short and long term. We sought to assess this potential in adult long-term survivors of childhood cancer. Subjects were identified from our hospital's Oncology database, and were specifically selected if they had had acute leukaemia or Wilms tumour, had received anthracycline treatment for childhood cancer without radiotherapy more than ten years prior, and had suffered cardiotoxicity at any time, recognised by an echocardiographic fractional shortening <25%.2, and the median time since cessation of chemotherapy was 16 (11 – 26) years. All patients scanned claimed to be asymptomatic.Of a total of 43 patients fitting these criteria, 18  were contactable and all agreed to be scanned. Their median (range) age at cancer diagnosis was 4 (1 – 12) years, the total anthracycline dose ranged from 180 – 360 g/m2 for males and 53 (43 – 71) g/m2 for females. Following gadolinium, and using conventional techniques, there was no evidence of late enhancement of the myocardium.Four male patients had normal LV volumes and systolic function. The remaining 14 patients all had elevated LV end-systolic volumes, and 5 of these had elevated LV end-diastolic volumes indexed for body size. The median (range) LV ejection fraction (LVEF) was 55% (33–71%), with LVEF < 50% in 3/17  patients. The indexed LV mass was low for the whole group, with median (range) mass being 62 (54 – 79) g/mThis pilot study specifically assessed patients identified on echocardiography to have had anthracycline-induced cardiac damage. A minority of these patients were found to have normal CMR findings. Most patients had poorly contractile LV myocardium, with low LV mass. Fibrosis or scarring, sought using conventional late gadolinium imaging techniques, was not evident in any patient. Further work is needed to find discriminative CMR indices to describe the long-term effects of myocardial toxicity and to predict prognosis in this patient group. See Figures


Myocardial hemorrhage (IMH) and persistent microvascular obstruction (MVO) are associated with impaired myocardial recovery and adverse clinical outcomes in STEMI patients. However, their relationship with circulating inflammatory biomarkers is unclear in human patients.Twenty consecutive patients referred for primary percutaneous coronary intervention of first STEMI were included in a prospective study. Blood sampling was performed at admission, 4, 12, 24, 48 hours, 7 and 30 days after reperfusion for inflammatory biomarker  and neutrophils count) assessment. At seven days, cardiovascular magnetic resonance (CMR) was performed for infarct size, MVO and IMH assessment. Median infarct size was 24.6% Interquartile range (IQR) [12.0–43.5] of LV mass and edema was 13.2% IQR [7.7–36.1] of LV mass. IL-6 reached a peak at H24 (5.6 pg/mL interquartile range (IQR) [2.5–17.5]), CRP at H48 (11.7 mg/L IQR [7.1–69.2]), fibrinogen one week after admission (4.4 g/L IQR [3.8–6.7]) and neutrophils at H12 (9.0 G/L IQR [6.5–12.7]). MVO was present in 11 patients (55% of the study population) and hemorrhage in 7 patients (35%). Patients with IMH had significantly higher IL-6, CRP, fibrinogen, and neutrophils levels compared to patients without IMH. Patients with persistent MVO had significantly higher CRP, fibrinogen and neutrophils level compared to patients without MVO, but identical IL-6 kinetics.In human patients with acute myocardial infarction, intramyocardial hemorrhage appears to have a stronger relationship with inflammatory biomarker release compared to persistent MVO. Attenuating myocardial hemorrhage may be a novel target in future adjunctive STEMI treatments. Cardiovascular disease, including acute myocardial infarction (MI), is the leading cause of death in Western countries ,2. EarlyContrast-enhanced cardiovascular magnetic resonance (CMR) is a non-invasive technique that allows the accurate assessment of infarct size, edema, and areas with persistent microvascular obstruction (MVO) or intramyocardial hemorrhage (IMH) . MVO andThe primary objective of our study was to assess the relationship between markers of CMR severity (IMH and persistent MVO) and the kinetics of the main pro-inflammatory biomarkers  in patients with a first acute ST-elevation myocardial infarction (STEMI) referred for primary percutaneous coronary intervention.Consecutive patients admitted with a STEMI and referred for primary percutaneous coronary intervention (PCI) were prospectively enrolled at a single tertiary university hospital. STEMI was defined by the presence of clinical symptoms associated with an ST-elevation of more than 2 mm in two contiguous leads on a standard 12-lead electrocardiogram, or recent Left Bundle Branch Block (LBBB), and presentation within 12-hours of symptom onset according to the European Society of Cardiology .Only patients with a single occluded infarct-related artery  and optimal reperfusion  were included. To obtain a broad sample of infarct size, half of the patient population had a STEMI in the anterior territory and the other half in the inferior territory (LAD and RCA culprit coronary respectively). These selection criteria were set before patient enrollment.Patients were included if they had: (i) no previous MI, (ii) demonstrated acute single-vessel occlusion; right coronary artery or left coronary artery, (iii) underwent optimal revascularization with TIMI flow ≥ 2 post PCI (iv) had no contraindications to CMR imaging.Reasons for non-inclusion were as follow: history of prior myocardial infarction, cardiogenic shock, prior cardiac arrest, any contraindication to cardiac CMR , presence of permanent atrial fibrillation, unconscious patient, severe renal insufficiency , long-term immunosuppressive therapy or chronic immunosuppression.Our institutional review board and Ethics Committee approved this prospective monocentric study. All patients gave written informed consent. The trial design and protocol have been registered ClinicalTrials.gov Identifier: NCT02823886.Seven blood samples were collected for each patient. Venous blood samples were collected at admission to the hospital immediately before PCI and 4 hours, 12 hours, 1 day, 2 days, one week and one month following successful revascularization . Each blood sample was centrifuged and treated carefully and stored at the NeuroBioTec Biological Resource Center at -80° C within 4 hours of blood sampling. All samples from our study population were thawed only once to avoid cytokine alteration.IL-6 concentrations were measured by the Human IL-6 Quantikine ELISA Kit . The limit of detection was 0.7 pg/mL. C-reactive protein (CRP) was determined using immunoturbidimetric methods. Fibrinogen levels was measured in plasma using the Clauss method. Leucocytes and neutrophils count were assessed using fluorescence-activated cell sorting (XN-9000 SYSMEX) at the Hospices Civils de Lyon laboratory.All patients were scanned on a 1.5T CMR MAGNETOM Avantofit system . An intravenous bolus of gadolinium  was injected by a power injector  flushed by 15 ml of saline serum. Late gadolinium enhancement (LGE) was evaluated 10 minutes after contrast injection using a 3D-gradient spoiled TurboFLASH sequence with a selective 180° inversion recovery pre-pulse, in the short axis covering the whole ventricle. LV function at rest was assessed with retrospective ECG-gated steady-state free precession pulse cine sequences (cine TrueFISP) in long and short axis views in the true heart axis. Left ventricular ejection fraction (LVEF), LV end-diastolic volume (EDV), LV end-systolic volume (ESV) and myocardial mass were calculated for each patient with the post-processing software CMR42 .Infarct size was assessed on the 3D data sets by manual planimetry of the LGE images using the post-processing software Osirix . Thus, for all slices infarct absolute mass in grams was measured according to the following formula:Infarct mass (g) = ∑ (hyper enhanced area(cm2)) ×slice thickness (cm)×myocardial specific density . Relative infarct size (%) was obtained by the ratio of (absolute infarct mass (g)/ LV myocardial mass (g)) ×100.Edema was quantified in T2 map images using the full-width at half maximum method. (FWHM). Edema was expressed as a percentage of the LV myocardial mass.Persistent microvascular obstruction was detected on LGE images as hypointense regions in the core of the infarct.Intramyocardial hemorrhage was identified using T2*-weighted imaging as a hypointense region of reduced signal intensity within the infarcted area, with a T2* value of <20 ms. Delineation of IMH and MVO was performed by two experienced readers (N.M and C.D.B).Levels of inflammatory biomarkers were identified as not normally distributed. Therefore, those variables were expressed as medians, and interquartile range (IQR) or 95% confident interval and non-parametric tests were used for comparison between groups. At each time-point, comparisons between groups were performed using a Mann-Whitney test. Categorical variables were analyzed using Fisher's exact test. Correlations were done using Pearson correlation method. We used GraphPad Prism 8.4.2. A p-value <0.05 was considered significant.Table 1. Briefly, they were 55±15 years old with 85% males. There were 55% of anterior MI and 45% of inferior MI. CMR imaging was performed for all the patients at a median of 8 days . Microvascular obstruction with late gadolinium enhancement CMR was present in 11 patients (55%). CMR infarct parameters are presented in Table 2.Twenty consecutive patients referred for primary percutaneous coronary intervention of first anterior or inferior STEMI were included. Patient characteristics at baseline are presented in ange IQR –8 days) All patients underwent blood sampling at seven-time points : before PCI, 4 hours (H4), 12 hours, 1 day, 2 days, 1 week and 1 month following successful revascularization.Fig 2. In our cohort we observed that IL-6 reached a peak at 5.6 pg/mL IQR [2.5–17.5] twenty-four hours after admission . C-reactive protein reached a peak forty-eight hours after admission at 11.7 mg/L IQR [7.1–69.2] . Fibrinogen reached a delayed peak seven days after admission at 4.4 g/L IQR [3.8–6.7] . Neutrophils reached an early peak twelve hours after admission at 9.0 G/L IQR [6.5–12.7] . The peak of each biomarker was significantly correlated with IS assessed by CMR . Furthermore, the peak of each biomarker was inversely correlated with LVEF assessed by CMR .Global kinetics of the four biomarkers is presented on The association between inflammatory biomarkers kinetics and IMH are reported in Fig 3A). Patient with IMH had higher CRP and fibrinogen levels one week after the admission for MI compared to patients without IMH  . Patients with IMH had significantly higher neutrophils count levels from H4 to 1 week following MI with a peak at H4  .Patients were divided into two groups according to the presence (n = 7/17) or absence (n = 10/17) of IMH. IMH was undetermined for 3 patients. Patients with IMH had significantly higher IL-6 peak levels (at H24) compared to patients without IMH  . However, patients with MVO had higher CRP level at H24 and H48 compared to patients without IMH . Patients with MVO had higher fibrinogen levels 1 week after MI compared to patients without MVO  . They also showed higher neutrophils level count from H4 to H24 following MI with a peak at H4  .Patients were divided into two groups according to the presence (n = 11/20) or absence (n = 9/20) of MVO. Patients with MVO had similar IL-6 kinetics compared to patients without IMH  intramyocardial hemorrhage is significantly related to systemic inflammation with a strong association with pro-inflammatory biomarkers ; 2) persistent microvascular obstruction was also associated with greater levels of inflammatory biomarkers but this association seemed to be weaker.et al. showed an accurate kinetics of inflammatory biomarkers but this kinetics was limited to the first 24 hours and it was evaluated in patient undergoing transcoronary ablation of septal hypertrophy whose pathophysiology differs from STEMI [Our study assessed kinetics levels of inflammatory biomarkers within 1 month and to date, it is the most detailed kinetics after STEMI. Liebetrau om STEMI . We obseThis is the first study to systematically study the relationship between different CMR markers  with inflammation biomarkers at the acute phase of reperfused ST-elevation myocardial infarction (STEMI). The results of our study show that IMH is significantly associated with a pro-inflammatory pattern.et al. [In patients with STEMI, MVO represents a failure to restore optimal myocardial reperfusion despite re-permeabilization of the epicardial artery by PCI . It is set al.  in a preet al. .Following myocardial infarction, the increased IL-6 synthesis and signaling by myocytes lead to the preservation of heart tissue, in which damage is limited by reducing cell contractility and inducing an anti-apoptotic program –26. Howeet al. [et al. [Concerning the presence of MVO, we found a significant association with the CRP peak level. This result is in agreement with the results of Ørn et al.  showing  [et al.  recentlyTaken together, our results show that IMH detected by CMR is associated with a systemic pro-inflammatory reaction potentially involved in the poor prognosis associated with this marker. The link between MVO and systemic inflammatory response appears to be weaker.The clinical perspectives of our study are important. Indeed, the detection of myocardial hemorrhage by CMR may allow targeting patients with the highest inflammatory burden. These patients would be the most likely to benefit from the anti-inflammatory therapies under investigation.A significant limitation of our study is related to the small sample size of our population. However, our population was homogeneous with infarct sizes, and a frequency of occurrence of MVO and IMH comparable with recent studies . This liDespite the high number of blood samples taken, considering the short half-life of different markers measured, it is possible we missed the peak values of its marker. Another important limitation is that the biomarkers used to evaluate inflammation are not specific . They reflect the subsequent consequences of the inflammatory activity but do not provide information on local tissue inflammation. Furthermore, if we have identified a relationship between IMH and systemic inflammation, the absence of anatomopathological comparison makes it difficult to describe a causal relationship.Finally, although the detection of myocardial hemorrhage by T2* sequences is currently the gold standard , T2* acqIn human patients with acute myocardial infarction, myocardial hemorrhage appears to have the strongest relationship with inflammatory biomarker release compared to persistent MVO or myocardial edema. Attenuating myocardial hemorrhage-induced inflammation may be a novel target in future adjunctive STEMI treatments.S1 FigST2 (A), IL-18 (B), IL-10 (C), TGF-β (D), IL-8 (E), MCP1 (F) kinetics according to the presence of IMH or no IMH on cardiac magnetic imaging 1 week after STEMI. Data are expressed as median with interquartile range (IQR). ST2: Interleukin 1 receptor-like 1, IL-18: Interleukin-18, IL-10: Interleukin-10, TGF-β: Transforming Growth Factor-β, IL-8: Interleukin-8, MCP1: Monocyte Chemoattractant Protein 1. Differences between curves were assessed using a mixed-effect model.(TIF)Click here for additional data file.S2 FigST2 (A), IL-18 (B), IL-10 (C), TGF-β (D), IL-8 (E), MCP1 (F) kinetics according to the presence of MVO or no MVO on cardiac magnetic imaging 1 week after STEMI. Data are expressed as median with interquartile range (IQR). ST2: Interleukin 1 receptor-like 1, IL-18: Interleukin-18, IL-10: Interleukin-10, TGF-β: Transforming Growth Factor-β, IL-8: Interleukin-8, MCP1: Monocyte Chemoattractant Protein 1. Differences between curves were assessed using a mixed-effect model.(TIF)Click here for additional data file.S3 FigST2 (A), IL-18 (B), IL-10 (C), TGF-β (D), IL-8 (E), MCP1 (F) kinetics within the first month after STEMI. Data are expressed as median with interquartile range (IQR). H4: four hours after admission, H12: twelve hours after admission, H24: twenty-four hours after admission, H48: forty-eight hours after admission.(TIF)Click here for additional data file.


With further subgrouping analysis based on history of diabetes or dyslipidemia, the sensitivity and specificity showed similar results. Based on the currently collected data and image acquisition conditions, the sTPD parameter has a clinical role for the diagnosis of CAD with a cutoff value of 3.5%.This study aimed to investigate the diagnostic performance of semi-quantitative parameters of thallium-201 myocardial perfusion imaging (MPI) for coronary artery disease (CAD). From January to December 2017, patients were enrolled who had undergone Tl-201 MPI and received cardiac catheterization for coronary artery disease within three months of MPI. Receiver operating characteristics (ROC) analysis was used to determine the optimal cutoff values of semi-quantitative parameters. A comparison of the sensitivity and specificity of these parameters based on different subgroupings was further performed. A total of 130 patients were enrolled for further analysis. Among the collected parameters, the stress total perfusion deficit (sTPD) had the highest value of the area under curve (0.813) under the optimal cutoff value of 3.5%, with a sensitivity and specificity of 73.5% and 74.5%, respectively ( Coronary artery disease (CAD) is a leading cause of death among adults in the developed world . The risIn the past 40 years, MPI has been widely used in the detection and evaluation of coronary artery disease. The inspection methods have changed; for example, they depend on different inducers of the stress phase  , differeMany different semi-quantitative parameters are currently being developed, including a 17-segment, five-point scoring system , the lefTherefore, the goal of this study was to compare the semi-quantitative parameters obtained by Tl-201 myocardial perfusion imaging with the results of cardiac catheterization. We tried to find the best cutoff values for the semi-quantitative parameters so that the imaging results could provide more diagnostic accuracy.The study was conducted retrospectively to analyze the medical records of patients who received single-day, stress and resting Tl-201 myocardial perfusion imaging in the Nuclear Medicine Department in Kaohsiung Medical University Hospital. The inclusion criteria were as follows: patients who (a) had undergone a single-day, stress and testing Tl-201 myocardial perfusion study, (b) were aged over 18 years, and (c) had had cardiac catheterization confirmation for coronary artery disease within 3 months of myocardial perfusion imaging. Patient consent was waived because all of the clinical data were collected via the review of medical charts retrospectively. However, written permission from patients upon the clinical visit and examination were acquired. The study design was approved by the Institutional Review Board in our hospital (KMUHIRB-E(I)-20180299, Date: 9 November 2018). Clinical data were collected from January to December 2017.Before the myocardial perfusion imaging, patient baseline blood pressure was recorded. Dipyridamole with a dosage of 0.56 mg per kilogram body weight was used to induce the vasodilatation of coronary arteries. With electrocardiogram (ECG) monitoring, a slow intravenous injection of dipyridamole for 4 min was performed. Four minutes later, 3 mCi of the radioisotope Tl-201 was then injected. Single photon emission computed tomography (SPECT/CT) imaging was performed with an L-shaped, double-headed gamma-camera  equipped with a low-energy, high-resolution collimator. The collection conditions were 180-degree arc photography with step capture from the patient′s right anterior oblique (RAO) position to the left posterior oblique (LPO) position (RAO 45 degrees to LPO 45 degrees). The matrix size of each image was 64 × 64, and one set was taken for 60 s to collect 32 plane images. Three to four hours after the stress imaging acquisition, the patients underwent resting imaging with the same acquisition conditions as for the stress imaging.The semi-quantitative parameters were obtained by using the automated computer software AutoQUANT Version 6.5  to analyze the myocardial perfusion images. This study explored the relevant parameters of the 17-segment, five-point scoring system, TID, LHR and TPD. These parameters have high reproducibility and good standardization, which can increase the objectivity of diagnosis .The perfusion territories of the three major coronary arteries of the left ventricle were divided into 17 regions on the bull’s eye projection, short axis and long axis by the method of the 17-segment, five-point scoring system. Every area had a score from 0 to 4 to evaluate the degree of perfusion defects. The higher the score, the more severe the ischemia caused by vessel stenosis . The summed stress score (SSS) stands for the summation of the scores of all 17 segments under stress imaging. Similarly, the summed rest score (SRS) stands for the summation of the scores of all 17 segments under the resting image. The summed difference score (SDS) can be obtained by subtracting the SRS from the SSS. The SDS parameters determine whether myocardial cells are ischemic and the severity of ischemia.When the heart is under the stress phase, the pressure in the left ventricle at the end of diastole increases and the pressure in the epicardium decreases. This causes a hypoperfusion of the subendocardial area, which results in a significant reduction in the radioactivity taken up. The image shows a thinner left ventricular myocardial wall and a larger ventricular cavity and thus reveals a picture of left ventricular dilation. TID stands for transient ischemic dilation of the left ventricle. The ratio is obtained as the stress left ventricular endocardial volume divided by the resting left ventricular endocardial volume.The LHR is defined as the ratio of the scintigraphic counts of the left lung divided by the scintigraphic counts of the left ventricular myocardial area obtained in the stress phase image. When the coronary stenosis occurs, the increased blood flow cannot enter the left ventricle and gathers in the direction of the pulmonary vein. Radiopharmaceuticals also accumulate in the lung tissues along with the blood flow, and a “brighter” image is observed in bilateral lungs, which, in turn, leads to a higher LHR.The TPD is a parameter that combines the severity and extent of perfusion defects. The TPD is defined as follows:In the equation, a and p represent the radial coordinates of the polar map, while A and P represent the maximum numbers of samples in each dimension. The score  means the pixel score at the location  on the polar map. Theoretically, the maximum value for TPD was 100% for a case without visible uptake  in the whole myocardium of the left ventricle. The value can be from 0 to 100%. The larger the value, the greater the severity and extent of myocardial ischemia. The TPD parameters can be subdivided into the TPD of the stress phase  and resting phase . The TPD of the stress phase minus that of the resting phase is the ischemic TPD parameter .Cardiac catheterization  is to insert a special sterile catheter into the coronary artery of the heart along the direction of blood flow. It is the gold standard for diagnosing coronary artery disease and an invasive procedure in which the treatment stents can be placed. We recorded patients as positive for CAD if one or more coronary artery occlusions with diameter stenosis ≥50% in the cardiac catherization procedure were identified; otherwise, they were defined as negative for CAD.p value < 0.05 was considered statistically significant.The Kolmogorov–Smirnov test was used for normality checks. Continuous variables are expressed as mean ± standard deviation. The optimal cutoff values for the variables were obtained using analysis of receiver-operating characteristics (ROC) curves with the highest Youden Index . The ROCThere were 1685 patients that underwent single-day, stress and resting myocardial perfusion imaging during the period of the collection dates. A total of 130 subjects who met the inclusion criteria were enrolled in this study. Their demographic and clinical characteristics regarding age, gender and relevant clinical history are summarized in Among the 130 patients examined, the mean values of the semi-quantitative parameters related to myocardial perfusion imaging were as follows: TID, 1.06 ± 0.16; LHR, 0.38 ± 0.07; SSS, 7.49 ± 7.77; SRS, 3.86 ± 6.25; SDS, 3.18 ± 3.17; sTPD, 8.99 ± 10.98; rTPD, 7.39 ± 9.25; and iTPD, 1.60 ± 6.40.p < 0.0001; 95% CI: 0.741–0.884). The sensitivity and specificity were 73.5% and 74.5%. The SSS and SRS have equivalent AUCs . Due to the overlapping 95% confidence intervals, the differences among the SSS, SRS and sTPD became insignificant. The case was the same for the pairwise comparisons of the ROC curves with sTPD. The ROC analysis for pooled parameters  was further conducted and showed an AUC of 0.811 (with a 95% CI of 0.733–0.874).The correlations between the semi-quantitative parameters obtained by myocardial perfusion imaging and CAD using the ROC curve were analyzed . The optp = 0.0010), patients who had type 2 diabetes (p = 0.0009), dyslipidemia (p = 0.0070), and end-stage renal disease (p = 0.029) or not.Using Spearman′s rank correlation test, the sTPD was positively correlated with patient age; however, the correlation was not statistically significant. Then, the Mann-Whitney U test was applied to test the difference of sTPD according to different clinical settings, as listed in Then we divided patients into subgroups according to gender, history of type 2 diabetes and dyslipidemia due to their statistical significance. The optimal cutoff values of sTPD in each subgroup were calculated. Further comparison of the difference of AUC, sensitivity and specificity corresponding to the optimal cutoff value of each subgroup was conducted.All 130 subjects were classified into male or female, diabetes-positive or negative, and dyslipidemia-positive or negative subgroups. The optimal cutoff values for sTPD in each subgroup are shown in The results indicated that every subgroup has statistically significant results for retrieving the optimal cutoff values. The optimal cutoff values for sTPD and its corresponding sensitivity and specificity are 8.5%, 54.9% and 93.1% for all male patients; 3.0%, 66.7% and 77.8% for all female patients; 8.5%, 53.1% and 100% for diabetes-positive patients; and 8.5%, 64.4% and 94.1% for dyslipidemia-positive patients. The 95% CIs ranged from 0.588 to 0.950.Gated MPI with SPECT provides clinical information regarding the myocardial perfusion status, e.g., reversible or fixed perfusion defects, regional wall motion, and LV volumes/functions, as well as regional wall thickening, etc. In some clinical situations, visual interpretation may be feasible; however, there are some problems, which include the time-consuming analysis and lack of reproducibility. Thus, it depends a lot on the observer′s expertise.Currently, a number of validated software packages, which are distributed by the main vendors of nuclear medicine imaging equipment, are available for automated quantification ,26,27,28Based on comparison with normal limits at a regional (per vascular territory) or global (per ventricle) level, there are various quantitative parameters derived from myocardial perfusion scans. For example, the extent of a perfusion defect can be expressed as the percentage of pixels in the polar map for which the severity is greater than a predefined statistical threshold . This measurement also reflects the size of the perfusion defect. The TPD, employed by the Cedars-Sinai Quantified Perfusion SPECT (QPS) module , is the This retrospective study was conducted using the correlation of semi-quantitative parameters from Tl-201 myocardial perfusion imaging and positivity for CAD. After using ROC curve analysis, sTPD, SSS and SRS had equivalent AUCs, for which the pairwise comparisons of ROC curves were insignificant. The Youden indices of these three parameters were all over 0.47. The AUC and its 95% CI for the pooled parameters  are similar to those of sTPD alone. In the clinical setting, the sTPD is easily assessed, in which both pixel-based severity and extent are presented. In our report, since the case number of patients was not large, some settings of the parameters may not be statistically meaningful. Instead, the parameters were determined by the convenience of image interpretation. Thus, the sTPD was selected as the studied parameter. According to our study results, the best cutoff value for sTPD was more than 3.5%. However, the TPD calculated in the current medical software is an integer, and there will be no numbers after the decimal point. Therefore, we defined the threshold of sTPD more than 3.5% as more than 4% in the clinical setting. Under the threshold of the stress phase TPD being equal to or more than 4% for predicting CAD, the sensitivity and specificity are 73.5% and 74.5%, respectively.There has been related research investigating different semi-quantitative parameters based on different subjects’ own conditions, and the thresholds for the diagnosis of CAD have been different. For example, among patients with type 2 diabetes, the TID value for CAD diagnosis has varied . The thrThe results of the current study show that sTPD played a helpful role in the diagnosis of CAD. Other literature has also confirmed that sTPD was more repeatable than subjective visual interpretation ,33. It bThere are some limitations in the current study. It was a retrospective study dealing with a relatively small patient population, where male patients predominated. A pharmaceutical induced-stress protocol using dipyridamole was used rather than the treadmill induced-stress test. We used coronary angiography as the gold standard for the diagnosis of CAD, and the criterion for positivity for CAD was defined as diameter stenosis ≥50% on the coronary angiography. Gould et al. had mentioned that compensatory changes of the distal coronary vascular bed varied depended on different degrees of coronary stenosis . Based oBased on the currently collected data and image acquisition conditions, the sTPD parameter has a clinical role for the diagnosis of CAD with a cutoff value of 3.5%. This result may improve the accuracy of CAD diagnosis.


Hypertrophic cardiomyopathy (HCM) patients with similar basal septal hypertrophy (BSH) can have significantly different degrees of dynamic obstruction, quantified by the left ventricular outflow tract gradient (LVOTG). Furthermore, an elevated LVOTG can be seen even with minimal BSH. Using advanced 3-dimensional whole-heart sequence on cardiac magnetic resonance (CMR), we observed a spectrum of acuity in the LV to aortic root angle (LVARA) in our study population of HCM patients Figure .Figure 1In HCM patients, we sought to determine if a steeper LVARA was associated with an increased LVOTG, independent of BSH.We studied 153 consecutive patients (≤ 65 years) with echo-documented HCM who underwent standard CMR  along with whole-heart 3D MR angiogram which was a navigator-assisted free-breathing, ECG-triggered, fat saturated, T2-prepared, segmented 3D SSFP sequence. Imaging parameters were as follows: TR = 3.8 ms, TE = 1.9 ms, flip angle = 70°, acquired matrix = 175–216 (phase direction) by 256 (readout direction) points (no interpolation), Grappa factor of 2, 24 reference lines and sampling bandwidth = ± 125 kHz. Typically, 60–70 slices were acquired at 1.5 mm thickness (interpolated) in order to cover the heart. The in-plane resolution was typically 1.3–1.6 mm. Images were acquired during a 150 msec data acquisition window in mid-to-late diastole. LVARA, LV volumes (indexed to body surface area) and BSH were measured on CMR. Maximal (resting or provocable) LVOT gradients were recorded on echocardiography. Inter and intra-observer concordance of LV-aortic root angle measurement was assessed in 14 HCM patients using intraclass correlation coefficient (ICC).2 ± 11 and 84 ml/m2 ± 16, respectively. Univariate and multivariate associations between maximal LVOT gradient and various factors are shown in Table The baseline characteristics were as follows: mean age 46 ± 14 years, 68 % male, 36 % hypertensives, 73 % were on beta-blockers. The mean LVARA, maximal LVOT gradient, BST, end systolic and end diastolic volume indexes were 134° ± 10, 82 mm Hg ± 60, 1.98 cm ± 0.6, 32 ml/mIn patients with HCM, a steeper LVARA predicts an increased LVOTG, independent of BSH. Steep LVARA, which likely represents accelerated remodelling of the LVOT, may explain why HCM patients with similar degree of BST have different degrees of dynamic LVOT obstruction. The prognostic importance of steep LVARA remains to be determined. This study demonstrates the clinical utility of multi-modality imaging, including CMR, in further understanding the varied phenotypic presentation and complex pathophysiology found in HCM.


Ross operation might be a valid option for congenital and acquired left ventricular outflow tract disease in selected cases. As the pulmonary autograft is a living substitute for the aortic root that bioinspired the Ross operation, we have created an experimental animal model in which the vital capacity of the pulmonary autograft (PA) has been studied during physiological growth. The present study aims to determine any increased stresses in PA root and leaflet compared to the similar components of the native aorta. An animal model and a mathematical analysis using finite element analysis have been used for the purpose of this manuscript. The results of this study advance our understanding of the relative benefits of pulmonary autograft for the management of severe aortic valve disease. However, it launches a warning about the importance of the choice of the length of the conduits as mechanical deformation, and, therefore, potential failure, increases with the length of the segment subjected to stress. Understanding PA root and leaflet stresses is the first step toward understanding PA durability and the regions prone to dilatation, ultimately to refine the best implant technique. International guidelines and position papers from professional societies recommend Ross operation as a valid option for congenital and acquired left ventricular outflow tract disease in selected cases ,5,6,7,8.As the pulmonary autograft is a living substitute for the aortic root that bioinspired the Ross operation, we have created an experimental animal model in which the vital capacity of the PA has been studied during physiological growth. Therefore, we have reinforced the PA with resorbable scaffolds or semi-absorbable composite prostheses capable of mediating a biomechanical effect and counteracting the abnormal process of the extracellular matrix disruption leading to PA dilatation when the conduit is subjected to systemic pressure. We further revealed the mechanisms of growth, remodeling, and stress shielding of the reinforced PA by means of an experimental large animal model supported by an ex vivo mathematical and physical model ,36,37,38This study aims to integrate the animal pattern with mathematical models from biomechanics. In detail, the present study aims to determine any increased stresses in PA root and leaflet compared to the similar components of the native aorta. Understanding PA root and leaflet stresses is the first step toward understanding PA durability and the regions prone to dilatation, ultimately to refine the best implant technique. First, we assumed the nonlinear constitutive stress–strain relationship, as evidenced by the mechanical tests, to examine the mechanical differences between the two vessels along the circumferential and the longitudinal directions ,39. SecoWe developed a “Ross experimental project” that is a European partnership of investigators who aim to provide the basis for studying how to prevent the expansion of pulmonary autograft used in aortic valve surgery. The project was initiated in January 2011 and required the collaboration of the Department of Cardiac Surgery of Centre Cardiologique du Nord, la Pitie Salpetriere Hospital and the Institute of Cardiovascular and Medical Sciences, University of Glasgow.The primary objective of the Ross experimental project was to combine the individual data of the experimental animal model by comparing nonreinforced and reinforced pulmonary autograft to provide an ideal substitute for aortic valve surgery. Using an experimental model of growing sheep based on the simulation of the Ross operation, the experimental project Ross estimated that the analysis of the results would have detected significant differences in the pulmonary autograft morpho-structure at the 6-month follow-up. The pulmonary autograft was inserted in the descending aorta, while the right ventricle outflow tract was reconstructed with a fresh homograft from another lamb of the same age and weight or native pericardial neo-conduit ,33,34,37In the first experimental studies, the comparison between reinforced and nonreinforced pulmonary autograft took into account the variable of somatic growth that is fundamental when the Ross operation is performed during the patient’s growing age ,36,39. IThe results were presented and discussed in June 2013 at the Seventh Biennial Congress of the Society for Heart Valve Disease and Heart Valve Society of America in Venice  . SubsequThe technical details of the experimental model of Ross Operation have been previously described ,34,37. Bn = 10 lambs received the prosthetic reinforcement of the PA. The mesh was cut into a rectangle measuring 20 mm in height corresponding to the height of the pulmonary autograft, rolled on a metallic candle, and then fixed with a suture, so as to create a cylinder with an internal diameter of 10 mm  and aortic root (n = 6) preserving the native valve. All samples were retrieved from the heart under standard aseptic conditions in a multi-organ heart beating donors’ (MOHBD) study cohort. All hearts were treated at the Saint Louis Tissue Bank, and processing started within 24 h after procurement. Tissue preparation was carried out in a clean room of Class A with vertical laminar flow in a Class C environment following the quality standards for tissues and cells strictly. After dissection, the heart valves and conduit were macroscopically examined, and those that were considered suitable for implant were immersed in a solution of an antibiotic cocktail. Three different types of antibiotics were added to 500 mL of RPMI 1680  to a final concentration of 320 mg/L gentamicine , 500 mg/L vancomycine , and 600 mg/L clindamycine . The antibiotic incubation proceeded for a minimum of 20 h at 4 °C. After decontamination, tissues were measured, transferred into a cryoprotective solution of 10% DMSO  and 20% human albumin  in RPMI, and sealed in a double pouch . The pouches were frozen in a program-controlled-rate freezer until −160 °C and then stored at the vapor phase of liquid nitrogen in a storage tank (−150 to −180 °C).Thirty-six mechanical stress–stretch tests were performed on 3.5 cm of animal explanted pulmonary  at the beginning of tissue processing (samples from myocardium and transport solution); (2) after antibiotic incubation (samples from myocardium). Samples (1) and (2) were added to a Schaëdler broth  and incubated for 10 days at 37 °C. The liquid medium was then homogenized and seeded; on the one hand into Chocolate agar with PolyViteX  for aerobic culture, Columbia agar + 5% sheep blood  for anaerobic culture, and Sabouraud Chloramphenicol Gentamicin agar  for fungal isolation and on the other hand, in aerobic and anaerobic BactA/ALERT culture media . The tissues with positive microbiological results in the post-antibiotic treatment were rejected. Frozen heart valves were thawed in a 40°C thermostatic bath and rinsed several times with a DMSO gradient in saline.The samples were tested to evaluate the mechanical properties in tension mode by a Dynamic Mechanical Apparatus , which guarantees precise control of stress, and low friction support. In detail, a total of 36 specimens were cut from each of the 12 human explanted roots. Among the 36 samples, 12 of 4 mm in width and 8 mm in length were collected from the valve leaflet, while 24 approximately 10 mm in width and 12 mm in length were taken from the wall of the roots. The latter was further divided as follows: 12 were obtained by cutting the roots longitudinally with respect to the root axis, while 12 were cut circumferentially. All lengths and widths were measured by a caliper (Mitutoyo model. 500–457) with the specimens mounted on the apparatus, while thicknesses were evaluated by a digital micrometer (Mitutoyo IP65) before mounting the sample. The nonlinear behavior of all samples was assessed in a force-controlled test up to about 240 kPa for the leaflet and 120 kPa for the walls. Appropriate grip insured constant contact with the sample, avoiding any undesired slip effect. The results are reported in terms of average engineering stress defined as force with respect to the initial cross-sectional area vs. average stretch ratio, including as actual over initial sample height.f) were converted to stresses (σ) in the principal directions  by Equations (1) and (2):t is the thickness and λ represents the stretch ratio (Equation (3)):The measured forces  library of the code ANSYS (ANSYS 13.0), the utilized advanced commercial FEM-based code , where a cylindrical geometry was utilized to describe both aorta and PA roots. Thickness, height, and diameter of both aorta and PA conduits were taken from the average undeformed states directly measured on the samples. To ensure accurate results, a hexahedral regular mesh was generated, each finite element being associated with eight nodes with three translational degrees of freedom. In particular, an ad-hoc custom made Ansys procedure, written in APDL parametric language, was developed to reconstruct the FE model of the whole system constituted by the aorta tract connected with the pulmonary autograft by means of the suture region. We developed an ad-hoc mathematical model to simulate the biomechanical response in terms of growth and remodeling of pulmonary arteries under systemic pressure during physiological growth, in both reinforced and nonreinforced conditions ,34,37. TPhysical evaluation revealed mechanical stress associated with progressive overstrain in the pulmonary artery wall under systemic pressure that might affect PA integrity and the endothelialization process ,36,39. TThe degradation process of the PDS-scaffold gradually reduced its mechanical contribution. The feedback was translated from the wall of the PA as a signal to start a stress-compatible progressive remodeling of the vessel. The result led to physiological changes in tissue microstructure and to achieve the mechanical properties required to support systemic pressures. Once the bioresorbable scaffold had completed its degradation program and the strengthened vessel walls could actively respond to the systolic pressure, the expanded Polytetrafluorethylen (e-PTFE) structure accompanied PA media and adventitia toward their progressive aortic somatic growth, by stretching its weave to gain stiffness and to confine further vessel expansion effectively, so avoiding tissue prolapse and aneurismal degenerative phenomena.Reference Aorta, regarding the modeling of an aortic tract subjected to internal systemic pressure, say pi, of 120 mmHg . This case establishes for the reference aorta selected benchmark quantities, say the physiological growth over a six-month period (represented by the evolution of both diameter and thickness of the vessel layers) and the wall mechanical stresses A.No Reinforcement, analyzing the case of a not reinforced pulmonary artery transposed into aortic position at the pressure pi and subjected to growth and remodeling processes. The results of this simulation are directly compared with the outcome of the control group of the animal model B.po, accounting for the e-PTFE armor elastic confinement whose value depends on the armor constitutive properties and evolves as a function of the pulmonary artery dilatation and growth  but with the almost exponential increase in the expansion of pulmonary autograft (42%) in reinforced Ross with bioresorbable vascular scaffold (BVS/Polydioxanone) and with semi bioresorbable vascular scaffold, which combines the Polydioxanone (PDS) and e-PTFE . In the reinforced Ross with a semi bioresorbable vascular scaffold, the PA behaved similar to the normal aorta matching the somatic growth. This was the first time in the history of the Ross operation that stress shielding, growth, and remodeling of the pulmonary autograft were studied by a mathematical and biomechanical analysis leading to a better understanding of the biological potential of pulmonary autograft.To note that, at 6 months, animal weight was doubled , suggesting a normal growth process. There were no significant differences in expansion of the PA between no reinforced vs. reinforced Ross with external nonresorbable polyester . These findings were coupled with a significant reduction in apoptosis in the reinforced Ross, supporting the idea of an active remodeling process in this group .Micro- and macroscopic results showed that the interaction between temporary bioresorbable reinforcement and pulmonary autograft orchestrated a complex vascular remodeling process based on a balance between inflammation and production of the extracellular matrix, resulting after biomaterial resorption, in a “neovessel”, which has characteristics similar to those of the aorta but still biologically alive and capable of growing. The use of resorbable polyester was also associated with higher production of the new extracellular matrix that was mainly characterized by a higher content of elastin fiber in the PA, as well as by a more compact organization of collagen fibers in the elastic zone of the vessel. Interestingly, the metalloprotease MMP-9 was found to be overexpressed, indicating an ongoing matrix remodeling process. In parallel, cell proliferation was found to be increased in this group as testified by the significantly higher percentage of ki67 positive cells  analyses were performed as above described, by ad-hoc building up a parametric model of the vessel tracts. By preliminarily interpolating the experimental stress–stretch curves, we, therefore, uploaded the hyperelastic behavior in the FE model, the results of the fitting being reported in detail in Increasing pressure values within the physiological range were considered for the analyses up to 80 mmHg, corresponding to a  maximum stress in PA of about 240 kPa and a diameter dilation overcoming two times the undeformed one B, cohereIn particular, Overall, the results of the FE analyses showed that the realistic response of the aorta-autograft ensemble cannot be captured by means of modeling simplifications, such as numerical simulations performed by taking into account the two vessels separately. As a matter of fact, the FE outcomes demonstrated that the interplay among material properties of the autograft and aorta, suture regions, geometry, and dilation constraints imposed by the annulus is crucial for determining the effects that actual stress concentrations, strain localization onsets, and deformation gradients have on the success of the Ross operation.In this study, the biomechanical properties of leaflets and arterial root were evaluated, with particular regard to monoaxial circumferential and longitudinal stress to which pulmonary autograft is subjected after its transposition in aortic position with increased pressure stress.The choice to perform a monoaxial stress test was based on a geometrical tetrahedron analysis. Considering a tetrahedron isolated around a point x, the ideal would be the analysis of the three planes parallel to the coordinated planes passing through the point considered. Otherwise, there is no difference between single-axis analysis and biaxial analysis.Therefore, we compared the results for both leaflet and conducts of PA and aorta to evaluate the mechanisms of PA failure daunting the long durability of Ross operation. We have generated an ideal model of Ross intervention in which the autograft was reinforced by material that did not affect growth and functionality.Our finding is in agreement with the previous study of Carr-White et al.  about thPA failure and valve regurgitation can lead to severe left ventricular dysfunction, which is a delicate problem that impairs outcomes and quality of life after Ross operation. Pulmonary autograft valve regurgitation has been reported to have an incidence of 40% after 20 years from procedure ,20 with We have already investigated the importance of the remodeling phenomena occurring in the PA and the reflexes on the biomechanical properties of the remodeled autograft by means an in vivo model of Ross operation and also reported the stress shielding effects that a resorbable mesh might exert when applied as a reinforcement for the PA ,34,35,37Results of the FE analyses showed that the realistic response of the aorta-autograft ensemble cannot be captured by means of modeling simplifications, such as numerical simulations performed by taking into account the two vessels as separate entities ,43,44. TWe added to the equation other important parameters regarding the difference in circumferential and longitudinal stress-bearing abilities of the aorta and the PA and the topographical differences of the biomechanical properties among the components of the aortic root. Indeed, while the aorta revealed a consensual increase in stress and deformation in both the directions, the pulmonary showed better adaptability in the longitudinal direction and a steeper curve in the circumferential response, suggesting the ability of the PA to evenly absorb mechanical stresses and potentially explaining the known dilatation tendency of the pulmonary over time. Second, a higher degree of resistance to deformation of the valve leaflets with a stiffer behavior with respect to the aorta for applied loads of about 240 kPa (1800 mmHg) was demonstrated. The significant physiological pressure value considered for the analyses was 80 mmHg, as also reported by Mookhoek et al. ,43, and This difference can be traced in the mechanical properties of the vessels, in the present case related to native PA (PA implanted before degeneration to expansive systemic load effect), while Mookhoek et al. ,43 referBased on the results of this study, we could draw the following conclusions and trace new avenues of future investigation in the field of Ross procedure. First, it is important to reconsider the assumption of a linear relation in the dimensional expansion of the PA structures and how it relates to the age of the PA implant, giving attention to the phase of the somatic growth of the patient. In this context, our findings imply a further analysis of the observations previously described by Horer et al. regarding the yearly diameter increase in the annulus, Valsalva sinus, and sinotubular junction of the PA ,38,48. SIn fact, when translating these considerations into the clinical practice, the age of implant in the period of somatic growth (before and after the six years) plays a crucial role in this context. Importantly, before six years of age, there is no difference in size between the annulus, Valsalva sinus, and sinotubular junction, and the pulmonary autograft can be considered as a cylinder with homogeneous size, and the miniroot technique appears to be the most appropriate in this case. After six years of age, three different dimensions, annulus, Valsalva sinuses, and sinotubular junction, are defined with supposedly different mechanical resistance to expansion ,35,38. AAlthough the study had insufficient power to draw definitive conclusions about the relative effects of the two types of stresses on the pulmonary conduit, we can speculate that the duration of stress application and the rates of dilation might be associated with the length of the conduit implanted. In our experimental setting, we found no significant changes for PA longer than 3.5 cm, but in the actual surgical practice the correct height of the pulmonary autograft to be implanted was difficult to determine in children, and the distal anastomosis was normally performed beyond the level of the neo-sinotubular junction in consideration of the somatic growth. For these reasons, a miniroot technique with reinforcement represents the most appropriate option for this age range, and the use of reinforcing materials that do not impair the compliance of the native PA is important at this stage ,15,38. IConversely, we can strongly support the advantage of the miniroot technique that preserves geometry and function of the pulmonary valve because it imparts homogenous distribution of circumferential and longitudinal forces within the entire system of root, annulus, and valve.The results of this study advance our understanding of the relative benefits of pulmonary autograft for the management of severe aortic valve disease, as demonstrated by Donald Ross 40 years ,49,50,51PA is an ideal substitute for aortic valve replacement not only in Mr. Ross’s dreams  but also


Accessory mitral valve tissue (AMVT) is a rare congenital cardiac anomaly that is often an asymptomatic incidental finding. However, it has also been reported to be an important cause of left ventricular outflow tract obstruction (LVOTO) in subset of patients. When symptomatic, patients can often present with symptoms, including dyspnea, chest pain and palpitations/arrhythmias. Surgical resection is indicated in symptomatic cases with significant LVOTO. We here report a 50-year-old male who presented with chest pain and was incidentally found to have AMVT on an echocardiogram. No evidence of LVOTO was seen at rest, Valsalva, or stress. We also provide a review of literature in regards to most relevant clinical implication of AMVT.  Accessory mitral valve tissue (AMVT) is a rare congenital anomaly with a reported incidence of 1:26,000, mostly diagnosed in the first decade of life . We hereA 50-year-old male with past medical history significant for hypertension presented to the emergency room with chief complaint of chest pain. He described the chest pain as sharp, non-radiating, midsternal with no alleviating or exacerbating factors. He denied any exertional chest pain, dyspnea, palpitations or syncope. His home medication included hydrochlorothiazide 25 mg daily. The patient admitted to non-compliance to his home medication. Family history was unremarkable for any cardiac disease or sudden cardiac death. He denied history of smoking, alcohol use or drug use.Physical examination was significant for elevated blood pressure of 169/88 mm Hg. Physical examination was normal with no murmurs or gallops. Electrocardiogram (EKG) showed normal sinus rhythm with non-specific T-wave inversions in lead V4-V6 and lead III and no evidence of left ventricular hypertrophy or pathological Q waves. Laboratory testing revealed normal blood count, renal function tests and troponin levels. The patient had a treadmill exercise stress echocardiogram for further cardiac evaluation. Resting cardiac echocardiogram showed normal cardiac chamber size, wall thickness and systolic function. The ejection fraction was noted to be 65%, and there were no regional wall motion abnormalities. Accessory anterior mitral leaflet tissue was noted, which prolapsed into the left ventricular outflow tract (LVOT) during systole Video .There was no evidence of dynamic LVOT at rest, Valsalva or stress Video .No associated mitral regurgitation was seen. Stress echocardiogram did not show any evidence of inducible wall motion abnormalities to suggest ischemia, and there were no EKG changes of ischemia. As AMVT did not cause any symptoms of LVOTO, a decision was made to follow the patient without any intervention.First reported in 1842, AMVT is a rare congenital cardiac anomaly. Although the exact origin is unknown, it is considered to arise as a result of incomplete separation of mitral valve from the endocardial cushions or as a remnant of endocardial cushions that did not fuse with the mitral valve leaflet . It can Based on the mobility, it has been classified into two main types by Prifiti et al: fixed and mobile. This is further subdivided based on insertion, relationship to the mitral valve and development of chordae. The most common presentation is type IIB leaflet form, located on ventricular side of the anterior mitral valve leaflet ,6. Although AMVT may remain asymptomatic in patients, it may lead to LVOTO in some patients. As suggested by Manganaro et al. based on previous literature, the symptoms usually present when the LVOT gradient is ≥50 mm Hg . InteresEchocardiography is considered the “gold standard” modality for the evaluation of AMVT. A transthoracic echocardiogram (TTE) can not only help diagnose this condition but can also detect associated congenital heart defects. Transesophageal echocardiogram (TEE) can be considered for further characterization of morphology, shape and attachments of AMVT. Other modalities such as cardiac magnetic resonance can also be used. Beta-blocker therapy can be tried in patients with AMVT who have significant degree of LVOTO at rest or with provocation . PrimaryData regarding follow-up surveillance in asymptomatic patients are still lacking with most case series reporting an annual follow-up.AMVT is a rare congenital cardiac anomaly that is usually an asymptomatic incidental finding; however, it may present with symptoms of LVOTO. When symptomatic, it is usually managed by surgical resection. Limited data are available regarding surveillance and anticoagulation in asymptomatic patients.


The association of pulmonary atresia, ventricular septal defect (VSD) and major aortopulmonary collaterals (MAPCA) is an extreme form of tetralogy of Fallot (TOF). It carries a high mortality risk if not intervened on during infancy with only 20% of unoperated patients surviving into adulthood. We present the case of a 40-year-old man who presented for evaluation prior to retinal surgery and was found to have hypoxia and a loud murmur. Cardiac catheterization was performed in the general catheterization laboratory, demonstrating a membranous VSD, pulmonary atresia, and MAPCA. We highlight the challenges and limitations that an adult interventional cardiologist may have when encountering these patients. A 40-year-old man with scoliosis and developmental delay presented for outpatient evaluation prior to retinal surgery. His physical exam showed a heart rate of 110 bpm, blood pressure of 160/70 mmHg, respiratory rate of 16/minute, oxygen saturation of 84%, clubbing, elevated jugular venous pressure, and a multifocal V/VI systolic murmur radiating to the back. Laboratory tests were remarkable for hemoglobin of 18 g/dL. An echocardiogram demonstrated biventricular hypertrophy, preserved biventricular systolic function, an overriding aorta , and a rA ventriculogram, right heart catheterization, and oximetry were performed. After initial femoral venous access, there was difficulty passing a J wire and angiography showed an interrupted inferior vena cava . TherefoA discussion was held with the patient and his family including surgical options; however, due to the potentially high operative risks and poor baseline functional capacity, they decided to pursue medical management and focus on quality of life.Currently, congenital heart disease (CHD) affects more adults than children in the United States . IdeallyThe association of pulmonary atresia, VSD, and MAPCA is a complex CHD that occurs in approximately 7 to 10 of 100000 live births , 3. CyanEchocardiography is insufficient to fully identify pulmonary atresia, VSD, and MAPCA; however, a dedicated congenital echocardiogram is the preferred first-line imaging in these patients. Cardiac magnetic resonance imaging and computed tomography could supplement anatomic details and even pulmonary blood flow analysis; however, due to the lack of detailed hemodynamic data in these two modalities, cardiac catheterization remains the gold standard for accurately diagnosing this condition .Identification of MAPCA during cardiac catheterization is of exceptional importance, since it will determine treatment strategies. Most MAPCAs have a thoracic origin (descending aorta and subclavian arteries), but they can also arise from cervical vessels , the abdSurgical management in children could be achieved with native pulmonary artery rehabilitation followed by complete repair, MAPCA unifocalization , or a combined strategy of the two approaches . HoweverThe association of pulmonary atresia, VSD, and MAPCA is a rare complex CHD that is mainly diagnosed with cardiac catheterization. When encountered by an adult interventional cardiologist, obtaining anatomic and hemodynamic details is challenging.


Beside their antihyperglycemic role, they also have an emerging cardiovascular protective role and are associated with natriuresis and diuresis, weight reduction, blood pressure reduction, reducing diabetes-related ventricular remodeling, and other potential cardiovascular benefits.Three approved agents of the SGLT2 inhibitors from the FDA are empagliflozin, canagliflozin and dapagliflozin. The most common side effects of SGLT2 inhibitors are polyurea, volume depletion (due to it osmotic effect) and genitourinary infections (as it causes high glucose in the urine). However, the serious infections, that may reach to urosepsis or pyelonephritis, are very rare. Other rare side effects are euoglycemic diabetic ketoacidosis and hypoglycemia particularly when is concurrently prescribed with insulin or sulphonylureas.3Over the last five years, SGLT2 inhibitors have had an exciting and growing role in cardiovascular (CV) protection that was reported in three landmark trials . For the first time in the history of type-2 DM, there are data that indicates CV benefits from the use of glucose-lowering drugs in patients with CV disease or at CV risk.4 Moreover, the CANVAS trial for canagliflozin and DECLARE-TIMI 58 trial for dapagliflozin, showed similar beneficial cardiovascular and renal effects in diabetic patients at cardiovascular risk.7The EMPA-REG OUTCOME trial demonstrated that empagliflozin reduces mortality, hospitalization for heart failure and renal events in type-2 diabetic patients with cardiovascular risk.8 Recently, the FDA approved its use in the heart failure management, based on DAPA-HF trial.Recently, the DAPA-HF trial showed that dapagliflozin reduced cardiovascular deaths and heart failure events when compared to placebo in patients already diagnosed to have heart failure with reduced ejection fraction (HFrEF). The primary composite outcome of worsening heart failure or death from cardiovascular causes was lower in the dapagliflozin group (16.3%) compared with 21.2% in the placebo group .Further evidence is needed to support the role of SGLT2 inhibitors in the management of heart failure and particularly for agents other than dapagliflozin. Therefore, the EMPEROR-Reduced trial was conducted to assess the efficacy of empagliflozin in management of heart failure with reduced ejection fraction, regardless of DM.New England Journal of Medicine (NEJM) in August 2020.9 The study enrolled 3730 patients with symptomatic and stable heart failure with reduced ejection fraction (EF ≤ 40%) to assess the efficacy and safety of empagliflozin in patients, regardless of diabetes mellitus.Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial is an international multicenter randomized placebo-controlled trial with double-blinded design. The study was published in One arm of patients received empagliflozin 10 mg once daily while another arm received placebo, in addition to optimized guideline directed medical therapy for heart failure in both groups. The study was intended to enroll patients with increased risk of serious HF events; by enrolling patients with severely impaired left ventricular (LV) function (EF ≤30%) or patients with moderately impaired LV function but have history of HF hospitalization or significantly high NT-Pro BNP.P < 0.0001) (Patients were followed up every 2–3 months (for median duration of 16 months) to assess outcomes, adverse events, functional capacity assessment, NT-Pro BNP and renal function. The study showed a significant reduction of the combined primary endpoints  in the Empagliflozin group compared to placebo  .P = 0.008). The empagliflozin group had a slower rate of decline in renal function (estimated by GFR). Moreover, patients assigned to empagliflozin were 20–40% more likely to experience an improvement in NYHA functional class and were 20–40% less likely to experience worsening of NYHA functional class. Empagliflozin arm showed higher uncomplicated urinary tract infection.The results were consistent in patients with or without diabetes and among those were on Angiotensin receptor/ Neprilysin inhibitor (ARNI) or not. Additionally; empagliflozin reduced the total number of HF hospitalizations  that have an emerging role in the management of heart failure with reduced ejection fraction through different mechanisms rather than the classical renin-angiotensin-aldosterone blockage mechanism.The EMPEROR-Reduced trial confirmed the results of DAPA-HF, that SGLT2 inhibitors reduce cardiovascular death and heart failure hospitalization compared to placebo. It showed this effect is a class effect (SGLT2 inhibitors) limited to dapagliflozin (drug effect). Additionally, it demonstrated this beneficial effect in patients with severe heart failure, who are at higher risk of adverse events and higher mortality, as more than 70% of the enrolled patients had EF ≤30% (as DAPA-HF enrolled patients with mild and moderate heart failure).https://clinicaltrials.gov/ct2/show/NCT03057951).The promising results of the EMPEROR-Reduced trial and the raising role of empagliflozin in heart failure with reduced ejection fraction encouraged the investigators to conduct an EMPEROR-Preserved trial to assess the efficacy and safety of empagliflozin in heart failure with preserved ejection fraction. That trial is still ongoing  that produces a significant improvement in cardiovascular death and heart failure hospitalization in patients with severe heart failure, whether diabetic or not. Additionally, it improves the functional capacity and quality of life.The EMPEROR-Reduced trial reinforced the results of DAPA-HF trial and confirmed the class effect of SGLT2 inhibitors in HFrEF patients, rather than drug effect (limited to dapagliflozin). The trial showed an early separation of the curves between the placebo and empagliflozin arms indicating the early benefit. Moreover, the trial yielded significant renal protection with empagliflozin in heart failure patients who are prone to worsening renal function.Regarding safety, serious adverse events related to cardiac disorders or worsening renal function were lower in the empagliflozin group.