Inhibition of sympathetic activity and renin–angiotensin system with renal denervation (RDN) was proved to be effective in managing refractory hypertension, and improving left ventricular (LV) performance in chronic heart failure. The inhibition of sustained sympathetic activation prevents or delays the development of cardiac fibrosis and dysfunction that occurs after myocardial infarction and ischemia–reperfusion (I/R) injury. The translational efficiency of RDN remains to be defined in preclinical animal studies.This study investigated the therapeutic role of RDN in adverse remodeling and intramyocardial inflammation in myocardial ischemia–reperfusion (MI/R) injury.in vivo, followed by histological and biochemical analyses.Herein, 15 minipigs were subjected to 90-min percutaneous occlusion of the left anterior descending artery followed by reperfusion. Eight animals received simultaneous RDN using catheter-based radiofrequency ablation (MI/R-RDN). Cardiac function and infarct volume were measured The infarct volume in I/R-RDN pigs reduced at 30 days postreperfusion, compared to I/R-Sham animals. The levels of catecholamine and cytokines in the serum, kidney cortex, the border, and infarcted regions of the heart were significantly reduced in I/R-RDN group. Moreover, the gene expression of collagen and the protein expression of adrenergic receptor beta 1 in heart were also decreased in I/R-RDN mice. Additionally, RDN therapy alleviated myocardial oxidative stress.RDN is an effective therapeutic strategy for counteracting postreperfusion myocardial injury and dysfunction, and the application of RDN holds promising prospects in clinical practice. Acute myocardial infarction (AMI), the most severe manifestation of coronary artery disease, is one of the leading causes of morbidity and mortality worldwide . The earIt is well established that neurohormonal activation, the overactivation of both sympathetic nervous system (SNS) and renin–angiotensin–aldosterone system (RAAS), as well as an intense sterile inflammatory response are major contributors to reperfusion injury and cardiac remodeling . PharmacHere, a catheter-based bilateral renal sympathetic nerve ablation followed by reperfusion was applied to an established porcine model of AMI with extensive ST-segment elevation myocardial infarction (STEMI). Involvement of both neuronal and humoral pathways allow us to study the signal transfer between renal and heart. We observed that RDN therapy has cardioprotective effects in AMI with I/R injury through improvement in cardiac function and structure. We also found that the protective effect of RDN acts through multiple pathways, including reversing adverse remodeling, decreasing infarct area, reducing neurohumoral changes, and decreasing of inflammation levels.All animal experimental procedures were approved by the Ethics Committee of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School (ethics code: 20200508) and conformed to the Guide for the Care and Use of Laboratory Animals according to Chinese National Regulations.® 50 (Virbac) and atropine sulfate were injected intramuscularly for anesthesia, and peripheral venous access was established. Propofol (5 mg/kg/h) was slowly injected intravenously during the operation for general anesthesia. After tracheal intubation to assist breathing, pigs were mechanically ventilated using a non-invasive ventilator . An IntelliVue MP30 electrophysiological recorder was connected to the subjects for continuously dynamically monitoring heart rate, respiration, oxygen saturation, and blood pressure. Randomization was set preoperatively which was blinded to the operator, and when the animals established the acute myocardial I/R, they were grouped with renal denervation (MI/R-RDN) or sham (MI/R-Sham) procedures accordingly.Eighteen 3-month-old Bama miniature pigs, weighing 15 ± 2 kg each, purchased from Taizhou Taihe Biotechnology Co., Ltd., were housed in animal care facilities. Prior to surgery, pigs were fasted for 12 h but with free water. ZoletilAll interventional procedures were performed under general anesthesia and electrocardiographic monitoring. A percutaneous sheath was placed in the femoral artery with a standard sterile technique. An 8F Fast-Cath  was used for LV angiography and heparin  injections, and a 6F EBU3.5  was placed at the ostia of the left coronary artery descending (LAD). Myocardial ischemia was induced by angioplasty balloon occlusion  with 10 atm. Preconditioned minipigs were successively subjected to triple episodes of 30 s, 1 and 5 min occlusion and 1 min occlusion followed by 5 and 15 min reperfusion, respectively, before the prolonged ischemia. Then LAD was occluded for 90 min followed by reperfusion before they were immediately treated with sham- or RF-RDN  was placed at the ostia of the renal artery, and then a 12 mm radiofrequency ablation catheter  was introduced into the main renal artery. The catheter had six electrodes to sequentially deliver radiofrequency energy, which were mounted on a basket that could be opened to achieve solid contact with the vessel wall. We performed a 120-s ablation with each electrode and two sets of ablations in the renal artery from the ostia to the bifurcation , and then repeated the procedure on the other side. The temperature was 60°C. Renal angiography was performed before, during, and after RF-RDN to confirm patency of the arteries  was performed with a CX-50 ultrasound system  equipped with an S5-1 array sector transducer probe at a frequency range of 3.5–5.5 MHz. To assess cardiac function, echocardiographic examinations of each minipig were performed under anesthesia to produce quality images at 1, 7, and 30 days post-myocardial ischemia–reperfusion (MI/R). Left ventricular diameter at end-systole or end-diastole , interventricular septal thickness (IVS), and left ventricular posterior wall thickness (LVPW) were measured from M-mode in parasternal short-axis or long-axis view at a level close to the papillary muscles. Three to six representative contraction cycles were used for analyses, and the left ventricular ejection fraction (LVEF) was calculated using the biplane Simpson method with the accompanying software. LV mass was calculated according to the recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging. LV diastolic function was evaluated using the ratio of early transmitral flow velocity (E) to late transmitral flow velocity (A) and the mean of transmitral E to early diastolic medial LV tissue velocity of the lateral wall . The velocity-time integral (VTI) of the left ventricular outflow tract (LVOT) was obtained from pulsed Doppler imaging by positioning the sample volume at the LVOT approximately 0.5 cm below the aortic valve. Two blinded examiners performed all measurements.Cardiac magnetic resonance imaging (CMR) was performed to assess the infarct area and cardiac function 5 and 30 days after the MI/R-Sham or MI/R-RDN operation using an Ingenia CX 3.0T system . Steady-state free-precession cine imaging was performed using a 32-element phased-array body coil with ECG gating in cardiac vertical and horizontal short-axis and long-axis orientations.The following scanning parameters were used: time of repetition (TR), 3.5 ms; time of echo (TE), 1.72 ms; field of view (FOV), 320 mm × 320 mm; layer thickness, 8 mm; the number of layers in the LV short axis, 8; the number of layers in the rest of the image, 3; flip angle (FA), 45°; and the number of excitations, 30 cardiac cycles. Ten to 15 min after the contrast agent injection , a T1-weighted segmented phase-sensitive inversion recovery gradient-echo sequence was acquired for cine images to detect late gadolinium enhancement (LGE). The following scanning parameters were used: TR, 5.1 ms; TE, 2.5 ms; FOV, 255 mm × 255 mm; layer thickness, 8 mm; the number of layers in the LV short axis, 8; the number of layers in the rest of the image, 3; FA, 45°; and the number of excitations, 30 cardiac cycles. The infarct area was assessed as the area of hyperenhancement on the LGE images, which was measured as absolute mass or as a percentage of the entire LV myocardial mass. The images were analyzed by two independent investigators with software  according to the manufacturer’s instructions.Peripheral blood samples were collected at baseline, post-MI, and 1, 7, and 30 days post-RDN. Renal cortex tissue and myocardial tissue were harvested at 30 days post-RDN, immediately frozen in liquid nitrogen, and stored at −80°C until catecholamine assays were performed. Portions of tissue from the necrotic, border zone (BZ), and remote zone (RZ) of the heart and right and left kidney cortex were mechanically homogenized in 10 volumes of ice-cold NaCl using a homogenizer. Plasma and tissue homogenates were assayed using high-performance liquid chromatography . Analytical run times of norepinephrine, adrenaline, and dopamine were 3.5, 3.95, and 8.10 min, respectively. The data are graphed as nanograms of analyte per gram (ng/g) of total tissue.Blood samples were collected and centrifuged at 3000 rpm for 20 min. Serum was collected to measure the plasma levels of tumor necrosis factor-alpha (TNF-α)  using ELISA kits according to the manufacturer’s protocol. High-sensitivity cardiac troponin T (cTnT) (Roche Diagnostics) was measured on Cobas e411 and i1000SR analyzers using the manufacturer’s calibrators and quality controls . The detMalondialdehyde (MDA) and superoxide dismutase (SOD) levels in LV BZ tissues were measured using kits  according to the manufacturer’s instructions.Thirty days after reperfusion, pigs were euthanized with potassium chloride . Tissues, including renal arteries and hearts, were collected for histological, biochemical, and molecular analyses. The renal arteries and surrounding tissues were subjected to immunohistochemical staining for hematoxylin and eosin (HE) and tyrosine hydroxylase . Briefly, renal artery segments were harvested and fixed in 4% paraformaldehyde for 24 h, washed and placed in 70% ethyl alcohol until tissue processing for paraffin embedding. Renal artery samples were embedded and sliced into 2 μm thick serial cross-cryosections. LV tissue isolated from the infarct zones (IZs), BZs, and RZs was cut into 1 cm sections and 5 μm cross-sections were mounted onto glass slides and stained with HE and Masson’s trichrome staining for analysis of the infarct area and fibrosis. CD163  were stain for inflammatory cells under established protocol.CT–ΔΔ formula was used for data analysis. The primers sequences are shown in The LV IZ, BZ, and RZ were lysed with RNAiso plus Reagent  according to the manufacturer’s instructions, and total RNA was extracted. Purified RNA was quantified, and cDNA was synthesized using SuperMix  and amplified with SYBR Green Master Mix  in a Quant Studio 6 Flex Real-Time PCR System (Applied Biosystems). GAPDH was used as a housekeeping gene, and the 2Heart tissue was quickly removed and immediately homogenized in EDTA-free RIPA buffer  at 4°C. After protein concentration measurement, the lysate was stored at −80°C for Western blot analysis. The lysate protein (20 μg) was electrophoresed and transferred to polyvinylidene difluoride (PVDF) membranes. After blocking with 5% non-fat dry milk, the membrane was incubated with primary antibodies at 4°C overnight. The following antibodies were used: beta 1 adrenergic receptor , and GAPDH . The next day, membranes were incubated with secondary antibodies at RT for 1 h, followed by protein detection with SuperSignal West Femto Maximum Sensitivity Substrate . Total protein expression was normalized to GAPDH.t-test for two-tailed comparisons at a single time point and two-way analysis of variance with Bonferroni correction to account for multiple comparisons. All data are presented as the mean ± standard error of the mean (SEM), and a (corrected) p-value less than 0.05 was indicative of statistically significance.Data were statistically analyzed using GraphPad Prism 8.4.0 software with Student’s unpaired Representative angiographic heart images before and during the induction of MI with balloon occlusion are showed in Representative pre-, during-, and post-RDN angiographic renal images confirmed patency of the arteries . The locPeripheral blood samples were obtained at baseline, post-MI, and 1, 7, and 30 days post-RDN. The renal cortex was obtained at 30 days post-RDN. Serum samples and kidney cortex tissues from the MI/R-RDN and MI/R-Sham groups were analyzed using liquid chromatography–mass spectrometry (LC/MS). Serum dopamine (DA), adrenaline (E), and norepinephrine (NE) levels were significantly reduced at 7 days post-RDN but not at 30 days post-RDN . Kidney To assess cardiac contractile function, we measured LV dimensions and volumes using TTE. There were no changes in LVEF, LVESD, LVEDD, LV mass, or IVS between the groups at 1, 7, and 30 days post-RND. However, diastolic function was improved at 7 days in the MI/R-RDN group compared to the MI/R-Sham group . In addiVentricular morphology was assessed with HE staining, and collagen content was quantified using Masson’s trichrome staining . LV homoSustained sympathetic signaling results in overactivation of beta-adrenergic receptor (Adrbs) and triggers deranged neural-inflammation circuits that lead to exacerbation of myocardial injury . We nextThe main findings of our preclinical work are that RF-RDN therapy reduces catecholamine levels, improves adverse cardiac remodeling, decreases infarct volumes and inhibits inflammation in an AMI/reperfusion minipig model. Taken together, our results indicate that RF-RDN is a simple, fast, and effective intervention therapy that allows us to address the crosstalk between the renal sympathetic system and the heart adrenergic system. Therefore, RDN is a potential supplementary therapy for AMI after revascularization.In the current study, the STEMI model was established by performing increasing episodes before reaching the index 90 min occlusion. Ischemic preconditioning could protect heart from a subsequent prolonged period of ischemia and offer one of the most powerful mechanisms for reducing the speed and extent of myocardial cell damage and the occurrence of malignant arrhythmia in an acute or sustained ischemic insult , 15. HenThe beneficial role of RDN in attenuating ventricular remodeling was confirmed in current study through assessing cardiac function and structure using cardiac TTE and CMR techniques. Clinical guidelines recommend TTE as the first-line diagnostic modality for the evaluation of cardiac diseases. Interesting results showed that at post-RDN day 7, there was an improvement in the E/A. Nevertheless, neither LVEF nor LV mass showed differences at post-RDN day 30 between the I/R-RDN group and the I/R-Sham group. This may due to the low value of LVEF at baseline resulting in no significant difference after the MI operation. CMR is well accepted as the gold standard for the quantification of infarct area –18. Our Acute myocardial infarction results in a severe imbalance of metabolic supply and demand of oxygen and nutrients, and leading to tissue hypoxia, which initiates a primary pathophysiological process that is compensated by SNS and RAAS activation . LongstaCatecholamines enhance the mechanical performance of the heart by activating cardiac Adrb. Although cardiomyocytes coexpress β1 and β2, β1 is the predominant subtype and principal driver of catecholamine-driven sympathetic responses in the healthy heart. We examined the protein expression of Adrb1 and observed a significantly reduction in the IZ and BZ of the hearts with RDN therapy but not in the RZ. These results indicated that RDN attenuated only overactivated SNS, but had no obvious inhibitory effect on the normal SNS. Besides, immune cells also express Adrbs. So, we performed the histological staining of CD168 for inflammatory cells staining , which sThe proinflammatory cytokines TNF, TL-1β, and IL-6 are markedly and consistently increased in experimental models of AMI or I/R injury and have provided important insights into the mechanisms of inflammation-induced adverse LV remodeling, which may be mediated by uncoupling of Adrb and impaired calcium cycling , 18, 21.Infarction and necrosis trigger a strong inflammatory response that induces endothelial cell adhesion molecule synthesis and leads to the recruitment of inflammatory cells to clear the wound of dead cells or matrix debris . The splTaken together, our data demonstrate that RDN ameliorates oxidative stress, neurohormonal activation, adverse LV remodeling, and inflammation in a large animal model of AMI with I/R injury. These results provide strong evidence of the feasibility and therapeutic efficacy of RDN and suggest the necessity for further development of this therapeutic modality.There are some limitations of our study. First, hemodynamic evaluations of parameters, such as the mean aortic pressure, were not recorded but no intraoperative hypotension was observed during the study. Second, circulating IL-1 and IL-6 levels after MI were below detection range in our model. Therefore, we were unable to assess the direct effect of RDN on systemic cytokines level. In addition, the long-term effects of RDN and its ability to treat complex models in clinical practice should be evaluated. Although, the severity and mortality of MI are higher in female patients regardless of age, our study did not evaluate gender differences and only female animals were used in the present study. Besides, this mice strain is sexually mature at 3 months of age. In order to compare with other miniature pig strains, the weight somewhat limits the age range. Last but not least, the lower Adrb1 expression detected in heart tissue cannot be ruled out as a result of reduced inflammatory cell recruitment and infiltration. Considering the heterogeneity and plasticity of immune cells, we will further explore their dynamic balance and molecular mechanism in myocardial injury and repair in the future.Renal denervation treatment attenuated cardiac remodeling and intramyocardial inflammation by inhibiting sympathetic activity in a porcine AMI with I/R injury model, which is similar to pharmacotherapies that target the autonomic nervous system to improve the prognosis.Understanding the cardioprotective effects of RDN therapy in AMI with I/R injury is essential in developing clinical management strategies that is in conjunction with primary PCI for STEMI patients to prevent late-onset heart failure.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by the Ethics Committee of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School (20200508).LK and BX conceived and designed the work. KW, LK, YQ, and QD performed the PCI and RDN surgeries. All co-authors participated in the material preparation, molecular experiments, and data collection. YQ, KW, and RG performed the data analyses. DM assisted the interpretation of CMR measurement data. NZ blindly performed the echocardiogram examination and statistically analyzed the data. YQ and KW wrote the first draft of the manuscript. BX, LK, LL, and RG revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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IntroductionA preliminary assessment of patients who suffer from severe and complex coronary artery lesions, such as three-vessel disease and/or a left main (LM) artery lesion, plays a critical contribution in determining prognosis and treatment plans for non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Therefore, a pre-angiography  predictor was required to cost-effectively evaluate severe and complex coronary lesions to efficiently direct our subsequent dealing.AimThis study aimed to compare two-dimensional (2D) and three-dimensional (3D) global longitudinal strain (GLS) at the regional level to assess extremely complicated coronary lesions using the SYNTAX score as a standard of reference in 100 patients with NSTE-ACS.Materials and methodsThis research included 100 patients with non-ST-segment elevation acute coronary syndrome who presented at the Cardiology Department at Fayoum University from December 2019 to July 2020. All patients underwent a complete history and physical examination, hemoglobin A1c (HbA1c), lipid profile, creatinine assessment, 12-lead electrocardiogram (ECG), and transthoracic echocardiography (TTE) to detect global and regional longitudinal strain by 2D and 3D speckle-tracking echocardiography (STE). Coronary angiography was done on all patients within 24 hours of admission after acquiring echo images. Then, the results of 2D and 3D regional and global longitudinal strain (GLS) to predict the severity and coronary lesion complexity in terms of the SYNTAX score were compared.ResultsThis study revealed that 2D GLS was −12.10 ± 3.51, which is significantly higher than 3D GLS of −11.64 ± 4.05 (p < 0. 001). The left anterior descending coronary artery (LAD) and left circumflex artery (LCX) territories revealed a significantly higher value using 2D regional longitudinal strain  than using 3D regional longitudinal strain  . There were significantly lower 2D GLS, 3D GLS, global circumferential strain (GCS), area strain, and global radial strain (GRS) in the intermediate and high score group than in the low score group of patients .Conclusion2D and 3D strain echocardiography including GLS, GCS, GRS, and area strain are a noninvasive and rapid tool with clinical utility for evaluating coronary lesions in patients with NSTE-ACS. They can be routinely used to diagnose and stratify high-risk patients with NSTE-ACS, thereby potentially resulting in improved patient assessment. GLS as measured by 2D and 3D STE at minimal effort is a significant risk factor for patients with complex NSTE-ACS. In NSTE-ACS cases, the GLS absolute value is significantly associated with the degree of complexity of coronary artery lesions. The acute estimation of cases with severe and complex coronary artery disease (CAD), such as three-vessel disease and/or a left main (LM) lesion, presents critical participation in determining prognosis and treatment plan for patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) .Clinical guidelines for NSTE-ACS management recently highly suggested initiating dual antiplatelet therapy as soon as possible with aspirin and one of the P2Y12 inhibitors including clopidogrel, ticagrelor, or prasugrel [Therefore, clinicians may withdraw P2Y12 inhibitors in cases of high risk of requiring CABG. Soon, the administration of double antiplatelet therapy would necessitate postponement of CABG due to concerns of intraoperative bleeding. However, delaying the treatment with these medications may lead to an increased risk of fatal situations in patients with NSTE-ACS .Thus, we require a single early  indicator to cost-effectively evaluate coronary artery lesions that are severe and complex to efficiently lead our subsequent treatment. The SYNTAX trial elucidated the synergy between Taxus-based percutaneous coronary intervention and cardiac surgery (SYNTAX score) . It was SYNTAX is an extensive angiographic scoring system due to the complex nature of lesions in the coronary arteries . The SYNSignificant coronary artery stenosis may result in chronically impaired longitudinal LV function at rest; thus, two-dimensional (2D) speckle-tracking echocardiography (STE) is better than the conventional 2D echocardiography in assessing myocardial function on a regional and global scale, as well as in determining the size of infarcts, the viability of the myocardium that has been infarcted, and mild variations associated with myocardial ischemia . STE is STE is a straightforward, rapid, and accurate technique for assessing myocardial functions; thus, it is preferable for evaluating regional contractile function by determining the peak systolic strain .A strong correlation has been recognized between the longitudinal strain and the left ventricular ejection fraction (LVEF) . AdditioReal-time three-dimensional speckle-tracking echocardiography (3D STE) can be used to noninvasively and quantitatively assess global and regional myocardial wall motion. Current investigations demonstrated that strain and strain rate were preferable to wall motion analysis and LVEF in assessing myocardial systolic dysfunction .A previous study demonstrated that 3D global peak longitudinal strain (GPLS) obtained from 3D STE technology can detect slight shifts in the longitudinal systolic function of the LV . Thus, sDistinguishing NSTE-ACS cases with a high chance of developing complex lesions early is critical to provide timely and optimal treatment. Nevertheless, global and regional longitudinal strain performance in evaluating the complex NSTE-ACS has not been thoroughly studied .SubjectsThe following procedures were performed on all patients.Detailed Medical HistoryWithin the first hour, the clinical data of patients were collected, including their cardiovascular risk factors, such as smoking, hypertension, diabetes mellitus (DM), age, gender, and symptom onset.Full Physical ExaminationThis includes a general examination, in which all participants were subjected to a complete physical examination, including first medical contact vital signs, systolic blood pressure (BP) at presentation, and heart rate (HR), and local cardiac examination, including heart sounds, additional sounds, and cardiac murmurs.Blood SamplesVenous blood samples were collected on admission before coronary angiography, and creatinine levels, lipid profile, and hemoglobin A1c (HbA1c) were measured.Standard 12-Lead Electrocardiogram (ECG)ECG is a necessary component of the diagnostic workup of all cases that is done within 10 minutes of initial contact with a medical professional to rule out ST-segment elevation myocardial infarction (STEMI).Transthoracic Echocardiography (TTE)TTE was done to detect longitudinal strains on a global and regional scale using 2D speckle-tracking imaging and then 3D. Echocardiographic data were acquired with an ultrasound Vivid E9 system , which was equipped with a two-dimensional 3.5-MHz transducer (M5S-D), three-dimensional 3.5-MHz transducer (4C-D), offline speckle-tracking analysis software, and background processing workstation .Estimation of longitudinal strain by 2D speckle-tracking: All participants were linked to the ECG and remained in the left lateral decubitus position throughout the study for the examination. Gated images were acquired with stable electrocardiographic traces during end-expiratory breath-holding, avoiding ventricle shortening, and allowing proper visualization of the endocardial border. The optimized frame rate is between 60 and 110 frames per second. Sector depth and width were kept to a minimum to concentrate the attention on the interest structure, three consecutive cardiac cycles were collected, and the final processing values were averaged. Apical three-chamber, four-chamber, and two-chamber views were obtained to detect/mark the reference landmarks (annulus and apex), trace the endocardial border, and adjust the region of interest width.Offline analysis of the recordings was conducted using semiautomated computer software for strain and strain rate evaluation. Finally, this section provides regional and global longitudinal strain (GLS) values, which represent longitudinal strain averaged across all segments and views.Measurement of longitudinal strain by 3D speckle-tracking: In the acquisition mode (3D full-volume mode), acquiring the entire apical volume in a single shot with clear endocardium was obtained by a 3D volumetric transducer with a frame rate between 18 and 25 frames per second. This larger pyramidal volume and subvolumes corresponding to 4-6 cardiac cycles in real time will be collected and stored. The dedicated software will calculate the 3D LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and regional and GLS.Coronary angiography: Coronary angiography by radial approach was performed on all patients within 24 hours of admission (after echo image acquisition). Clinically significant stenosis was defined as a reduction in the left main coronary artery diameter by >50% or a diminution in the diameter of at least one major epicardial coronary artery or its main branches by >75%. The SYNTAX score was calculated after the angiographic procedure by two cardiologists, with experience performing interventional procedures, who are not aware of the study protocol or patient demographics. If scores differ, the final result was calculated using the mean values. Patients with a score of 22 or greater were classified as having severe and complex ACS. After getting the results of 2D and 3D strain echo and coronary angiogram of all study populations, the results of 2D and 3D regional and GLS to predict the severity and complexity of coronary lesions in terms of the SYNTAX score were compared, and the results of 2D and 3D longitudinal strain of different myocardial segments  and segmental coronary lesions by coronary angiography were correlated.Ethical concerns: All patients provided written informed consent before participating in the study. Each patient was assigned a unique file with a unique code number. All investigations and findings were solely used for scientific purposes, with strict adherence to patient confidentiality. Unexpected risks that arose during the research were promptly communicated to the participants and the ethical committee.Statistical methodThe Statistical Package for the Social Sciences version 21  for Windows was utilized to analyze the data. Data were initially checked for normality using the Kolmogorov-Smirnov one-sample test.Numbers and percentages were applied to describe the qualitative data. The Chi-square test was utilized to determine the association between categorical variables. Mean ± standard deviation (SD) was used for normally distributed data, while median (minimum-maximum) was used for non-normal data. The Student’s t-test was used for normal data and to compare the two groups, whereas the Mann-Whitney test was used for non-normal data.Continuous data were correlated using the Spearman correlation. The receiver operating characteristic (ROC) curve was used to determine the sensitivity and specificity at various cutoff points.SignificanceThe significance threshold was set at the 5% level  for all the abovementioned statistical tests, and the findings were considered significant when p < 0.05.The lower the p-value, the more significant the findings will be. Significant variables are entered into a logistic regression model using statistical techniques to predict the most important determinants and account for potential interactions and confounding effects. The ROC curve was used to determine the sensitivity and specificity at various cutoff points.Demographic data analysis revealed that the mean age distribution for all populations was 60.28 ± 10.92 years, and 76% were males and 24% were females.Risk factor evaluation revealed that 44% were hypertensive, 48% were smokers, 58% were diabetics, 76% had dyslipidemia, 50% had a BMI of >25 and 50% had a BMI of <25, and 38% had a family history of coronary heart disease as shown Table Table Table Table Table The LM was affected in 16% of the study population, the LAD in 58%, the left circumflex artery (LCX) in 53%, and the right coronary artery (RCA) in 46%. Normal or nonsignificant lesion was observed in 24%, single-vessel disease in 26%, double-vessel disease in 12%, and triple-vessel disease in 38%, as shown in Table Regarding speckle-tracking echo parameters between both groups, 3D EF, 2D GLS, 3D GLS, GCS, GRS, and area strain all had a significant correlation between low and high SYNTAX score groups with a p-value of ≤0.001 for all, as shown in Table In the comparison of both groups in terms of the affected vessel, 5.6%, 55.6%, 55.6%, and 33.3% of the LM, left anterior descending coronary artery (LAD), LCX, and RCA, respectively, were affected in group I, whereas 37.8%, 100%, 86.5%, and 86.5, respectively, were affected in group II, with significant p-values of 0.001, ≤0.001, 0.004, and ≤0.001, respectively. Regarding the number of affected vessels, a significant correlation was found between both groups (p ≤ 0.001) , area strain, 2D LAD, 2D LCX, 2D RCA, 3D LAD, 3D LCX, and 3D RCA territories and the number of affected vessels .The best cutoff value considering 3D GLS in intermediate prediction and high SYNTAX score is −5.5 with 80% sensitivity, 94.1% specificity, 50 positive predictive value, 98.5 negative predictive value, and 0.96 area under the curve (AUC), as shown in Table A rapid evaluation of patients with severe and complex CAD, such as a left main lesion and/or three-vessel disease, is essential to determine the prognosis and select an appropriate NSTE-ACS treatment approach. The recently issued clinical guidelines for NSTE-ACS management strongly recommend initiating dual antiplatelet therapy as soon as possible, with aspirin and P2Y12 inhibitors, including clopidogrel, ticagrelor, or prasugrel [However, in patients undergoing preoperative CABG surgery, a combination of antiplatelet therapy may raise the possibility of perioperative bleeding complications. Therefore, clinicians may choose to discontinue clopidogrel in cases in which CABG surgery is likely to be required. The prompt initiation of dual antiplatelet therapy would necessitate postponing CABG surgery due to intraoperative bleeding concerns. In contrast, delaying the P2Y12 inhibitor treatment may increase fatal events in patients with NSTE-ACS .Thus, an early  indicator capable of cost-effectively evaluating complex and severe coronary artery symptoms is required to efficiently instruct our subsequent treatment .The SYNTAX trial established the synergy between cardiac surgery (SYNTAX score) and percutaneous coronary intervention with Taxus. In 2005, it was described as “a coronary angiographic tool to measure CAD based on its complexity” .The SYNTAX score is a diligent angiographic scoring system based on the complexity of lesions in the coronary arteries. The SYNTAX score can be used to determine the degree of coronary artery stenosis and evaluate the presence of coronary artery calcification and tortuosity-, bifurcation-, or trifurcation-type lesions. Nonetheless, it is a minimally invasive procedure that utilizes coronary angiography ,13.Real-time 3D STE can be used to noninvasively and quantitatively determine the global and regional motion of the myocardial wall. This technology has been compared to that of MRI tagging .Earlier research demonstrated that 3D GPLS originates from 3D STE technology and is capable of detecting subtle changes in the longitudinal systolic function of the LV. Thus, strain or strain rate may be beneficial in the prompt detection of complicated CAD. It is critical to promptly distinguish NSTE-ACS cases with a high probability of developing complex lesions to provide treatment that is both timely and optimal. However, the effectiveness of GPLS in evaluating the difficult NSTE-ACS has not been thoroughly investigated .Therefore, this research was conducted to compare 2D and 3D regional longitudinal strain in assessing coronary artery lesions that are intricate in 100 patients with NSTE-ACS using the SYNTAX score as a reference standard.All patients were evaluated for a complete history and physical examination, HbA1c, lipid profile, and creatinine assessment, 12-lead ECG, and TTE to measure the global and regional longitudinal strain using 2D speckle-tracking imaging, followed by 3D and SYNTAX score calculation.The participants in the current study have a mean age of 60.28 ± 10.92 years, with the majority being male (76%). Of the cases, 58% had DM, 44% had HTN, 76% had dyslipidemia, and 48% was a smoker. Additionally, 38% had a positive family history of CAD, and a BMI of either <50 or >50 was equally distributed.In agreement with the current study, Lapu-Bula et al. evaluated the potentially related factors to NSTEMI and reported a modestly significant positive correlation between NSTEMI and elevated systolic blood pressure (BP). Other clinical factors, such as a history of HTN or CAD, smoking, and DM, were not associated with NSTEMI .Similarly, Ralapanawa et al. reported that HTN was significantly more prevalent in patients with NSTEMI. Their study also showed that smoking, a family history of ACS, DM, HTN, all types of ACS, and dyslipidemia were prevalent .Additionally, Brunori et al., in their cross-sectional study on 150 patients admitted to the hospital due to acute coronary syndrome, revealed that the overwhelming majority of patients (44.6%) were overweight, followed by those with normal BMI (33.3%), those who were obese (21.4%), and those who were underweight (0.7%) .In harmony with our work, Radwan et al., in their study, included 96 patients with NSTEMI and demonstrated a male predominance (66.7 %) in the study population, as well as an elevated prevalence of dyslipidemia (69%), DM (65%), smoking (56%), and HTN (52%) .In the current study, the mean value of HbA1c was 7.86 ± 2.32, s.Cr was 0.988 ± 0.35, troponin was 2.3 K0 , LDL was 179.24 ± 66.01, and HDL was 22.94 ± 10.94.Brunori et al. revealed that the mean LDL values were either close to or exceeded the established norms; however, the mean HDL level was low . MoreoveIn the current study, 32 (32%) cases had no significant changes or inverted T-wave, 10 (10%) had ST-segment depression, nine (9%) had Q-waves and poor R-wave progression, six (6%) had BBB, five (5%) had LVH, four (4%) had biphasic T-wave, and two (2%) had sinus bradycardia and inverted T-wave.Similarly, Birnbaum et al. concluded that alterations in the ECG are found in many patients; these changes are often minimal or reflect a reperfusion state . Numerous distinct ECG patterns have been identified in cases with NSTE-ACS as T-wave inversion with isoelectric ST segments or with a minor ST deviation. Generally, isolated T-wave inversion is not regarded as a concerning sign in NSTE-ACS. Flat/mild isolated T-wave inversion, particularly in leads with prominent R-waves, is frequently observed following the resolution of symptoms and is regarded as a sign of reperfusion .Strain variations assist in determining ischemic myocardium during rest and stress echocardiography and may provide prognostic information. Additionally, it may aid in defining the magnitude of myocardial infarction transmural and the presence of viable myocardium. Ischemic myocardium exhibits decreased or absent regional systolic longitudinal and circumferential shortening, as well as radial thickening . In the This difference was explained by the validation of 2D STE for assessing myocardial deformation, while 3D STE has been recently lauded as a potentially more fruitful technique for precisely assessing segmental and global LV function. Since the foreshortened views did not affect 3D STE, avoiding the weakness of out-of-plane motion that occurs as the heart enters and exits the incident imaging plane reduces or eliminates the ability to track the same speckle throughout the heart cycle. Additionally, 3D STE required only a single apical four-chamber view to conduct all assessments .In line with our work, Radwan et al. reported that GLS values ranged from −14.21 to −17.87 with a mean of −15.8 ± 0.83 in 96 patients with NSTEMI. The GCS value ranged from −25.65 to −33.93 with a mean of −31.2 ± 1.9 .Additionally, Caspar et al. revealed that GLS was significantly more numerically altered in cases with three-vessel disease (−15% ± 2.3%) than in those with one-vessel disease (−17.3% ± 3.7%) or two-vessel disease (−16.6% ± 2.8%); however, none of these differences were statistically significant .In the current study, a significantly higher value was found in the GLS, LAD territory, and LCX territory using 2D regional longitudinal strain  than that using the 3D regional longitudinal strain  . Additionally, no significant changes were found in the RCA territory (p = 0.429).Similarly, Abd Allah et al. revealed that the territorial strain of the LAD was significantly (p = 0.05) greater than those with nonsignificant LAD lesions (−17.6% + 3.5%) and those with significant LAD lesions than the control group (−20% + 2.1%). In severe RCA disease, the territorial strain values were −13.7% + 4.2%, which was significantly higher (p = 0.05) than those with nonsignificant RCA lesions (−17.6% + 3.9%) and in comparison to the control group (−19.6% + 3%). Lastly, the territorial strain of the LCX was accompanied by significant (p < 0.05) reductions in mortality compared to those with nonsignificant LCX lesions (−16.7% + 4.8%) or the control group (−20.2% + 2.3%) .Similarly, Choi et al. demonstrated that resting GLS was significantly lower in cases with severe CAD (three-vessel/left main CAD), which did not have resting echocardiographic regional wall motion abnormalities than in cases with CAD that involve one or two vessels .In the current study, the LAD was affected in the majority of cases (58 (58%)), followed by the LCX in 53 (53%), RCA in 46 (46%), and LM in 16 (16%). According to the number of affected vessels, 38 (38%) had a triple-vessel disease, 26 (26%) had a double-vessel disease, 24 (24%) had normal/nonsignificant lesion, and 12 (12%) had a single-vessel disease.This result was supported by Brunori et al., who revealed a greater proportion of patients (69.3 %) who had one or two affected coronary arteries .However, the study by Sidhu et al. revealed that 81% of patients underwent coronary angiography. The most prevalent pattern of coronary artery association (43.3%) was a single-vessel disease, with the LAD as the most frequently involved vessel (62.8%). The RCA was the second most frequently involved vessel, with 202 (40.2%) patients. In our study, the LCX has affected 161 (32%) cases .According to Vilela, 100 patients with NSTE-ACS underwent coronary angiography, of which 48% had a 70% lesion in the LAD, 36% had a 70% lesion in the circumflex coronary artery, and 27% had a 70% lesion in the RCA. Eleven of those cases exhibited collateral circulation, whereas the remaining had an occluded distal bed [Conversely, Tanaka et al. revealed that one-vessel disease was the most prevalent type, affecting 148 (41.2 %) subjects. Three-vessel disease was the least prevalent (19.2%). However, their results were similar to our findings in terms of the target vessels for percutaneous coronary intervention; the LAD was the most frequently encountered, accounting for 281 (52.3%) lesions [In the current study, the median SYNTAX score among the study group was 24.5 (33.4%), while 36 (49.3%) had a lower score, of which 32 (43.8%) had an intermediate score, and five (6.8%) had a high score.Our results were higher than that of Tanaka et al., with a mean SYNTAX score of 19.1 ± 11.4 .Additionally, Cai et al. enrolled 59 inpatients with NSTE-ACS and revealed a mean SYNTAX score of 19.52 ± 8.09, and 27 (45.8%) patients had three-vessel disease (including left main lesion). GPLS had a mean value of −12.24% ± 3.50% [Additionally, according to the study of Obeid et al., the total number of patients stratified by SxSIILow, SxSIIMid, and SxSIIHigh tertiles was 245, 245, and 244, respectively. The mean SYNTAX score for anatomical characteristics was 17.56 ± 9.3, with a median of 16 and an interquartile range (IQR) of 13 .In the current study, there was a significantly lower 3D EF, 2D GLS, 3D GLS, GCS, GRS, and area strain and lower 2D LAD, 2D LCX, 2D RCA, 3D LAD, 3D RCA, and 3D LCX territories in the intermediate and high score group than in the low score group of patients .Similarly, Cai et al. revealed that LVESV, LVEF, and GPLS were significantly associated with the SYNTAX score (p < 0.001) .In line with the current work, Cho et al. reported that patients with low SYNTAX score had a significantly greater EF compared to those with a higher score  .Moreover, Serdar Kuyumcu et al. revealed that the high SYNTAX score group (score of ≥32) had significantly higher rates of collateral vessels .Parallel findings have been reported by Radwan et al., wherein the GLS of the apical inferior, mid-anterior, basal inferior, and mid-inferior were significantly decreased in the high-risk group (HRG), while the group with low-intermediate risk demonstrated a significant reduction in the LS of the mid-anterolateral, apical lateral, and apex. Generally, the GLS demonstrated a statistically significant (p = 0.02) reduction in the high-risk group (15.4 ± 0.6) compared to the low-intermediate-risk group (16 ± 0.8) .Additionally, Fahim et al. classified 20 (24.7%) patients into the normal coronary group, 27 patients (33.3%) with one-/two-vessel CAD corresponding to the low-risk group (LRG), and 34 (42%) patients with three-vessel/left main CAD reflecting the HRG. In the HRG, GLS, global longitudinal strain rate (GLSR), global radial strain rate (GRSR), mid-circumferential strain (MCS), and mid-circumferential strain rate (MCSR) were significantly lower than in the LRG  .The current study revealed a significantly higher incidence of affected LM, LAD, LCX, and RCA in patients with intermediate and high scores than those with low scores (p < 0.05). Additionally, the number of affected vessels was significantly higher in patients with intermediate and high scores than in those with low scores (p < 0.001).Cho et al. reported significantly fewer multiple-vessel lesions in cases with lower SYNTAX scores  .Additionally, Obeid et al. reported that the angiographic characteristics revealed significant differences, including a higher rate of microvascular decompression in patients with LAD involvement (74.2%) in the SxSII high tertile compared with cases in the lower tertiles .Moreover, Serdar Kuyumcu et al. revealed that the high SYNTAX score group (score of ≥32) had significantly higher rates of coronary artery involvement with multiple vessels and chronic total occlusion compared with the low SYNTAX score group (score of <32) .The current study revealed a significant positive relationship between the SYNTAX score and HbA1c, s.Cr, and LDL; 2D GLS, 3D GLS, and GCS; LAD, LCX, and RCA territories; and the number of vessels. A significant negative relationship was found between the SYNTAX score and HDL, EF, and GRS; however, no significant relationship was found between the SYNTAX score and age and troponin.Similarly, when Vrettos et al. examined 71 cases, they discovered that GLS values were inversely related to SYNTAX score values. In the low SYNTAX score group, this correlation was weaker , whereas it was lost in the high SYNTAX score group  [The current study revealed a cutoff of −5.50 and AUC of 0.96, and 3D GLS had 80% sensitivity and 94.1% specificity with 93.2% accuracy for predicting intermediate and high SYNTAX scores. This demonstrated that the GPLS may be superior to conventional echocardiography and stress testing in diagnosing coronary disease.Similarly, Vrettos et al. demonstrated that the optimal GLS cutoff value for identifying patients with a high SYNTAX score was −13.95  .Moreover, Cai et al. revealed that by comparing the GPLS score to the SYNTAX score, the analysis of the ROC curve demonstrated the value of GPLS in diagnosing severe and complex NSTE-ACS. The AUC was 0.882 (p < 0.001). The ROC curve analysis demonstrated that the optimal cutoff value for GPLS in the diagnosis of severe and complex NSTE-ACS was −11.76%, with a sensitivity of 82.6% and a specificity of 83.3% .Additionally, Choi et al. revealed that 2D STE-derived resting GPLS could be used to monitor patients with left main and/or three-vessel CAD. They demonstrated that a cutoff value of −11.76% was the optimal value for evaluating patients with a SYNTAX score of intermediate or high, with a sensitivity of 82.6% and a specificity of 83.3% .Moreover, Caspar et al. revealed a high GLS diagnostic performance for the prediction of CAD in the ROC curve analysis (AUC = 0.92), with a sensitivity of 81% and a specificity of 88% at the optimal cutoff of −19.7%. When the GLS cutoff value was raised to −21%, the sensitivity increased to 100% with a specificity of 68% .The study by Abdelrazek et al., using a GLS cutoff value of 17.8%, expected a low SYNTAX score with 84% sensitivity and 70% specificity. In contrast, a GLS cutoff value of 15.9% postulated a rising SYNTAX score, with a sensitivity of 97.1% and a specificity of 90% .This study was conducted in response to the demand for a noninvasive and simple method of identifying patients with CAD. We hypothesized that global longitudinal peak systolic strain (GLPSS) is associated with CAD severity. This study aimed to investigate this hypothesis-generating concept, which has the potential to improve patient selection for coronary angiography. Our findings indicate that GLPSS can assist in identifying patients with severe CAD manifested by a high SYNTAX score.The current study establishes that 2D and 3D STE are noninvasive, reproducible, and effective techniques, which may be clinically used to evaluate coronary lesions in patients with NSTE-ACS. They can be routinely used to diagnose and stratify patients at high risk of NSTE-ACS, thereby resulting in improved patient management.


T2* was measured in the interventricular septum of three healthy volunteers at 1.5T  and 3T . T2*3.0T was converted based on the equation derived from the phantom (T2*eq). Results: R2* at 1.5T and 3T showed linear association, but a different relationship was observed according to the scanners . In the normal myocardium, T2*eq and T2*1.5T showed no significant difference . The mean squared error between T2*eq and T2*1.5T was 16.33, and Bland–Altman plots revealed a small bias . Conclusions: a phantom-based, site-specific equation can be utilized to estimate T2* values at 1.5T in centers where only 3T scanners are available.Background: Myocardial T2* mapping at 1.5T remains the gold standard, but the use of 3T scanners is increasing. We aimed to determine the conversion equations in different scanners with clinically available, vendor-provided T2* mapping sequences using a phantom and evaluated the feasibility of the phantom-based conversion method. Methods: T2* of a phantom with FeCl Myocardial T2* mapping is a noninvasive and robust method that is used to identify myocardial iron accumulation in iron storage diseases ,2. It is−1) = 1000/T2* (ms)) quantifications at 3T have been previously demonstrated, particularly for interventricular septum [Recently, the use of 3T scanners has been increasing, given their advantages of higher signal-to-noise ratio and scan time, and the number of institutions with only 3T scanners is increasing. Considering this, it is important to accurately calculate the iron burden at 3T. Quantification of myocardial T2* at 3T is challenging because of substantially decreased T2* values and vulnerable quantitation with higher susceptibility artifacts ,7. Despir septum ,9.R2* is known to be approximately halved from 3T to 1.5T . SeveralIn addition, a recent study suggested that myocardial T1 values can be standardized among different scanners with a phantom-based correction method . We hypoIn this pilot study, we aimed (i) to determine the conversion equations in different scanners using a phantom and (ii) to assess the feasibility of the site-specific equation for estimation of T2* values at 1.5T from a 3T scanner in the myocardium.This experimental study was performed in two tertiary care hospitals (Institutions A and B) from June 2019 to December 2020. It was approved by the institutional review board of both institutions, and informed consent was obtained from the participants.3 was created, and five samples with increasing concentrations of 3.53, 4.32, 5.90, 10.63, and 20.09 mM were used  14–20 (minimum TR), and number of echoes 6–8. Detailed scan parameters are described in A phantom with different concentrations of FeClere used A. The phere used B. Multi-The region of interest (ROI) was drawn on T2* maps by two independent cardiothoracic radiologists (S.C. and K.S.B.). Readers were blinded to the results measured by the other reader. All measurements were repeated three times at 1-week intervals. Readers drew circular ROIs as large as possible in the phantom. In human hearts, iron deposition preferentially occurs in the subepicardial area, but no systematic variation occurs between myocardial regions, and the mid-ventricular septal iron is highly representative of global myocardial iron from a previous autopsy study . In addi3.0T) of healthy volunteers were converted to the equivalent values at 1.5T (T2*eq) using the conversion equation obtained from the phantom study using the MR-B scanner. T2*eq and the measured values at 1.5T (T2*1.5T) were compared using paired t-test, mean squared error, and Bland–Altman plots. Statistical analyses were performed with SAS version 9.4 , SPSS version 24.0 , and R version 4.0.2 .R2* has a linear association with the field strength . Therefo1.5T = 0.76 × R2*3.0T − 2.23, R2 = 0.999; MR-A3, R2*1.5T = 0.95 × R2*3.0T − 34.28, R2 = 0.973; MR-B, R2*1.5T = 0.76 × R2*3.0T − 3.02, R2 = 0.999; The linear association between R2* values at 1.5T and 3T was found with good fit, but a different relationship was observed according to the MR scanners  and 35.5 ± 3.5 , respectively, without any significant statistical difference  between the predicted T2* values and measured T2* values at 1.5T. Moreover, bias remained small when considering each independent reader .Our study reveals that different conversion equations are required for different scanners with clinically available, vendor-provided T2* mapping sequences. The phantom-based, site-specific equation enables the estimation of equivalent T2* values at 1.5T from 3T scanners with acceptable mean squared error and small bias, suggesting the feasibility of the phantom-based T2* estimation method in clinical practice. T2* mapping has been utilized for iron quantifications in the heart and liver. While calibration of hepatic T2* against liver biopsy has been made for estimation of liver iron concentration ,17, tissTheoretically, R2* has a linear association with the field strength . In the 1.5T) and the calculated value using a site-specific equation (T2*eq) in normal myocardium revealed no significant difference. Therefore, we suggest that caution is needed when interpreting T2* values at 3T and that phantom validation is necessary for each scanner in clinical practice.In addition, a prior study reported that myocardial T1 values can be standardized among different scanners with a phantom-derived equation . We hypoOur study has some limitations that are important to pinpoint. First, we included only healthy volunteers in the validation experiments. It would have been important to also include patients with iron overload (T2* < 20 msec at 1.5T), given their clinical relevance. Therefore, further investigation of a large number of patients with iron overload is necessary. Second, only a small number of healthy volunteers were included in our study. This has to do with the fact that the normal myocardium study was used only for validation rather than derivation of the equation and that consistent results through the repeated measurements were obtained. Third, the difference between the two high-concentration samples in the phantom (10.63 and 20.09 mM) was high. The relationship could have been derived more accurately with intermediate concentration samples. Fourth, phantom results may not reflect the susceptibility of the tissue. Yet, in our study, there was no evidence of any significant susceptibility artifacts in the interventricular septum. Moreover, the predicted T2* value derived from the site-specific equation did not show a significant difference from the measured value at 1.5T in repeated measures. Hence, we suggest the usage of the site-specific equation only in cases where significant errors are not detected, which can be prevented by proper acquisition and analysis.Our study demonstrates that different conversion equations can be required for different scanners with clinically available, vendor-provided T2* mapping sequences. Therefore, caution is needed when interpreting T2* values at 3T, and that phantom validation is necessary for each scanner in clinical practice. A phantom-based, site-specific equation may be utilized to estimate T2* values at 1.5T in centers where only 3T scanners are available. However, further studies involving larger populations and different myocardial iron burdens are needed before its clinical application.


Hypertension is one of the most important cardiovascular risk factors, associated with significant morbidity and mortality. Chronic high blood pressure leads to various structural and functional changes in the myocardium. Different sophisticated imaging methods are developed to properly estimate the severity of the disease and to prevent possible complications. Cardiac magnetic resonance can provide a comprehensive assessment of patients with hypertensive heart disease, including accurate and reproducible measurement of left and right ventricle volumes and function, tissue characterization, and scar quantification. It is important in the proper evaluation of different left ventricle hypertrophy patterns to estimate the presence and severity of myocardial fibrosis, as well as to give more information about the benefits of different therapeutic modalities. Hypertensive heart disease often manifests as a subclinical condition, giving exceptional value to cardiac magnetic resonance as an imaging modality capable to detect subtle changes. In this article, we are giving a comprehensive review of all the possibilities of cardiac magnetic resonance in patients with hypertensive heart disease. Hypertension presents a massive burden for health systems worldwide and is one of the most important cardiovascular risk factors . The incIn this review, we emphasize the emerging diagnostic and prognostic role of cardiac magnetic resonance in patients with HHD.Cardiac magnetic resonance can provide important information in patients with hypertensive heart disease with its high reproducibility, the evaluation of systolic and diastolic dysfunction, and easier and faster evaluation of treatment effects. It is of great value in fibrosis assessment, ischemia detection, and differentiation of multiple causes of left ventricular hypertrophy . The mosLong-standing hypertension through increased afterload causes cardiomyocyte hypertrophy and accumulation of interstitial collagen fibers, resulting in left ventricular hypertrophy and diffuse myocardial fibrosis . Left veConsidering the advantages in evaluating patients with hypertensive heart disease, cardiac magnetic resonance, aside from being the gold standard for ventricular function and mass assessment, did not find its place in everyday practice, mostly due to the limited capability of a large number of hospitals to perform it on an everyday basis. Different non-invasive diagnostic modalities have been developed and improved with great correlation to cardiac magnetic resonance in evaluating patients with hypertensive heart disease. In patients with myocardial hypertrophy, ECG showed low sensitivity and specificity, while echocardiography overestimated or underestimated certain clinical forms due to high inter-observer variability . It is sPathophysiological mechanisms of hypertensive heart disease involve myocardium remodeling, muscle fibrosis, cardiomyocyte hypertrophy, and hypertrophy of intra-myocardial coronary vasculature. The evolution of the disease is affected by the duration and severity of hypertension, hereditary predisposition, and the effects of cytokines and neurohormonal factors which subsequently lead to systolic and diastolic dysfunction, myocardial fibrosis, or ischemia . CardiacOptimal evaluation of hypertrophy patterns, especially between hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD), is of great importance considering an increased cardiovascular risk in patients with advanced left ventricle hypertrophy . AdditioGlobal systolic function in the early stages of hypertension is usually preserved. Measuring the intramyocardial strain by cardiac magnetic resonance in these patients is important as this parameter is usually depressed, especially in the septum. Myocardial tissue tagging is a modality that can access longitudinal and circumferential shortening, determine pathophysiological changes, and follow-up left ventricle wall motion changes in patients with hypertensive heart disease. It is shown that in patients with hypertensive heart disease, global circumferential, longitudinal, and radial strain rates were associated with the mean arterial pressure, left ventricular mass index, and age, which is important in preventing the possible consequential decrease in global ejection fraction. Global longitudinal strain is decreased in patients with hypertensive heart disease, regardless of the presence of late gadolinium enhancement phenomenon, and is associated with left ventricular end-diastolic volume, LV ejection fraction, and LV mass index . CertainDiastolic dysfunction often develops as a consequence of long-standing hypertension, while atrial dilatation correlates with the severity of hypertension and is associated with increased morbidity and mortality . QuantifOverall, having in mind previously mentioned morphological and functional changes of the myocardium, and based on the clinical impact of hypertension on the heart, hypertensive heart disease can be divided into four categories. The first one consists of isolated left ventricular diastolic dysfunction but without LV hypertrophy. These patients should be closely monitored, and their hypertension controlled as well as possible to prevent further complications. The second one consists of diastolic dysfunction but with concentric LV hypertrophy. This category is usually still a subclinical stage of the disease but with an increased risk of cardiovascular complications, predominantly heart failure. The third stage is a clinical heart failure presentation with preserved ejection fraction (HFpEF). The fourth one implies a dilated cardiomyopathy with reduced ejection fraction . These cExpansion of extracellular space in myocardial fibrosis is leading to the accumulation of gadolinium with hyperenhancement on LGE imaging. The presence and degree of focal myocardial fibrosis detected by LGE is an independent and powerful predictor of adverse cardiovascular events in many cardiac conditions ,37,38. TDiffuse myocardial fibrosis is present in nearly all chronic cardiac conditions. It impairs cardiac function and therefore has a crucial role in the development of heart failure and its outcomes. Estimating the degree of myocardial fibrosis in hypertensive heart disease could be a difficult task having in mind the characteristics of fibrotic changes and the possibilities of different imaging modalities to identify it. Cardiac magnetic resonance, with its superior possibilities in terms of tissue characterization, is a useful tool capable to estimate, not only the presence, but also the extension and severity of fibrosis. A limitation of LGE imaging solely is that it is a qualitative technique, dependent on the difference in signal intensity between normal and fibrotic myocardium. This is why the estimation of diffuse myocardial fibrosis by LGE imaging is inexpedient. The main novel diagnostic modalities used for the evaluation of diffuse myocardial fibrosis are native T1 and post-contrast T1 mapping, and the evaluation of extracellular volume fraction.The native T1 time can be prolonged due to the expansion of extracellular space caused by myocardial infarction, edema, fibrosis or infiltration, while it can be shortened with the accumulation of fat or iron in the myocardium. One of the main advantages of native T1 time is that it can be measured without the administration of a gadolinium-based contrast agent. Detecting both focal and diffuse myocardial fibrosis is important in predicting chronic heart failure, arrhythmias, and sudden cardiac death. Native T1 time can be prolonged even in the absence of visible LGE phenomenon, pointing out the subclinical phase of diffuse myocardial fibrosis and the potential advantages of novel therapeutic modalities that can prevent the chronic, irreversible stage .Extracellular volume fraction (ECV) is one of the most important tools in estimating myocardial fibrosis. Extracellular volume correlates better than T1 mapping or LGE with histologically determined diffuse myocardial fibrosis. The increased value of ECV is a product of different factors including inflammation, tissue remodeling, atherogenesis, and metabolic disorders. It is shown that ECV has a good correlation with the amount of collagen deposition on myocardial biopsy in various cardiological conditions. The measurement of ECV relies on the values of native T1 and post-contrast T1 time adjusted for blood hematocrit. The pre-contrast T1 value reflects both the intracellular and extracellular compartment, while the post-contrast T1 value primarily reflects the extracellular compartment . The extHypertrophic cardiomyopathy can be distinguished from hypertensive heart disease by using ECV and native T1, mostly septal native T1 as the most significant discriminator in these cases . HinojarThe most important limitations in measuring ECV by cardiac magnetic resonance are subtle differences between normal patients and patients with hypertensive heart disease. This may limit the clinical usage of T1 mapping and ECV in discovering diffuse myocardial fibrosis, but it is undoubtedly an important imaging modality if applied technically correctly.In patients with hypertensive heart disease, several structural alterations develop in the coronary microvasculature. Increased medial thickness, reduced maximal cross-sectional area of pre-arterioles and arterioles, and decreased vascular density are the key pathophysiological mechanisms of impaired microcirculatory function . These cThe possibilities of cardiac magnetic resonance to provide anatomical, physiological, and functional data are of great importance in following the effects of treatment in patients with hypertension. Certain CMR studies have provided enough evidence of the positive role of anti-hypertensive drugs, mainly in terms of left ventricle hypertrophy reduction and changes in cardiac functional parameters ,59. ReceNumerous studies have evaluated the prognostic value of cardiac magnetic resonance in patients with hypertensive heart disease (as presented in 2), which makes this examination limitative in patients with chronic kidney disease. Claustrophobia is also an important patient-related limitation that should be taken into consideration.Aside from its accurate and reproducible non-invasive assessment of biventricular function and comprehensive tissue characterization, the extensive application of CMR is hampered by certain limitations. Long examination time, lack of availability and expertise, time-consuming post-processing, and high cost present important technical disadvantages of this imaging modality. Scanning patients with metallic clips, pacemakers, and other non-CMR conditional cardiac devices is not indicated, due to safety reasons. Additionally, paramagnetic contrast agents can not be used in patients with reduced glomerular filtration rate (less than 30 mL/min/1.73 mA wide range of clinical and especially subclinical presentations of hypertensive heart disease is often hard to discover, challenging to evaluate properly and incorporate into a proper real-life clinical scenario. The majority of these changes are accessible to the frequently performed diagnostic modalities in an advanced stage of the disease, with an already established high risk of adverse cardiovascular events. Cardiac magnetic resonance is a non-invasive, sophisticated diagnostic tool that can provide more detailed information on left ventricle volumes, tissue characterization, and scar quantification with excellent reproducibility and less inter-observer variability in patients with hypertensive heart disease. It can detect subtle changes in ventricular mass and volume parameters, access overall and regional LV function, and estimate the presence of focal or diffuse myocardial fibrosis. Although it is not recommended as a golden standard in hypertensive heart disease due to its poor availability and relatively low cost–benefit ratio, cardiac magnetic resonance is indicated if there is a severe, progressive left ventricular hypertrophy, an inconclusive echocardiogram or poor acoustic window, and a mismatch between clinical evaluation, ECG, and echocardiography. Additionally, it is of great importance in estimating the positive effects of treatment, as well as an optimal tool in clinical trials. Further studies will bring more information about the benefits of cardiac magnetic resonance in patients with hypertensive heart disease, leading to the more pronounced implementation of this important imaging modality into everyday practice.


Heart failure with reduced ejection fraction (LV-EF < 35%) is diagnosed in app. 11,000,000 patients worldwide. For the treatment of these patients, guideline directed medical therapy has proven to reduce mortality and rehospitalization regardless of the disease’s etiology. It is implemented to treat clinical symptoms by improving the left ventricular ejection fraction. Patients with a transient risk of ventricular tachycardia and sudden cardiac death can be protected by a defibrillator vest. The defibrillator vest is capable to detect and terminate ventricular arrhythmias during Guideline Directed Medical Therapy (GDMT). It is based on the recommendations of the European society of cardiology for 3 months. Afterwards, the WCD wear time could be prolonged, or, in case of persistent low ejection fraction (LV-EF ≤ 35%), an implantable cardioverter defibrillator (ICD) should be implanted, as shown in the WEARIT-II-registry. Our goal was to evaluate the effects of GDMT on LV-recovery and reduction of ICD implantations under protection with a defibrillator vest—depending on the uptitration of GDMT. Methods: 339 consecutive patients between August 2017 and September 2020 with newly diagnosed cardiomyopathy and an EF ≤ 35% were analyzed retrospectively by chart review. All patients were protected by a wearable cardioverter defibrillator (WCD). GDMT as recommended by the ESC started at discharge from hospital. The left ventricular ejection fraction (LV-EF) was determined by transthoracic echocardiography at week 4, 8 and at week 12 (in case of prolonged WCD wear time). Uptitration was performed after 4 and 8 weeks during patient visits. We focused on baseline medication as per GDMT and the dosage increase at week 4, 8 and 12. The aim was the uptitration to the maximum dosage tolerated by the patient. We also compared the LV-EF improvement in the group with and without uptitration of medication dosage. Results: The patient age was, on average, 63.2 years (SD ± 11.9 years). A total of 129 pts (38%) had ICM, 196 (58%) had NICM (incl 66 pts (19%) with DCM and 51 pts (15%) with Myocarditis, 79 pts (24%) with unknown origin) and 14 pts (4%) had other entities . In total, 21 pts (6%) had an LV-EF of less than 16%, 130 pts (38%) between 16–25% and 183 pts (54%) between 26–35%. GDMT started at discharge from the hospital included treatment with beta blocker for 327 pts (96.5%), ACE-inhibitors/Angiotensin/ARNI for 283 pts (83.5%) and Mineralcorticoid receptor antagonists (MRA) for 334 pts (88.4%). Uptitration was performed in all groups at a rate of 82.3%, 91.1% and 81.0% after 4 weeks and 64.7%, 50.3% and 66.3% after 8 weeks, respectively. After 4 weeks, 25 pts (7.4%) and, after 8 weeks, 171 pts (50.4%) had an EF increase of 5% or more (mean 14.2%). After 4 weeks, 81 patients had an LV-EF more than 35%. A total of 169 pts had a wear time of 12 weeks and an improvement of LVEF of more than 35%. Interestingly, in our study we did not find a significant difference in LV-EF improvement between the group with no uptitration and the group with uptitration. Conclusions: Guideline-directed medical therapy under protection with a WCD from ventricular arrhythmia can reduce the need for implantation of an ICD and can lead to an improvement of ejection fraction. Interestingly, the LV-EF improvement depends on the GDMT at discharge. Current guidelines recommend an initiation of all therapy columns of GDMT  at once and further uptitration to the maximal dosage (ESC Guidelines 2021). A further uptitration of all drugs of GDMT should lead to improvement of LV-EF and consequently to a reduction in ICD implantations. Guideline Directed Medical Therapy (GDMT) is indicated for patients with heart failure (HF) and reduced left ventricular ejection fraction. GDMT comprises four therapy columns: Renin-angiotensin-aldosterone system inhibitors (RAAS/AT1-receptor blockers (ARB)), Valsartan/Sacubitril (ARNIs), mineralcorticoidreceptorantagonists (MRA) and beta blocker (BB) [Patients with HF with reduced ejection fraction have a higher risk for SCD. Solomon et al., 2005 .The DINAMIT trial  showed tOptimized medical therapy for improvement of left ventricular systolic function is needed in order to prevent remodeling processes of the myocardium. This might result in an LV-EF improvement. Guidelines recommend medical treatment for 3 months before making the decision for an implantable cardioverter defibrillator (ESC guidelines 2016).In the ESC guidelines for heart failure therapy from 2021, it is emphasized that optimized medical therapy should be started as fast as possible when heart failure with reduced ejection fraction is diagnosed. Furthermore, all therapy columns of GDMT should be applied at once.The wearable cardioverter defibrillator (WCD) according to ESC guidelines from 2016 provides a temporary protection against ventricular arrhythmias. It also has several diagnostic features that enable the treating health care professional to continuously monitor several vital parameters such as heart rate (HR), activity and body position .The purpIn a single center clinical, a retrospective study in the Kerckhoff Heart center Bad Nauheim 339 consecutive patients between August 2017 and September 2020 with newly diagnosed cardiomyopathy and an EF ≤ 35% were protected against SCD with a wearable cardioverter defibrillator (WCD). Further differentiation of the underlying form of cardiomyopathy was conducted before by cardiac MRI or coronary angiography. The study was performed according to good clinical practice guidelines.The WCD will deliver a defibrillation as per the programmed settings .For all patients, GDMT started at baseline at discharge from hospital. ACE/AT1-inhibitors or ARNI;Beta blockers;Aldosteronantagonists.GDMT consists of the following substances:After initiation of GDMT, uptitration is performed in order to aim for the target dose  was carried out by transthoracic echocardiography in our hospital at week 4, 8 and 12. Uptitration of GDMT was performed under hospital surveillance after 4 and 8 weeks. In our study, LV-EF improvement is considered after an increase of more than 5% compared to the initial value of LV-EF. If the LV-EF was improved to a value of more than 35% after 4 or 8 weeks, the WCD was no longer indicated and the wear time was stopped. If there was no improvement after 8 weeks under GDMT, the WCD wear time was prolonged until planned ICD implantation (between 3 and 4 weeks after 8 weeks follow-up). So, this means an ICD was implanted (in case of an LV-EF under 35% at time of implantation) after 12 weeks, which corresponds to the guidelines. If there was an improvement of LV-EF after 8 weeks, but the value is less than 35%, the wearing time of the WCD was extended for another 4 weeks. Afterwards, the LV-EF was re-evaluated with transthoracic echocardiography. If, then, the LV-EF was still under 35%, the patient was supplied with a defibrillator.Uptitration is associated with an increase in dosage of each drug included in GDMT. Uptitration was only performed if the patient tolerates the medication and the blood pressure was stable. That means the patients did not develop any symptoms of hypotension. Regarding ACE-inhibitors or AT-receptor blockers, we always tried to upgrade to sacubitril/valsartan after 4 weeks if there were no contraindications. We analyzed baseline medication as per whether GDMT was started or not. Afterwards, we looked to see if GDMT was uptitrated or not. Another important part of the analysis was how far uptitration of GDMT was possible to the target dose after 4 and 8 weeks.Uptitration was described by the percentage of patients receiving any increase in medication dosage and the percentage of maximal medication dosage tolerated by patients compared to the target dose. It was also an important issue to know if uptitration of GDMT was possible after 4 and 8 weeks or if there were differences noticeable between these different timepoints.We focused on descriptive statistics by calculating the mean values of LV-EF improvement, the distribution of cardiomyopathy forms, the adherence of patients GDMT, the percentage of any medication dosage increase (uptitration) performed and the percentage of ICD implantations. Adherence to GDMT means, in that case, whether patients took the prescribed medication in the defined dosage. If malignant arrhythmia was detected by the WCD, a shock therapy was applied. A comparison group where patients did not wear a WCD was not included because our focus was on the effect of GDMT and its uptitration in patients with heart failure with reduced ejection fraction.The patient characterics are summarized in In five patients, the LV-EF was unknown, because these patients were supplied with a WCD after device explanation or for secondary prevention after ventricular tachycardia.The average wear time of the WCD was 56 d (±36.8). The compliance during each day worn was 23.44 h (±4.1).Baseline medication started in hospital included treatment with Beta blocker (BB) for 327 pts (96.5%), ACE-inhibitors/Angiotensin-1-inhbitors/ARNI for 283 pts (83.5%) and Mineralcorticoid receptor antagonists (MRA) for 334 pts (88.4%) . UptitraThe percentage of uptitration was, after 8 weeks, lower than after 4 weeks. After 4 weeks, 25 pts (7.4%) and, after 8 weeks, 171 pts (50.4%) had an EF increase of 5% or more (mean 14.2%). The median EF increase was 13 % . NICM paAn improvement of LV function of more than 35% can be detected in 81 (24%) patients after 4 weeks and 65 pts after 8 weeks. A total of 169 patients had an LV function above 35% after 12 weeks . In totaThe rate of ICD recipients was slightly higher in the group that did not receive uptitration. This trend was not statistically significant (65.1% vs. 67.4%).With the WCD, patients with increased risk for SCD can be protected transiently  from ventricular arrhythmias. Implementation and uptitration of GDMT reduces the need for ICD implantation due to improvement of LV-EF. As shown in the results, there were not any differences noticed between different forms of cardiomyopathy .Patients benefit from a high percentage of GDMT at discharge. This is recommended in the new ESC guidelines from 2021, where all drugs should be started at once. In the past, GDMT was applied sequentially. The rate of ACE-inhibitor/ARNI is lower compared to beta blocker and MRA. A reason for that fact could be the lack of hemodyamic tolerance at the beginning especially for Entresto.Due to an already high percentage of GDMT at discharge, it was more difficult to achieve an uptitration after 8 weeks compared to 4 weeks. This led to a decrease in the percentage of uptitration of medication.Our study has shown that implementation of GDMT and the early uptitration under clinical settings can improve LV-EF and consequently reduce the number of ICD implantations. The clinical appointments after 4 and 8 weeks helped in general to adjust the GDMT and titrate it to the optimal dosage tolerable for the patients. This kind of heart failure therapy with close follow-ups after discharge is addressed, for example, by Roth et al. . Their sThe ESC guidelines from 2021 give a Class IC recommendation based on evidence-medicine for GDMT after discharge and optimizing it at follow-up visits .Unfortunately, uptitration of all medications to the target dosage was not possible in all patients, which can be seen in The CHAMP-HF registry underlines the positive association of initiation and uptitration of GDMT and reduction of heart failure events . In our study, we were not able to find any significant difference in LV-EF improvement between the group in which GDMT was uptitrated at week 4 and 8 and the group with no further GDMT uptitration. We only found a slight trend noticeable after uptitration, which may depend on the high number of GDMT at the timepoint of discharge from hospital. After 2 months, the number of primary prophylactic ICD indications is reduced to a third. This amount of ICD implantations is less compared to the PROLONG study by Duncker et al. . In the The WCD is a useful tool to protect patients from malignant ventricular arrhythmia. Fortunately, we had in our cohort no ventricular tachycardia terminated by shocks in the Vest trial . In totaOur results give a possible hint that the LV-EF improvement could depend on a high rate of GMDT at discharge and further uptitration after discharge. Gracia et al.  also shoImplementation and uptitration of GDMT with close ambulatory follow-ups (4 and 8 weeks) for patients with heart failure with reduced ejection fraction (EF < 35%) under protection with a WCD from ventricular arrhythmia can reduce the need for the implantation of an ICD. An improvement of LV function to more than 35% can be detected in nearly half of the patients.The surveillance of these patients after discharge and adjustment of GDMT over 2 months allowed us the reduction of ICD implantations due to improvement of left ventricular function to a significant low rate. This effect could be also observed in other clinical trials . However, compared to them we could show that a high percentage of optimized medical therapy at discharge and its uptitration in the hospital has a positive effect regarding the reduction of ICD implantations after the waiting period.As emphasized in the current ESC guidelines from 2021, it is important to establish all pillars of GDMT at once and not sequentially.In our study, there was no significant difference if uptitration of medication was performed or not, but there was a slight trend noticeable in favor of patients experiencing uptitration of GDMT.All in all, WCD and, more importantly, initiation and uptitration of GDMT, can prevent patients with heart failure from ICD implantations and lead to improvement of LV-EF.This analysis was retrospective. It is not clear if dosage change was only conducted in the hospital or by a general practitioner between the hospital visits after 4 and 8 weeks. Moreover, it is not possible to describe the patient’s compliance with optimized medical therapy. We could not find all reasons why some patients had no uptitration of GDMT. Medication compatibility can differ among patients from the study.


She was submitted to cardiac magnetic resonance  and 2, w It is essentially caused by two mechanisms: the impact of the hypertrophied septum in the left ventricle free wall, generally with interposition of the hypertrophied papillary muscle, and anomalous insertion of the hypertrophied anterolateral papillary muscle directly in an anterior elongated mitral leaflet.Another more rare obstructive mechanism is that resulting from impedance to flow in the middle of the left ventricular cavity, called mid-ventricular obstruction, a distinct phenotype of hypertrophic cardiomyopathy, occurring in approximately 10% of patients.The diagnosis of mid-ventricular obstruction is considered when there is a mid-ventricular gradient estimated at 30mmHg. Obliteration is caused by marked septal hypertrophy, resulting in contact with the hypercontractile left ventricle free wall, and not by systolic anterior motion of the mitral valve anterior leaflet.,5,6 Moreover, the formation of apical aneurysms is more frequent in this subtype of hypertrophic cardiomyopathy.Patients with mid-ventricular obstruction tend to present many symptoms - dyspnea is the most common, and have increased risk of progressive heart failure and death (sudden death and arrhythmic events), according to studies in this population.The initial treatment of this condition is usually conservative. The interventions are reserved for cases of persistent symptoms after initiating drug therapy.After assessing the images, discussing the case, and establishing the obstruction mechanism, she initiated on beta blocker, with appropriate initial response. It was decided to carry on drug therapy, with strict clinical follow-up, due to the risk of complications associated with the disease.


Pressure–volume (PV) loops provide comprehensive information of cardiac function, but commonly implies an invasive procedure under general anesthesia. A novel technique has made it possible to non-invasively estimate PV loops with cardiac magnetic resonance (CMR) and brachial pressure which would enable good volume estimation of often anatomically complex ventricles without the need of anesthesia in most cases. In this study we aimed to compare how hemodynamic parameters derived from PV loops in patients with Fontan circulation differ to controls.Patients with Fontan circulation  and healthy controls  were examined with CMR. Short axis balanced steady-state free-precession cine images covering the entire heart were acquired. PV loops were derived from left ventricular volumes in all timeframes and brachial blood pressure from cuff sphygmomanometry.Fontan patients had lower stroke work, ventricular mechanical efficiency and external power compared to controls. Fontan patients with dominant right ventricle had higher potential energy indexed to body surface area but lower contractility (Ees) compared to controls. Fontan patients had higher arterial elastance (Ea) and Ea/Ees ratio than controls. Contractility showed no correlation with ejection fraction (EF) in Fontan patients irrespective of ventricular morphology. No difference was seen in energy per ejected volume between Fontan patients and controls.This non-invasive PV-loop method could be used in future studies to show the potential prognostic value of these measures and if changes in ventricular function over time can be detected earlier by this method compared to changes in ventricular volumes and EF. In contrast to patients with acquired heart failure, Fontan patients had similar energy per ejected volume as controls which suggests similar ventricular oxygen consumption to deliver the same volume in Fontan patients as in controls. Until recently, however, it has not been possible to reliably obtain PV loops without an invasive procedure [The Fontan procedure is a palliative operation for children with functional single ventricles allowing blood flow from the systemic veins to drain passively directly into the pulmonary circulation , 2. The rocedure . Recentlrocedure , 12. TheThe aim of this study was to compare how hemodynamic parameters derived from non-invasive PV loops in patients with Fontan circulation differ to controls. The purpose was to simplify the assessment of cardiac function in a patient group in need of many repeated examinations during their lifetime, and to better understand the pathophysiology of single ventricular pumping.Patients with Fontan circulation were retrospectively included. The diagnosis and type of Fontan are reported in Table Cardiac magnetic resonance imaging with retrospective gating was performed using a 1.5 T Achieva  or a 1.5 T Magnetom Aera . The use of two different vendors was due to change of scanners at the hospital. Short axis balanced steady-state free-precession cine images covering the entire heart were acquired with retrospective ECG gating. Typical imaging parameters at Magnetom Aera and Achieva respectively were: acquired temporal resolution 43 ms and 47 ms for adults and varied between 50 and 55 ms for children; TE/TR 1.2/2.7 ms and 1.4/2.8 ms and 1 ms; flip angle, 70 and 60°.http://segment.heiberg.se) with an in house developed method for analyzing PV loops were used [Left ventricular (LV) endocardial borders were manually delineated in all timeframes. Segment software  as a measure of ventricular contractility. The negative slope of the line between the ESPVR point on the PV loop and the end-diastolic volume represents the arterial elastance (Ea) as a combined measure of the steady and pulsatile components of the arterial load [The energy needed by the LV to eject the stroke volume (SV) is called stroke work and can be derived from the area within the PV loop, Fig. 0 . The sloial load , 17. Theial load , 19. Potial load . The eneStatistical analysis was performed using GraphPad . Continuous variables are presented as mean ) or median (interquartile range (IQR)) according to normal distributions and categorical variables as absolute numbers and percentages. Student t test was used to evaluate differences between Fontan patients and healthy volunteers. Correlation coefficient, r, of > 0.70 was considered as strong linear relationship, 0.50 < 0.7 as moderate, 0.30 < 0.50 as weak, 0 < 0.30 as very weak.Fontan patients were somewhat younger and had slightly lower BSA, lower systolic blood pressure and EF, and higher end-systolic volume indexed to BSA (ESVi) compared to controls, but diastolic blood pressure and end-diastolic volume indexed to BSA (EDVi) were not different.Pressure–volume loops in a healthy volunteer and in a patient with Fontan circulation is shown in Fig. The results from the non-invasive PV loops are shown in Table Ventricular mechanical efficiency correlated strongly with EF for both Fontan patients divided into subgroups based on the dominant ventricular morphology  and controls . Stroke work indexed to BSA correlated with EF in Fontan patients  but not in controls . Contractility showed no correlation with EF in Fontan patients  but a moderate correlation for controls . The negative correlation for Ea/Ees to EF was strong for both Fontan patients  and controls .There was no correlation between contractility and cardiac index in neither Fontan patients  or controls .The reanalysis of the patient with LV end-diastolic pressure of 22 mmHg resulted in that stroke work increased with 0.06 J (8% difference). Since ventricular mechanical efficiency, external power and energy per ejected volume are derived from stroke work, ventricular mechanical efficiency increased by 2% (4% difference), external power increased with 0.09 J/s (8% difference) and energy per ejected volume increased with 0.7 J/ml (4% difference). There was no difference in contractility or potential energy.This study used CMR and brachial pressure for non-invasive PV-loops for detailed assessment of ventricular systolic function in patients with Fontan circulation and healthy controls. We found that Fontan patients had lower stroke work and ventricular mechanical efficiency compared to controls. Fontan patients with a dominant RV had higher potential energy indexed to body surface area and lower contractility than controls. The ratio of arterial elastance to ventricular elastance (Ea/Ees) was increased in patients with Fontan circulation independent of ventricular morphology indicating suboptimal ventricular-arterial coupling. Energy per ejected volume was similar to controls, indicating that patients with Fontan circulation has the same ventricular oxygen consumption of the myocardium to eject blood to the systemic circulation as in healthy controls.. By using PV loops they found that patients with hypoplastic left heart syndrome and Fontan circulation could increase their contractility under stress.Stroke work was lower in Fontan patients than in controls, especially in Fontan patients with dominant left ventricle. End-systolic elastance as a measure of contractility did not have any correlation with EF in our study and was reduced in patients with dominant right ventricles. These results are in line with earlier studies using echocardiography . The expThe ventricular-arterial coupling, measured by Ea/Ees, has been suggested as a prognostic marker for patients with Fontan circulation . When EaMean potential energy indexed to BSA was higher in Fontan patients with dominant RV compared to controls. Potential energy is energy that at the end of systole will be converted into heat, thus wasted energy . Stroke Ventricular efficiency was decreased in patients with Fontan circulation in comparison with healthy controls. Ventricular efficiency correlated strongly with EF as shown earlier for patients with heart failure and healthy volunteers . StudiesThe finding that patients with Fontan circulation has the same ventricular oxygen consumption of the myocardium to eject blood to the systemic circulation as in healthy controls is in contrast to patients with acquired heart failure and reduced EF where we have demonstrated increased energy per ejected volume and thus higher ventricular oxygen consumption . This shPV loops acquired non-invasively from CMR offers in depth physiological information of ventricular function that may detect subclinical changes in ventricular function over time. The benefits compared to invasively acquired PV-loops are that there is no need of radiation or general anesthesia, and the elimination of the risks associated with LV catheterizations.0, the volume at pressure 0 mmHg, to be zero (Fig. 0 is probably reasonable also in most cases but might in Fontan patients with more complex anatomy be underestimated which would affect the derived values of contractility and potential energy.A limitation to the method is that it requires an unobstructed communication between the systemic ventricle and the brachial artery however no subjects participating in this study had any signs of aortic valve stenosis or other obstruction of the aorta or subclavian artery. The method approximates Vero Fig. , althougThe non-invasive PV loop uses an estimation of the ventricular end-diastolic pressure. Within a range between 0 and 15 mmHg previous studies showed low influence on the hemodynamic parameters . In the No invasive measurements were performed in this study, and the non-invasive PV loops have not been validated in Fontan patients. However, the method is based on time-varying elastance, which has been shown to be highly consistent irrespective of cardiac function or loading conditions in a variety of mammals –32 and cLoad-independent measures of ventricular function in patients with Fontan circulation can be estimated non-invasively from PV loops with CMR and brachial pressure without radiation. Patients with Fontan circulation have less efficient ventricular-arterial coupling and decreased ventricular efficiency compared to controls, whereas contractility is less affected. Also, energy used per ejected volume, as a measure of ventricular oxygen consumption, is normal in contrast to patients with acquired heart failure, showing the differences in pathogenesis. Future studies could use this non-invasive PV loop method to show the potential prognostic value of these measures and if changes in ventricular function over time can be detected earlier by this method compared to changes in ventricular volumes and EF.