Advanced heart failure (HF) may occur at any level of left ventricular (LV) ejection fraction (LVEF). The latter, which is widely utilized for the evaluation of LV systolic performance and treatment guidance of HF patients, is heavily influenced by LV size and geometry. As the accurate evaluation of ventricular systolic function and size is crucial in patients with advanced HF, the LVEF should be supplemented or even replaced by more specific indices of LV function such as the systolic strain and cardiac power output and size such as the LV diastolic diameters and volumes. Conventional treatment  is often poorly tolerated and fails and advanced treatment  is required. The effectiveness of MCS is heavily dependent on heart size, whereas HTx which is effective in the vast majority of the cases is limited by the small donor pool. Expanding the MCS indications to include patients with small ventricles as well as the HTx donor pool are major challenges in the management of advanced HF. Heart failure (HF) is a chronic evolving syndrome. Although a lot of patients respond to treatment some patients with HF develop advanced HF characterized by increased morbidity and mortality risk which increases with each subsequent HF hospitalization ,2,3. SevIn addition, the Interagency Registry for Mechanically Assisted Circulation (INTERMACS) classification system was developed to risk stratify patients with advanced HF  6]..6].Advanced HF may occur at any level of left ventricular (LV) ejection fraction (LVEF). In a recent study including 936 patients with advanced HF, 42.3% had HF with reduced (<40%) LVEF (HFrEF), 14.3% HF with midrange (40–49%) LVEF (HFmrEF), and 43.4% had HF with preserved (≥50%) LVEF (HFpEF) . Most imThis paper attempts a holistic approach of advanced HF, emphasizing that the use of LVEF as a diagnostic and treatment guide in this subgroup of HF patients may be misleading regarding pathophysiology, diagnosis, and management.The pathophysiologic mechanisms operating at the advanced stage of HF are virtually similar with those involved at the earlier stages of the disease, with the potential differences being quantitative rather that qualitative ,10. FluiOrthostatic stress is a simple test that can be used for the evaluation of splanchnic vascular capacitance. The existence of orthostatic symptoms in a HF patient indicates normal to high splanchnic  capacitance, whereas the absence of orthostatic symptoms suggests the opposite . Venous 2 without support or <2.2 L/min/m2 with support] and increased pulmonary capillary wedge pressure ([PCWP] ≥15 mm Hg)  * k (k = conversion factor = 1/451). LV-CPO integrates pressure (afterload), flow and heart rate (chronotropy) [2 and more than triples with stress (maximum LV-CPO) [LV cardiac power output (LV-CPO), which corresponds to the energy transferred from the LV to the aorta, is determined by the equation: LV-CPO (Watts or Watts/m LV-CPO) ,47. In a LV-CPO) .Under the LV-CPO umbrella the LV-CPO reserve (maximum LV-CPO-resting LV-CPO) is also included. Moreover, some studies have demonstrated that indexing LV-CPO to LV mass may be a better measure of myocardial function ,50. RestThe RV in pulmonary hypertension initially adapts to the increasing vascular load by enhancing contractility (“coupling”) to preserve flow, whereas during the late phase ventricular dilation develops in an attempt to limit the decrease in stroke volume, with uncoupling and increased wall stress as a consequence . It is tTreatment of advanced HF may be divided into conventional and advanced .General measures. The treatment of underlying causes should be eradicated if possible  and comorbidities treated  when feasible [1. feasible .Medical treatment. Treatment of congestion is of the upmost importance but is frequently challenging as diuretic resistance is a characteristic feature of advanced HF. Diuretic resistance implies a failure to increase fluid and sodium (Na+) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level (80 mg of furosemide once or twice daily or greater in those with reduced glomerular filtration rate) [2. on rate) . The paton rate) . Additioon rate) ,64. Indeon rate) . Variouson rate) . Multineon rate) . Ultimaton rate) .2 consumption, and BNP were observed after switching from milrinone to levosimendan based IIT [Hemodynamic instability often ensues as a result of cardioprotective treatment with neurohumoral inhibitors given on top of severe LV dysfunction or even severe LV dysfunction per se necessitating medication downregulation or even interruption. Eventually cardiogenic shock may develop. Ambulatory inotropic support in patients with hemodynamic instability, either with continuous infusion or intermittent inotropic therapy (IIT) of cyclic adenosine monophosphate (cAMP) dependent agents  and/or calcium sensitizers  is utilized in ambulatory advanced HF patients for palliative care or as a “bridge” to HTx and LVAD implantation) ,68,69. Iased IIT . It is nased IIT ,73. Hypoased IIT . NorepinDevice treatment. Cardiac resynchronization therapy (CRT) is indicated in HF patients in NYHA class II or III that remain symptomatic despite optimal medical treatment and have a LVEF ≤ 35% and a QRS width > 130 ms or ≥150 ms depending on the presence or absence of left bundle branch block (LBBB), respectively [3. ectively . The potectively . It is dectively . Both grectively .Patients with advanced HF and hemodynamic instability are candidates for temporary mechanical circulatory support (MCS), chronic MCS including myocardial recovery, or heart transplantation (see below).1. Short-term (temporary) MCS. Although vasopressors increase mean arterial pressure and may sustain hemodynamic status in advanced HF and cardiogenic shock, their use can impair microvascular organ perfusion, increase LV afterload and myocardial work, and cause myocardial ischemia . As a re2. Long-term (durable) MCS. LVAD are indicated in inotrope-dependent heart failure (HF) patients with pure or predominant LV dysfunction. The survival benefits are less evident in ambulatory, advanced HF . Timing One of the most significant causes of postoperative morbidity and mortality post-LVAD implantation is RV failure which is estimated to manifest in 9% to 42% of the patients, based on the criteria used for the diagnosis . Once bi3. Myocardial Recovery. The majority of patients with an LVAD remain on durable MCS until HTx or death. LVAD withdrawal with ventricular recovery represents the optimal outcome for patients previously implanted with an LVAD but is rare. In the INTERMACS registry  the percentage of device explanted due to myocardial recovery were 0.9% at 1-year, 1.9% at 2-year, and 3.1% at 3-year follow-up . As the 2, whereas maximal oxygen consumption with exercise >16 mL/kg/min was an optional criterion. The primary end point of the study was the proportion of patients with sufficient improvement of myocardial function to reach criteria for explantation within 18 months with subsequent freedom from transplant/ventricular assist device/death at 12 months. 19 patients were explanted . The 15 ongoing explanted patients are now 2.26 ± 0.97 years after explant. Survival free from LVAD or transplantation (after LVAD explantation) was 90% at 1-year and 77% at 2 and 3 years [2 and a peak oxygen intake > 50% of predicted, and had successfully undergone a 4-phase weaning assessment. At 1 year, Kaplan–Meier estimated survival was 88%, whereas at 6 years, it was 77% [The explant rates in more recent studies are higher and this has been attributed to the availability of percutaneous or minimally invasive short-term MCS. In the Remission from Stage D Heart Failure (RESTAGE-HF) study 40 chronic advanced HF patients with nonischemic cardiomyopathy receiving the Heartmate II LVAD were enrolled . LVAD sp 3 years . Prior t was 77% .Major limitations of the current studies on LVAD explantation include the small number of patients and the absence of comparison data between successfully explanted and not-explanted patients, which could have shed more light on the eligibility criteria. Further, in all of these studies in which evaluation of LV systolic function is critical, the LVEF used for this purpose is affected by a multitude of factors including LV size. It is erroneous, therefore, that in a recent study evaluating the effect of LVAD on LV function, a LVEF cut-off of 40% and a LVID of 6 cm were used to classify response to LVAD , conside4. Heart transplantation. Heart transplantation (HTx) is considered the “gold-standard” treatment in advanced HF. However, it has been restricted by donor availability, despite expansion of the organ pool by the greater willingness to accept marginal hearts , and use of hearts from donors who died of a drug overdose, donors with hepatitis C viremia, and donors after circulatory death ,104. MorOne principal alteration to the new allocation system was the breakdown of the previous single highest urgency status (1A) into 3 separately ranked statuses deemed to be in descending order of sickness   106,107107. In tAdvances in donor organ selection, considering factors such as sex, weight, and allosensitization, offer more effective matching of donors and recipients. Sex-mismatch has been recognized as a risk marker for the most unfavorable prognosis, especially in male recipients of female heart. Although this has been ascribed to dissimilarities in the cardiovascular system between women and men, interfering variables as age, urgent transplantation, and size-mismatch should also be taken into account . Donor wCardiac xenotransplantation might be a promising approach to bridge the gap between the supply and demand of a donor heart . StrikinAdvanced HF may occur at any level of LVEF, which reflects LV size rather than LV function in this setting. The introduction of specific indices for the evaluation of ventricular systolic function, such as ventricular strain and CPO, is of the upmost importance in advanced HF as these indices are better predictors of outcome than the LVEF. Undoubtedly LVEF has been used for years for the guidance of both conventional and advanced treatment in HF. However, treatment with neurohormonal inhibitors, which may be effective over a wide range of LVEF, may not be tolerated in advanced HF due to hemodynamic instability. Likewise, there is evidence to suggest that device treatment  is of limited usefulness in advanced HF. Regarding advanced treatment, mechanical circulatory support is more effective in bigger than in smaller LV due to technical issues and, therefore, the indices of LV size should be determined in all candidates for this treatment modality. In this regard, as the prevalence HFpEF is increasing in number in the aging population of the Western world, the obstacle of the small LV in this patient population can be overcome by developing adaptive MCS devices that unload the left atrium. As HTx is effective regardless of LV size, the development of technics to increase the donor pool represents a major challenge in the management of advanced HF.


Radiotherapy is an established method of cancer treatment, improving patients’ survival; however, it is associated with possible life-limiting late complications, including cardiovascular diseases. The cardiotoxic effects depend on the doses of radiation delivered to the heart. Despite significant advances in radiotherapy techniques, resulting in reduced doses of ionising radiation, cardiac dysfunction remains a common problem after mediastinal irradiation. The present study emphasises the need to calculate the radiation doses delivered to several parts of the heart, revealing relationships between doses delivered to the left anterior descending artery (LAD) and the whole heart, along with echocardiographic markers of early systolic dysfunction of the left (LV) and right ventricles (RV).rho = 0.6468, p = 0.034), the maximum dose to the LAD and LV anterior LS , the median and the mean dose to the whole heart and LV anterior LS , and the total irradiation dose and RIMP . The calculation of irradiation doses allows the identification of patients at risk of cardiac dysfunction detected by modern STE.The aim of this study was to assess the effects of radiotherapy involving the heart on LV and RV function using modern speckle-tracking echocardiography (STE), and in relation to the radiation dose applied to the LAD. This retrospective, single-centre study included 12 patients after a median of 51 months after irradiation for mediastinal lymphoma, in whom we were able to delineate the LAD. Correlations between doses of ionising radiation and echocardiographic parameters reflecting the systolic function of the LV and RV were analysed. The median irradiation dose delivered to the whole heart was 16.4 Gy (0.5–36.2 Gy), and to the LAD it was 15.1 Gy (0.3–35.3 Gy). LV longitudinal strain (LS) was impaired in the anteroseptal and anterior walls. Parameters reflecting RV function were normal, with the exception of RV myocardial performance index (RIMP). Significant correlations were found between the median dose to the LAD and LV global LS ( Radiation-induced heart disease (RIHD) is a cardiovascular disorder induced by ionising radiation administered as a part of anticancer treatment. The pathomechanism is complex, and involves oxidative stress, inflammation, endothelial dysfunction, mitochondria, and endoplasmic reticulum injury . It ofteSpeckle-tracking echocardiography (STE) enables the early detection of systolic ventricular dysfunction. It measures the myocardial deformation as a longitudinal shortening in a given region of the ventricle, calculated by comparing the distance between two speckles during systole and at the baseline length. Properly contracting cardiomyocytes shorten; thus, the distance decreases, and normal longitudinal strain (LS) is negative.This study aimed to evaluate the effects of radiotherapy involving the heart on the function of the left and right ventricles, assessed using modern speckle-tracking echocardiography in relation to the irradiation dose applied to the LAD.This study is a part of an ongoing research project on the early detection of complications from radiotherapy using echocardiography in patients undergoing chest irradiation. In the present study, we focused on patients treated for mediastinal lymphoma. Patients were recruited from the Cardio-Oncology Outpatient Clinic at the Medical University of Gdansk, and the inclusion criterion was at least three years after the end of radiotherapy. Out of a total of 63 patients in the present study, we included those treated between 2007 and 2018, in whom we were able to perform a retrospective analysis of computed tomography scans and LAD contouring. The exclusion criteria were as follows: no scans or insufficient quality of computed tomography for LAD delineation, no imaging of more than 2 segments of the left ventricle in two-dimensional echocardiography and at least 1 segment of the free wall of the right ventricle, previously diagnosed cardiac disease , and the patients’ refusal to undergo echocardiography. Demographic data, time since chest irradiation, other cancer therapies, comorbidities, and cardiovascular risk factors were analysed.A radiation oncologist reviewed all computed tomography scans, and all dosimetric data were obtained from the dose–volume histograms. According to Feng’s guidelines, the LAD was contoured using the Eclipse v. 16  radiation planning system . A schemEchocardiographic acquisitions were performed using the Vivid S6 or the Vivid E95 ultrasound systems . All recordings were later analysed offline with echocardiographic quantification software , in line with the current recommendations of the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) ,13,14. TThe LV systolic function was determined by the LV ejection fraction (LVEF), LV fractional shortening (LV FS), stroke volume (SV), and LV global longitudinal strain (LV GLS). The LVEF was calculated via the Simpson method. The RV function was determined based on the tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (RV FAC), RV peak systolic velocity (RV s′), RV free-wall LS, and myocardial performance index of RV (RIMP), obtained from tissue Doppler imaging (TDI). RIMP, also known as the Tei index, is the ratio of non-ejection time to the RV ejection time, and can be calculated using two methods. In this study, TDI was preferred over pulsed-wave Doppler (PW) for RIMP calculation, because it is less load-dependent, and all measurements can be made within one heartbeat, limiting potential errors.t-test was used to verify dependencies between variables in the event of normal distribution, and the Mann–Whitney U test was used for variables without normal distribution. We assessed the correlations between echocardiographic parameters reflecting the LV systolic function  or RV function , RV free-wall LS, RIMP), and the irradiation doses applied to the LAD, to the whole heart, and the total dose of administered radiotherapy. In the event of normal distribution of the variables, the correlations were expressed with Pearson’s rho; for the variables without normal distribution, Spearman’s R was used.Statistical analysis was performed using Statistica 13.3  software. The Shapiro–Wilk test verified all data of interest to check for normal distribution. Student’s We included 12 patients (75% were women) with a mean age of 39 ± 13 years at the time of echocardiographic examination. Seven patients were treated for Hodgkin lymphoma , four for diffuse large B-cell lymphoma , and one for T-cell lymphoblastic lymphoma. The patients’ characteristics at the time of echocardiographic examination are presented in 2 (160–400 mg/m2). Chemotherapy was followed by irradiation using the anteroposterior/posteroanterior (AP/PA) fields technique: two AP/PA fields in three patients (25%), three AP/PA fields in one patient (8.3%), two AP/PA fields with two lateral fields in one patient (8.3%); two tangential fields in one patient (8.3%), and multi-beam intensity-modulated radiotherapy (IMRT) in six patients (50%). In seven patients, irradiation was applied to the mediastinum (58.3%); in three, it was applied to the mediastinum and neck (25%), in one (8.3%) to the right breast, and in one (8.3%) to the upper mantle . The planned total dose (median) in the studied group was 33.3 Gy (19.8–40.0), and was applied in (median) 18 fractions (11–22). The median irradiation dose delivered to the whole heart was 16.4 Gy (0.5–36.2 Gy), and to the LAD it was 15.1 Gy (0.3–35.3 Gy). The data on irradiation techniques and doses are shown in All patients received chemotherapy containing doxorubicin at a median dose of 300.0 mg/mIn 9 (75%) patients, the maximal dose delivered to the LAD was higher than 20 Gy. The maximal dose applied to the whole heart was (median) 33.0 Gy, and ranged between 19.5 and 42.3 Gy. Among patients treated with IMRT, the maximal LAD doses were rather high—median: 28.5 Gy (9.4–37.8 Gy). In the patient irradiated with tangential fields, the maximal dose applied to the LAD was 0.4 Gy, which was significantly lower in comparison to the rest of the patients.At the time of echocardiographic examination , arteriaEchocardiography was performed after (median) 51 months (34–139) from mediastinal irradiation completion, and data obtained from this examination are shown in 2, respectively. LV diastolic function was normal in 10 patients (83.3%) and indeterminate in 2 (16.7%).The LV and left atrial dimensions were within normal ranges, and LV systolic function was preserved, as indicated by the LVEF of 64 ± 11%, LV GLS of −19.0 ± 2.2%, and LV FS of 31.5 ± 6.9%. LV contractility disorders were detected in one (8.3%) patient by visual assessment, and were located in the anterior and anteroseptal LV walls. The LV GLS was abnormal in two (16.7%) patients and borderline in two patients (16.7%). Detailed analysis revealed that LV LS was impaired in the anteroseptal and anterior walls, where it was −16.0 ± 3.2% and −15.2 ± 4.2%, respectively. Abnormal and borderline anteroseptal LS was found in six (50%) and three (25%) patients, respectively while the anterior LS was abnormal in five (41.7%) and borderline in four (33.3%) patients. LV stroke volume (SV) and the LV SV index were below normal values—44.5 ± 19.5 mL and 24.5 ± 8.6 mL/mp = 0.79 compared to the patients treated with the other techniques). It was abnormal in one (16.7%) patient and borderline in another (16.7%) patient. We found impaired anteroseptal LS of −14.7 ± 2.1%  and anterior LS of −15.6 ± 4.9% (p = 0.77). Abnormal LV LS values above −16% were detected in four (66.7%) patients in the anteroseptal wall and two (33.3%) patients in the anterior wall, while borderline values were found in these regions in two (33.3%) and three (50%) patients, respectively    (There was a significant correlation between the median dose applied to the LAD and the LV GLS (CI 0.95) . MoreoveCI 0.95) . We alsoectively . MoreoveCI 0.95) .The use of modern echocardiography, such as STE, which allows the assessment of the longitudinal deformation of the left and right ventricles, allows for the early detection of systolic dysfunction of the ventricles, when it may still be reversible ,17. AnotTransthoracic echocardiography is a very useful tool in RIHD diagnosis, as it is widely available, safe, and inexpensive. In the assessment of LV systolic function, the most frequently used parameter is LVEF, but the decrease in LVEF appears with a delay—usually with irreversible LV damage. Longitudinal strain and diastolic function impairment occur earlier in LV dysfunction, and are mainly reversible.  EchocardIn the present study, the mean 2D biplane LVEF was within the normal range, and no significant correlation was found between LVEF and irradiation dosage. The average LV GLS was not affected, but detailed LS analysis showed worsened strain in the anteroseptal and anterior LV walls. The location of the anterior part of the LV muscle in the anterior part of the chest causes these LV segments to receive the most ionising radiation. The radiation-induced myocardial injury resulted in LV regional contractility abnormalities, which were detected early by strain analysis before the visual inspection.The RV is at risk of irradiation-induced injury for the same reason as the anterior part of the LV. In contrast to the numerous studies assessing LV function, the RV has been rather neglected in most studies. Conventional 2D echocardiography is of limited use in assessing RV due to its complex shape, which makes appropriate presentation difficult. Reliable RV assessment is preferably performed using 3D echocardiography or magnetic resonance imaging; however, access to these techniques is still limited ,19,20,21The importance of RIHD has long been underestimated due to the generally poor prognosis of cancer patients. Moreover, cancer patients are typically excluded from cardiovascular studies, further reducing the data regarding their morbidity. Furthermore, many studies on RIHD are based on small, heterogeneous groups of patients, which makes it difficult to compare their results. Finally, and especially in Hodgkin lymphoma—a disease with a generally good prognosis—the oncological observation period is often too short for revealing late cardiovascular complications. This is especially true for those treated in adolescence ,6,22. CuAccording to the Danish Breast Cancer Cooperative Group’s recommendations, the dose of 20 Gy per LAD should not be exceeded, V20 (the heart volume receiving 20 Gy) should be limited to 10% of he hear volume, and V40 (the heart volume receiving 40 Gy) should be limited to 5% of the heart volume . To meetToday, the development of radiotherapy techniques has led to the reduction in the doses of ionising radiation administered to the organs at risk, including the heart. Nevertheless, RIHD is still a life-limiting disease, even with lower doses of radiation ,10,24,33Our study group was small, and the patients were treated in different years and, thus, with different radiotherapy techniques. Due to the small sample number, the irradiation with AP/PA fields was not compared with the IMRT technique. The effects of doxorubicin or concomitant cardiovascular risk factors on the results cannot be ruled out. However, all patients were treated with doxorubicin, and similar LS disturbances were observed in areas with increased radiation exposure. Three-dimensional (3D) echocardiography was not performed.Our preliminary study found that increased irradiation doses delivered to the coronary arteries and the entire heart are associated with an increased risk of cardiac injury, as demonstrated by modern speckle-tracking echocardiography. Currently, delineation of the coronary arteries is not routinely performed during radiotherapy planning, but it should be implemented in clinical practice until such semi-automatic calculations are provided. Even modern IMRT has been linked to the administration of high doses to the LAD. Further prospective studies, carried out in larger groups of patients, will allow us to determine the risk of cardiac injury with the use of current modern radiotherapy.


The left ventricular aneurysm is a pathological condition defined as an akinetic or dyskinetic area of the left ventricle (LV) wall associated with reduced ejection fraction. The most common surgical technique to reconstruct a left ventricular aneurysm is endoventricular patch plasty (Dor procedure). In this case, endoventricular reconstruction of the left ventricular aneurysm using a double-layer extracellular matrix was performed. One of the most common surgical solutions for reconstructing a sizable left ventricle aneurysm is the endoventricular patch technique (Dor procedure). It improves the ventricle size and geometry, reduces wall stress and paradoxical movement, and increases the LV ejection fraction. Commonly used materials as a patch for reconstructing the LV aneurysm are Dacron, bovine pericardium and Teflon. We present our experience in reconstructing the apical LV aneurysm using a double-layer extracellular matrix  endoventricular patch.The left ventricular aneurysm is a pathological condition defined as an akinetic or dyskinetic area of the left ventricle (LV) wall associated with reduced ejection fractionA 61-year-old male was admitted to the hospital due to dyspnea symptoms, sharp chest pain during physical activity and profuse sweating. He had a history of ST-elevation myocardial infarction (STEMI) two years earlier, when he underwent primary percutaneous coronary intervention with implantation of two drug-eluting stents in the left anterior descending artery. The postprocedural period was uneventful.Cardio-specific enzymes (high-sensitivity troponin T and CK-MB) were in the referent range at admission to the hospital. Transthoracic echocardiography  revealed a dyskinetic apical segment of the left ventricle (LV) and compression of the lateral apical wall and apical segment by an organized thrombotic mass measuring 110 × 47mm . EjectioThe surgical procedure was performed through a median sternotomy. Cardio-pulmonary bypass was instituted by ascending aorta and right atrial appendage cannulation. A blood cardioplegic solution was used to arrest the heart. A giant LV apical aneurysm was found after extensive dissection of the pericardial adhesions . Longituth postoperative day.During the early postoperative period, the patient had a short episode of disorientation, which was medically treated. The remainder of the postoperative period was uneventful, and the patient was discharged from the hospital on the 7The control ECG-gated CT scan performed 30 days after the surgical procedure showed left pleural effusion without new pseudoaneurysm and local complications of the reconstructed ventricle . The 600. Progressive heart failure, persistent angina, thromboembolism and uncontrolled recurrent ventricular arrhythmias indicate surgical reconstruction. The primary aim of surgical treatment is LV “reshaping”, which improves cardiac function, symptoms and life expectancy. In the late 1980s, cardiac surgeon Vincent Dor developed the new surgical concept of LV aneurysm reconstruction using an endoventricular Dacron or pericardium patch. This technique has four advantages: it excludes the akinetic segment of the interventricular septum; restores the physiological geometry of the ventricular cavity; preserves the left anterior descending artery for coronary bypass; and eliminates the need for external prosthetic materials, which can cause persistent pericardial adhesions. The routine reconstruction of the LV wall is performed using an autologous, homologous or synthetic material. The main disadvantages of autologous or bovine pericardium are postprocedural fibrosis, thickening, and calcification. They may result in pseudoaneurysm formation, tissue retraction and rupture after the surgical repair. In addition, a synthetic material such as woven nylon (Dacron) could promote reactive inflammation and increase the risk of endocarditis,6. After implantation, the material becomes incorporated by fibrotic encapsulation and cannot fully restore the functionality of the regional tissue.Less than 5% of patients after transmural myocardial infarction develop LV aneurysm-8. Yanagawa et al. showed initial experience with interventricular repair using extracellular matrix. However, the short-term period (207±211 days) was uneventful. Patients with congenital heart disease who underwent cardiac surgery to reconstruct a pulmonary artery, right ventricular outflow tract, ascending aorta, and heart valve had no evidence of patch-related complications in the medium term. There is no evidence of long-term results after LV reconstruction using an extracellular matrix patch. McCready et al. present long-term results after carotid artery reconstruction using multilayer extracellular patch to increase 0.3% of new formed pseudoaneurysms during 72 of months follow-up.The novel biological material, an extracellular matrix, has been introduced in surgery due to its positive characteristics , which has been increasingly used in recent years. Tissue remodelling and regeneration are shown in preclinical experiments and clinical practice. Pathohistological examination revealed that the extracellular matrix was replaced by organized collagen, neovascularization and reendothelization, we performed a double-layer Proxicor patch to reconstruct the LV aneurysm.Because of these characteristics, we decided to use the extracellular matrix as an endoventricular patch to reconstruct the LV. In addition, due to the risk of postoperative rupture and pseudoaneurysm formation, which were described as an early postoperative complicationThe extracellular matrix can be used as a substitute for a Dacron, bovine and autologous pericardium in the endoventricular reconstruction of the left ventricle aneurysm. In addition, the double-layer surgical technique could be implemented to increase the patch strength and prevent potential adverse events.


Effects of Sacubitril/Valsartan (S/V) on left ventricular (LV) mechanics and ventricular-arterial coupling in patients with heart failure with reduced ejection fraction (HFrEF) are not completely understood. The aim of this study was to evaluate both cardiac and vascular remodeling in a group of HFrEF patients undergoing S/V therapy.es), arterial elastance (Ea), and ventricular-arterial coupling (VAC).Fifty HFrEF patients eligible to start a therapy with S/V were enrolled. Echocardiographic evaluation was performed at baseline and after 6 months of follow-up (FU). Beside standard evaluation, including global longitudinal strain (GLS), estimated hemodynamic forces (HDFs) and non-invasive pressure-volume curves (PV loop) were assessed using dedicated softwares. HDFs were evaluated over the entire cardiac cycle, in systole and diastole, both in apex to base (A-B) and latero-septal (L-S) directions. The distribution of LV HDFs was evaluated by L-S over A-B HDFs ratio (L-S/A-B HDFs ratio). Parameters derived from estimated PV loop curves were left ventricular end-systolic elastance , ejection fraction and GLS significantly improved . A reduction of Ea  and an improvement of Ees  and VAC  were observed. Re-alignment of HDFs occurred, with a reduction of diastolic L-S/A-B HDFs ratio .At 6 months of FU indexed left ventricular end-diastolic and end-systolic volumes decreased (EDVi: 101 ± 28 mL vs. 86 ± 30 mL, S/V therapy leads to a complex phenomenon of reverse remodeling involving increased myocardial contractility, HDFs distribution improvement, and afterload reduction. Sacubitril/Valsartan (S/V) was proven to significantly modify the clinical course of patients with heart failure with reduced ejection fraction (HFrEF), improving symptoms, outcomes and functional capacity as a consequence of cardiac reverse remodeling (RR) –7. StudiIn this prospective, observational, single-center study, fifty symptomatic patients with HFrEF and an indication to receive S/V according to recommendations  were conEpiq 7, Philips). Left and right ventricle (LV and RV) dimensions, wall thickness, global and regional systolic function, indexes of diastolic function, presence and grade of valve stenosis and regurgitation were evaluated according to current guidelines . LV end-diastolic pressure (EDP) was also estimated  and after 6 months. During medical evaluation cardiovascular risk factors, past medical history, medical therapy, New York Heart Association (NYHA) functional class, systolic and diastolic blood pressure were collected. Blood test including blood count, creatinine and plasmatic potassium were collected. Trans-thoracic Echocardiography (TTE) was performed using standard equipment . The software automatically traced the endocardial border of the left ventricle in apical three, two and four chamber views, providing the mean value of endocardial global longitudinal strain (Endo-GLS).ST-E analysis was performed using an automated 2D strain analytical software t, Pt). In the PV loop the classic phases of the cardiac cycle are displayed: isovolumetric contraction, ejection, isovolumetric relaxation, and diastolic filling. Based on this integrated PV loop analysis, the following hemodynamic parameters were calculated . LV volumes, estimated EDP and brachial systolic and diastolic pressures were used as input. The software reconstructs the PV loop by determining the end-systolic pressure-volume relationship (ESPVR) and end-diastolic pressure-volume relationship (EDPVR) using the single-beat algorithms previously described in literature –13. Oncelculated , 15:LV systolic elastance (Ees): reflecting LV contractility and representing the slope of the end-systolic pressure-volume relation (ESPVR);- Arterial Elastance (Ea): reflecting the effective arterial afterload and representing the slope of the line connecting EDV on the volume axis to the end-systolic PV point on the PV loop;- Ventricular-Arterial Coupling (VAC): calculated as the ratio between Ea/Ees;- troke Work (SW): the external work performed by the myocardium to eject blood, computed as the area enclosed by the PV loop;- SMechanical Potential Energy (PE): the energy generated within the contraction that is not converted to external work and calculated as the area enclosed by the ESPVR line, the isovolumic relaxation line and the end-diastolic pressure-volume relation (EDPVR);- Pressure-volume area (PVA): the total mechanical energy generated by the contraction of the left ventricle, equal to the sum of PE and SW;- Work efficiency (WE): the efficiency of the mechanical energy transfer from the ventricle to the arterial tree, expressed as the SW/PVA ratio.- LV end-diastolic stiffness coefficient (β): representing LV end-diastolic passive filling properties and calculated as the curve-fit parameter β of the EDPVR curve.- The mathematical formulas used are reported in HDFs represent the flow forces exchanged between the blood and the endocardial boundary. HDFs were assessed using a dedicated prototype software  based on a previously validated mathematical model . Both syBased on all parameters derived by standard and advanced echocardiography the following features were described:Cardiac remodeling in terms of changes in LV volumes and systolic function, GLS, Ees, LV diastolic stiffness, HDFs strength and distribution, non-invasive systolic pulmonary pressure, mitral regurgitation grade;- Vascular remodeling in terms of changes in blood pressure measurements and Ea;- Ventricular-arterial coupling and energy conversion efficiency in terms of changes in VAC, SW, PE, PVA and WE.- Intra-observer and inter-observer variability for HDFs and PV loop measurements were assessed in a sample of 10 patients. Two investigators measured blinded the same exam, and one investigator repeated the analysis 1 week later, blinded to the previous measurements.t-test or Wilcoxon test, when appropriate. Paired comparisons of categorical variables were conducted with the McNemar test. Interclass correlation coefficients (ICCs) were calculated to assess inter-observer and intra-observer agreement of HDFs and PV loop measurements. Differences were considered statistically significant when p < 0.05.Statistical analysis was performed with Statistical Package for Social Sciences, version 23.0 . Variables have been analyzed to test normal distribution. They were presented as mean ± standard deviation or median and 25th−75th percentiles, when appropriate. Paired comparisons of continuous variables were performed with two-tailed paired Student's General and clinical characteristics of the whole population are depicted in p < 0.001), LVEDVi (p < 0.001) and LVESVi (p < 0.001) and an improvement in LVEF (p < 0.001) were observed (p < 0.001) (p < 0.001) and, consequently, in EDP (p < 0.001) was observed. LV end-diastolic stiffness coefficient β did not change. After S/V treatment patients with moderate-to-severe mitral regurgitation had halved (p = 0.001). Left atrial volume also decreased, although its reduction was not statistically significant (p = 0.276). Moreover, there was a significant reduction in PASP (p =0.006). At follow-up there was also an improvement in HDFs alignment, with an increase in HDFs A-B values and consequently a significant reduction of HDFs LS/AB ratio in every phase of the cardiac cycle (Standard and advanced echocardiographic parameters and their comparison between baseline and follow-up are depicted in observed . Twenty-< 0.001) . A signiac cycle .p = 0.002 and p = 0.001, respectively) (p = 0.008) (Systolic and diastolic blood pressure showed a significant reduction after 6 months of therapy with S/V (ctively) . As eval= 0.008) .p < 0.001). While SW did not differ between baseline and follow-up (p = 0.899), potential energy . Thus, WE significantly improved (p = 0.001).After 6 months of S/V therapy, VAC significantly improved . These findings are in line with previous reports investigating the effect of S/V on myocardial strain  shifts down-left along the EDPVR. Thus, the decrease in filling pressure after S/V are mainly due to a reduction in volume overload. We should acknowledge that the follow-up period in our study is relatively short and possible effects of S/V on LV diastolic stiffness may need a longer time. Another known beneficial effect of S/V is the reduction in severity of functional mitral regurgitation due to lower cardiac preload, reduced LV volumes and increased LV systolic function leading to a rebalancing of closing and tethering forces. All the aforementioned beneficial effects, summed with a possible role of S/V in reducing the pulmonary vascular tone, concur to an improvement of post-capillary pulmonary pressures  was observed in 47% of the total cohort. Our results are in line with previous reports in literature. Several studies have shown that the therapy with S/V induces cardiac remodeling , 4 with l strain , 20. Prel strain . Moreoveressures , 23.In our report, we documented a realignment of HDFs during S/V therapy. HDFs are forces exchanged between the blood and the myocardium during the cardiac cycle. Blood flows into the cardiac chambers because of intra-ventricular pressure gradients (IVPGs), changing throughout the entire cardiac cycle. They are generated by the totality of the cardiac structure  . Recentla. Reduction of blood pressure may be explained not only by the diuretic and natriuretic effect but also by vascular remodeling. S/V was proven to improve endothelium-dependent and independent vasorelaxation , showing how EF is affected both by inotropic state and total afterload (a/Ees)/2] /2] . An optiThe most important limit of our study is the small sample size. Therefore, our results, especially those regarding HDFs estimation, should be considered as preliminary observations. Moreover, HDFs computation by echocardiography depends on image quality and it has to be considered as an estimation of real hemodynamic forces. Vascular afterload was assessed only with PV loop derived parameters. Finally, significant clinical outcomes were not evaluated, due to the limited number of major cardiac events observed during follow-up.After 6 months of S/V therapy, cardiovascular remodeling was observed in our cohort of HFrEF patients, in terms of volumes reduction, increased myocardial contractility, intraventricular-pressure gradients distribution improvement and optimization of vascular afterload. The ultimate effect is an amelioration of ventricular-arterial coupling and mechanical energy conversion efficiency. Our findings highlight the pleiotropic effect of S/V therapy generating a virtuous circle of both cardiac and vascular remodeling.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Policlinico Umberto I. The patients/participants provided their written informed consent to participate in this study.SM, DF, LA, and VM contributed to conception and design of the study. MS and FL organized the database. SM performed the statistical analysis and wrote the first draft of the manuscript. DF, SC, MN, MM, LIB, GB, GT, GP, and CDV wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.This study received funding from Novartis. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.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. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Despite technological advances, it remains the top choice among research labs for reporting heart function to this day, and is often overstated in applications. This unfortunately may lead to misinterpretation of data. Clinical approaches have now surpassed research methods, allowing for deeper analysis of the tiers of cardiovascular performance . Analysis of each tier is crucial for understanding heart performance, mechanism of action, and disease diagnosis, classification, and progression. This review will elucidate the differences between the tiers of cardiovascular function and discuss the benefits of measuring each tier  An increase in metabolic demand from the body (in situations such as exercise) mandates an increase in cardiac output to meet this demand. The heart increases cardiac output mulation . These imulation . Thus, tThe overall health of cardiovascular performance .Shown in While there are multiple means to diagnose heart disease in patients , stress test, electrocardiogram, and invasive such as angiography and cardiac catheterization), a common choice for diagnosis is echocardiography due to cost and ease. Typically, a special emphasis is placed on EF, which can be calculated through a multitude of techniques ranging in accuracy.EF can be measured by short or long-axis M-mode, which follows the displacement of the walls of the heart along a user-drawn line, which has user-dependent error and is highly variable. The most accurate method of measuring EF is 3D echocardiography to measure full LV chamber volume at systole and diastole . AlternaIn vivo modulators of heart function  result in changes to preload, a greater SV, and thus increased CO  and with good reason. This method remains the simplest and cheapest method to assess cardiovascular function over multiple time points throughout an experiment, allowing for assessment of progression of disease. However, this method falls short of assessing all tiers of cardiovascular performance. Specifically, standard echocardiography cannot assess diastolic function or cardiac contractility. Researchers often revert to alternative methods of assessing cardiovascular function, such as intra-left ventricular catheterization for pressure-volume analysis (PV loops) . Althougin vivo effects of alterations to ECC proteins  is also important in helping to ascertain disease mechanisms, testing if new treatment strategies  will be beneficial, etc. Another traditional in vivo measurement of contractility is performed via intra-left ventricular catheterization to measure pressure-volume changes in the heart. Indices such as dP/dtmax and dP/dtmin  reflect isovolumetric contraction and relaxation and can be obtained from PV loops  is the process by which the cardiac myocyte contracts and changes in myocyte contraction will alter contractility . Hence tproteins , signaliproteins , etc. asPV loops . UnfortuAlthough this review is focused on contractility, with the recent explosion of HFpEF, it is also vitally important to measure diastolic function. Unfortunately M-mode echocardiography, unlike STE, does not provide any measures of diastolic function.in vivo to enhance the reliability, relevance, and translational aspects.Due to the small heart size and fast heart rate, there are a lack of techniques to measure true parameters of heart performance in mice. Thus researchers, all too frequently, misuse parameters of cardiovascular performance, heart performance, systolic function, diastolic function, and contractility. Often researchers revert to using EF as a measure of systolic function or contractility. Other commonly misused parameters include SV, MAP, CO, and FS –5 which Thus, researchers should explore nonterminal procedures that can properly evaluate of all aspects of heart function. Parameters of cardiovascular performance, heart performance, systolic function, diastolic function, and contractility with their proper corresponding accurate measurement are listed in For basic research application, echocardiography has the advantage of longitudinal measurements for changes in heart function over time, rather than being the endpoint of an experiment. Traditional methods of echocardiography acquisition are often performed in M-mode, which traces the movement of the heart walls that occurs on a line drawn through the left ventricle. Besides misusing parameters obtained, this technique also introduces many sources of error and variation between measurements  as well as sources of variation in analysis . DespiteSTE has only in recent years infiltrated basic cardiovascular sciences as a means of measuring heart function in research models . STE anaMonitoring and maintaining a close to physiological heart rate during measurements of heart function is incredibly important for accurate recordings . VariabiSTE and its subsequent measurements also have the distinct advantage of deciphering early onset of disease, specifically in certain axes of strain. Circumferential strain and strain rate have been shown to be sensitive enough to detect early onset of disease. Strain and strain rate decrease earlier than EF, and thus can be used as earlier indicators of onset of disease. Circumferential strain has also been indicated as an independent predictor of negative outcomes and ventricular remodeling after myocardial infarction . LongituSTE can also elucidate regional functional measurements . Regionain vivo analysis of the tiers of heart performance, providing indices that measure not only heart structure, but cardiovascular performance and heart performance. Most importantly, STE is a nonterminal procedure that can provide indices of contractility not previously been accessible to basic research via echocardiography.In summary, STE is the superior method of The purpose of the heart is to pump blood to meet the metabolic demands of the body. In order to meet these demands, the heart needs healthy components of all aspects of function, including proper systolic and diastolic function and contractility. Proper evaluation of all the tiers are essential for the determining mechanism of action, the development, and progression of heart disease. A critical hallmark and determining factor of heart disease is a blunted contractility , which s


Microvascular obstruction (MVO) and Late Gadolinium Enhancement (LGE) assessed in cardiac magnetic resonance (CMR) are associated with adverse outcome in patients with ST-elevation myocardial infarction (STEMI). Our aim was to analyze the diagnostic performance of segmental strain for the detection of MVO and LGE.Patients with anterior STEMI, who underwent additional CMR were enrolled in this sub-study of the CARE-AMI trial. Using CMR feature tracking (FT) segmental circumferential peak strain (SCS) was measured and the diagnostic performance of SCS to discriminate MVO and LGE was assessed in a derivation and validation cohort.Forty-eight STEMI patients (62 ± 12 years old), 39 (81%) males, who underwent CMR  after primary percutaneous coronary intervention (PCI) were included. All patients presented with LGE and in 40 (83%) patients, MVO was additionally present. Segments in all patients were visually classified and 146 (19%) segments showed MVO , 308 (40%) segments showed LGE and no MVO , and 314 (41%) segments showed no LGE . Diagnostic performance of SCS for detecting MVO segments  showed an AUC = 0.764 and SCS cut-off value was –11.2%, resulting in a sensitivity of 78% and a specificity of 67% with a positive predictive value (PPV) of 30% and a negative predictive value (NPV) of 94% when tested in the validation group. For LGE segments  AUC = 0.848 and SCS with a cut-off value of –13.8% yielded to a sensitivity of 76%, specificity of 74%, PPV of 81%, and NPV of 70%.Segmental strain in STEMI patients was associated with good diagnostic performance for detection of MVO+ segments and very good diagnostic performance of LGE+ segments. Segmental strain may be useful as a potential contrast-free surrogate marker to improve early risk stratification in patients after primary PCI. The presence of microvascular obstruction (MVO) in patients with ST-segment elevation myocardial infarction (STEMI) is a predictor of poor functional recovery, congestive heart failure and mortality , 2. TherThe participants of this study were enrolled in the CARE-AMI trial  . DetaileScans were performed on a 1.5 Tesla system . Standard steady state-free precession 8 mm slice thickness ciné images were acquired covering the left and right ventricle in a short-axis (SAX) stack without gap and as well three long axis (LAX) views were obtained to cover for the whole ventricle to assess ventricular function and dimensions. For the LGE images, patients received gadobutrol as a contrast agent (0.2 mmol/kg) and 10–15 min post injection of contrast agent LGE images were acquired as described elsewhere .All CMR data were read by readers blinded to patient information and coronary angiography findings. Semi-quantitative LGE images were analyzed by the five standard deviation approach for %-of enhanced myocardial mass . MVO was42, Calgary, Canada, version 5.12) software. End diastolic, epi-, and endocardial contours were placed using the automatic contouring tool on a SAX stack, and three LAX  ciné images, and adjusted manually by the reader if necessary. Strain was calculated for systolic deformation parameters represented by peak strain (point of maximum deformation), time to peak strain (within the cardiac cycle), along with systolic strain rate (change of strain over time) in both the circumferential and longitudinal orientations   , 11. Meap-value < 0.05. Patient characteristics and global findings are reported for the entire cohort, as well as grouped by the presence or absence of MVO. These groups were compared by a Chi-square test or an independent t-test, for categorical or continuous variables, respectively.Continuous variables were expressed as mean ± standard deviation unless defined otherwise or median and interquartile range based on normality. Categorical variables were presented as frequency and percent of the population. Statistical significance was defined as a two-tailed lmer and emmeans  and a validation group of 18 patients (288 segments). In the derivation group, receiver-operator characteristic (ROC) curves were created to test the ability of strain measures to first discriminate between scar and no scar (LGE+ vs. LGE–), MVO and no MVO (MVO+ vs. MVO–) and for MVO discrimination within scar (LGE+/MVO+ vs. LGE+/MVO–). ROC curve analysis for peak strain was performed in a derivation cohort and then tested in a validation cohort. Optimal cut-off values for the different ROC curves were calculated with the Youden Index using the pROC function . These cImages of 10 randomly selected participants were replicated by a second independent reader and inter-observer reliability of one segment was assessed using a two-way intraclass correlation (ICC) test for absolute measures. Statistical analyses were performed with R software , GraphPad Prism version 9.0  with SPSS version 24 .p = 0.013)  remained for the purpose of the present analysis (96%). Thirty-nine (81%) patients were male. CMR exams were performed during the hospital admission within a mean of 3.0 ± 1.5 days after PCI. A total of 722 segments of 753 segments (96%) for short axis slices could be analyzed and 653 of 768 segments (89%) for longitudinal orientation. Detailed demographics for patient’s characteristics are depicted in = 0.013) .p ≤ 0.007, p ≤ 0.020 for all comparisons). With segmental longitudinal time to peak strain and systolic strain rate, only LGE– territories differed from LGE+/MVO+  segments were categorized as LGE+/MVO+, 308 segments (40%) as LGE+/MVO–, and 314 (41%) segments as LGE–. SCS significantly differed between all categories, and was significantly impaired in LGE+/MVO+ segments (–9.0 ± 0.6%) in comparison to LGE+/MVO– (–10.4 ± 0.5%), and LGE– (–17.4 ± 0.5%) (GE+/MVO+ . LogistiGE+/MVO+ .p = 0.017). Application of these cut-offs in the validation group for SCS yielded a sensitivity of 76%, a specificity of 74%, a positive predictive value (PPV) of 81% and a negative predictive value (NPV) of 70%. SLS yielded to a sensitivity of 88%, a specificity of 65%, a PPV of 73%, and a NPV of 71%.For scar (LGE+/MVO+ and LGE+/MVO–) vs. no scar (LGE–), ROC curve analysis of SCS showed an area under the curve (AUC) of 0.848 with an optimal cut-off of –13.8%. For SLS AUC was 0.806 and the cut-off was calculated at –13.5% (comparison between AUC p = 0.020).For MVO (LGE+/MVO+) vs. no MVO (LGE+/MVO– and LGE–) ROC curve analysis of SCS showed an AUC of 0.764 with an optimal cut-off of –11.2%. SLS showed an AUC of 0.728 with an optimal cut-off of –11.5% .For MVO discrimination within scar (LGE+/MVO+ vs. LGE+/MVO–) the ROC curve analysis for SCS showed an AUC of 0.606 with an optimal cut-off of –11.5%. For SLS AUC was 0.612 with an optimal cut-off of –11.4%  for SCS and 0.779  for SLS.The intraclass correlation coefficient for intrareader variability was 0.869  for SCS and 0.765  for the SLS. With regard to the inter- and intrareader variability for LGE mass (5SD method), we refer to a recent publication by our group, where the technique has proven to be a robust method . KEK Bern, Switzerland approved the study. The patients/participants provided their written informed consent to participate in this study.CG, AS, and KF analyzed the data and wrote the first draft. MF, AW, SE, AH, DG, RV, AR, SD, DH, SW, JL, and TP involved in acquiring the data from invasive coronary angiography, cardiac magnetic resonance imaging, post-processing, and contributing to writing the manuscript. All authors contributed to the article and approved the submitted version.http://www.ctu.unibe.ch/research/declaration_of_interest/index_eng.html. SD reported research grants to the institution from Pfizer. JL reported grants from Bangerter-Rhyner Foundation and grants from University of Bern during the conduct of the study. The remaining 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.TP reported research grants to his institution from Edwards Lifesciences, Boston Scientific, and Biotronik; personal fees from Biotronik and Boston Scientific as a speaker and HighLife SAS for clinical event committee participation; and proctoring with Medtronic and Boston Scientific outside of this study. SW reported research and educational grants to his institution from Abbott, Amgen, AstraZeneca, BMS, Bayer, Boston Scientific, Biotronik, Cardinal Health, CardioValve, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Johnson and Johnson, Medicure, Medtronic, Novartis, Pfizer, Polares, OrPha Suisse, Regeneron, Sanofi Aventis, Terumo, Sinomed, and V-Wave. SW served as unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, BMS, Boston Scientific, Biotronik, Cardiovalve, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave and Xeltis, but has not received personal payments by pharmaceutical companies or device manufacturers. He was also member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. RV reported grants from Clinical Trials Unit of the University of Bern during the conduct of the study. CG reported receiving funding from the Swiss National Science Foundation. DH reported affiliations with the Clinical Trials Unit Bern of the University of Bern, which has a staff policy of not accepting honoraria or consultancy fees; Clinical Trials Unit Bern is involved in design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organizations, and pharmaceutical and medical device companies provide direct funding to some of these studies. An up-to-date list of Clinical Trials Unit Bern’s conflicts of interest is at 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. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.This study was supported by dedicated grants from the Clinical Trial Unit of the University of Bern and the Bangerter-Rhyner Foundation.We thank Laura Morf, Nicole Reusser, and Lukas Lüthi from the research study team for their excellent technical and administrative support.https://www.frontiersin.org/articles/10.3389/fcvm.2022.909204/full#supplementary-materialThe Supplementary Material for this article can be found online at: Supplementary Figure 1ICC Bland-Altman plots. Top row: Interreader variability of SLS on the left and SCS on the right, respectively, with 95% confidence interval for the levels of agreement. Bottom row: Intrareader reliability of SLS on the left and SCS on the right with 95% confidence interval for the levels of agreement.Click here for additional data file.Supplementary Figure 2Confusion matrices for SCS and SLS for tissue discrimination. On the left: Confusion matrix showing the discrimination between LGE+/MVO+ (2), LGE+/MVO– (1) and LGE– (0) in a validation cohort with the use of cut-offs for SCS of –13.8 and –11.2%. Prediction results in a big FP rate for LGE+/MVO+, as can be seen in comparison of the row sums against column sums. On the right: The same can be seen for performance of SLS in a validation cohort with the cut-offs of –13.5 and –11.5%, which also result in a high amount of FP values for LGE+/MVO+. Of note: A perfect confusion matrix only shows results for the diagonal.Click here for additional data file.


The right heart is mainly supplied with blood by the right coronary artery (RCA). The impact of RCA chronic total occlusion (CTO) on the function of the right heart [right atrium (RA) and ventricle (RV)] and whether successful recanalization of a RCA CTO improves the function of the right heart is not clearly understood yet. We aimed to evaluate right atrial function after recanalization of the RCA using transthoracic echocardiography with additional strain imaging.p 0.086), RA area (p 0.093), RA major dimension (p 0.32) and RA minor dimension (p 0.139) at baseline and follow-up. Mean RA reservoir strain at baseline was 30.9% (21.1–43.0) vs. 33.4% (20.7–47.7) at follow up (p < 0.001). Mean RA conduit strain was − 17.5% (− 10.7–(− 29.7)) at baseline vs. − 18.2% (− 9.6–(− 31.7)) at follow-up (p = 0.346). Mean RA contraction strain was − 12.9% (− 8.0- (− 21.3)) at baseline vs. − 15.5% (− 8.7–(− 26.6)) at follow-up (p < 0.001).Fifty-five patients undergoing RCA CTO recanalization at the University Medical Center of Mainz were included in the study. Right atrial strain was assessed before and 6 months after successful CTO revascularization. The median age of the total collective was 66 (50–90) years. We did not find difference in our analysis of RA Volume (Right atrial function was altered in patients with RCA CTO. Successful revascularisation of an RCA CTO improved RA function assessed by strain imaging at follow-up. Coronary chronic total occlusions (CTO) are encountered in about 15–25% of patients with coronary artery disease undergoing coronary angiography. After initial neutral findings, recent evidence from clinical studies has demonstrated several benefits after successful CTO revascularization, especially in terms of angina relief and myocardial ischemia reduction, as well as regarding cardiac function .F.F13].Figp value of < 0.05 was considered to be statistically significant. The statistical analyses were performed using SPSS .Normal distribution of the variables was tested by QQ-plot analysis and the Kolmogorov–Smirnov test. Categorical data are presented as frequency and percentage, normally distributed data as mean ± standard deviation and not normally distributed variables are presented as median . To compare means the Student`s t-test was used and medians the Mann–Whitney U-Test was performed. A two-sided The data of 55 patients were analysed. All patients were in sinus rhythm at the time of the echocardiographic examination and showed no signs of (moderate or severe) valvular heart disease. Demographic parameters at baseline are shown in Table Fifty one (92.7%) of the patients had arterial hypertension and forty-eight (87.3%) had hyperlipidaemia. In addition, 70.9% of the collective were male, and the median age was 66 (50–90) years. Mean follow-up period was 192.5 ± 39 days.p 0.88).Clinical parameters at baseline are shown in Table p < 0.001) respectively in 38 patients . Complete freedom of angina was achieved in 74.5% of the patients in our collective and 63.6% of the patients reported to have no limitation of physical activity in daily life (NYHA stage 1) at follow-up  and the CCS stages (CCS = Canadian Cardiovascular Society Classification) at baseline and follow-up. We found an improvement in NYHA and CCS stage in 34 patients . Compared to the values of the left ventricle (LVEF and GLS), we found significant differences of the values of the function of the right ventricle . Results of the assessment of the right and left ventricular function is shown in Table We found grade 1 diastolic dysfunction in 27 (49.1%) and grade 2 diastolic dysfunction in 8 (14.5%) patients. There was no evidence of diastolic dysfunction in 20 36.4%) patients. At baseline mean LVEF (left ventricular ejection fraction) was 55% (20–59) and GLS  was − 16% (− 6.1–(− 22.7)) and at follow-up mean LVEF was 55% (21–55) and GLS was − 16.2% (− 5.2–(− 25.6)). There was no significant difference of this values at baseline and follow-up .Mean RA area was 16.65 ± 4.92 cmp 0.139) respectively the major dimension showed no difference (46.25 p 0.32). Right atrium dimensions and volumes were not altered compared to the reference ranges of the guidelines for the Echocardiographic Assessment of the Right Heart in Adults (2010) and guidelines of the European Association of Cardiovascular Imaging (2017) (RA area (reference: < 18 cm2 vs. 16.6 cm2), RA volume indexed for BSA (reference < 30 ml/m2 vs. 22.23 ml/m2), the RA minor dimension (reference < 4.4 cm vs. 3.9 cm) and RA major dimension (reference < 5.3 cm vs. 4.6 cm)). In the follow-up, values were still within the normal range [Analysis of the minor dimension at baseline vs. follow-up  for RA reservoir strain, − 17.5% (− 10.7–(− 29.7)) for RA conduit strain and − 12.9% (− 8.0–(− 21.3)) for RA contraction strain. Comparing our values for the right atrial function assessed by two-dimensional speckle tracking echocardiography with the reference values recommended by the World Alliance of Societies of Echocardiography Study, we found an impaired right atrial reservoir and contraction strain function in patients with RCA CTO (RA reservoir strain reference: 45.8 ± 13% vs. 30.9 (21.2–43.0)%; RA contraction strain reference − 27.6 ± 9.7% vs. − 12.9 (− 8.0–(− 21.3)) . The val.1–43.0 fAt follow-up RA reservoir strain was 33.4% (20.7–(− 47.7)), conduit strain − 18.2% (− 9.6–(− 31.7)) and contraction strain was − 15.5% (− 8.7–(− 26.6). Analysis showed a significant increase in the average values of RA reservoir and contraction strain.The results of the assessment of the right atrial function are presented in Table Inter-observer reproducibility was tested at baseline. Inter-observer reproducibility was good  as determined by intraclass correlation coefficients.This study evaluated right atrial function in patients with RCA CTO and compared baseline two-dimensional speckle tracking echocardiography parameters with control parameters 6 months after successful recanalization. The major findings of the study include the following: (1) right atrial function assessed by 2DE STE is impaired in patients with chronic total occlusion of the right coronary artery compared to reference values; (2) successful recanalization increases reservoir and contraction strain, atrial dimension and volume is not altered; (3) health status of patients with successful RCA CTO PCI improved.To date, studies described an improvement of the health status of patients after successful CTO PCI. Werner et al. found an improvement of angina frequency, quality of life and physical limitation in patients after successful CTO PCI compared to patients treated with optimal medical therapy at 12 month follow-up . These fIn contrast to the echocardiographic assessment of the right and left ventricle and the left atrium, the assessment of the right atrium is not yet part of the clinical routine. Standardized values of right atrial size and function were recently presented by the World Alliance of Societies of Echocardiography . Before Khedr et al. demonstrated in a collective with patients with stable CAD that the right atrial function is altered, atrial volumes and diameters were not affected. An altered right atrial function appears early in patients with stable CAD . EisvandWe showed an impaired right atrial reservoir and contraction strain function assessed by two-dimensional speckle tracking echocardiography in our collective. In a collective of 70 consecutive patients with inferior myocardial infarction and right ventricular infarction Nourian et al. showed an impaired atrial function assessed by 2DSTE. One reason could be the impaired right ventricular function in patients with right ventricular infarction, which affects the function of the right atrium .In our collective of patients with RCA CTO we found decreased right atrial and right ventricular function. Since ventricular function strongly influences atrial function, this could be an explanation for the decreased phasic RA function and its improvement after successful recanalization as the right heart is mainly supplied with blood by the right coronary artery . In CTO-. Due to the small sample size and our hypothesis , no regression analysis could be performed. Our study is hypothesis generating, studies with larger collectives are needed to confirm our results and show if altered right atrial function has a prognostic value in the CTO PCI setting.Apart from coronary artery disease, RA function could have been altered due to other factors . Also, RA strain imaging is not yet part of the clinical routineIn our study, we found that right atrial reservoir and contraction strain was impaired in patients with a chronic total occlusion of the right coronary artery. We demonstrated that right atrial reservoir and contraction strain was improved after successful recanalization, whereas conduit strain remained unaffected.


T2) relaxation distributions include 3 components that evolve with ripening time and position, corresponding to water inside the casein gel network, water trapped in casein, and fat. Two-dimensional T1-T2 relaxation experiments provided enhanced resolution of the 3 components, allowing quantification of the relative proportions of each phase. Furthermore, diffusion (D)-T2 relaxation correlation experiments revealed the bimodal size distribution of fat globules. The study demonstrated that single-sided NMR can provide spatially resolved signal intensity, relaxation, and diffusion parameters that reflect structural changes during the ripening process and can be exploited to understand and monitor the ripening of cheeses.The noninvasive, longitudinal study of products and food processing is of interest for the dairy industry. Here, we demonstrated that single-sided nuclear magnetic resonance (NMR) can be used for noninvasive monitoring of the cheese ripening process. The maturation of soft-ripened Camembert-like molded cheese samples was monitored for 20 d measuring 1-dimensional and 2-dimensional NMR relaxation and diffusion data at various depths, ranging from the hard surface layer to the soft center. Gelation and gel shrinkage were observed throughout ripening, and a complete loss of free water signal was observed at the cheese rind. Transversal ( Cheese is a dairy product derived from milk that can have a range of flavors, textures, and shapes depending on source materials and production conditions . Cheese During cheese production, a cheese gel network is formed . Cheese NMR) techniques have been widely exploited in food science (T2) relaxation is sensitive to the rotational mobility of molecules, which is affected by composition and chemical structure, as well as molecular exchange  and easy to automate. Diffusion experiments provide direct information about Brownian motion of molecules, reflecting molecular and aggregate sizes. Multidimensional correlation experiments improve the resolution and information content of relaxometry and diffusometry  and transverse relaxation times, whereas D-T2 experiments correlate the molecular diffusion coefficient (D) with T2 relaxation time, allowing, for example, the identification of water and liquid fat components , and 500 µL of rennet (Åströmin Jälk. Oy). The starter culture was a lyophilized mixture of Lactococcus lactis ssp. lactis, L. lactis ssp. cremoris, L. lactis ssp. lactis biovar diacetylactis, and Streptococcus salivarius ssp. thermophilus. The milk was warmed for 15 min at 30°C, and then calcium chloride was added to the milk. The mixture was stirred for 5 min with a spatula. Then, the bacteria and mold were added, and the mixture was left to stand for 15 min at 30°C. Finally, rennet was added and the mixture was left for 30 min at room temperature. The mixture was then filtered using a custom-made colander made from a plastic box with small perforations in the bottom. The remaining solid mass in the box was pressed for 12 h to drain the excess whey. Finally, the cheese was cut into 5 × 5 cm sections and salted with non-iodized salt. The samples were cured for 20 d in a room at 21°C and 15% humidity. Ripening measurements were performed on 2 different samples. Weight measurements were taken every day on one of the samples.Each cheese was made from 400 mL of pasteurized milk containing 3.2% fat , 2 mg of calcium chloride (Biochem s.r.l.), 2 mg of bacteria starter culture (Biochem s.r.l.), 2 mg of mold . The cheese sample was set on the top of the NMR-Mouse  of the cheese. Experiments were performed once a day for 20 d at room temperature.The NMR experiments were performed using a Magritek Profile NMR-Mouse PM 25 with an operating MR-Mouse , and T2 T2 relaxation data were measured using a Carr-Purcell-Meiboom-Gill (CPMG) sequence (n), 2.5-s repetition time, and 128 scans; the experiment time was 5.8 min. The T1-T2 data (T1 recovery time (t1) was varied from 1 to 2,500 ms in 32 log spaced steps. A 200-µs echo time (2τ), 512 echoes (n), 32 scans, and 2.5-s repetition time were used. The experiment time was 44 min.The sequence  with a 2-T2 data  were mea-T2 data  block fo-T2 data . SaturatS) observed in the T1-T2 experiment is described as follows:P is the T1-T2 correlation probability distribution.The signal (D-T2 data (S) observed in the D-T2 is given as follows:g is the gradient strength, δ is the time between 90° pulses, Δ is the diffusion encoding time, and P is the D-T2 correlation probability distribution.The -T2 data  were mea-T2 data  followed-T2 data . The dif1H signal intensity was defined as the signal at the fifth echo of the CPMG sequence corresponding to S(t = 1 ms). The T2 probability distribution, P(T2), was calculated from CPMG data using a 1-dimensional (1D) inverse Laplace transform (ILT) with ITAMeD implementation  and P distributions were calculated using the 2-dimensional (2D) ILT  ILT  with ITA(2D) ILT . Complethttps://doi.org/10.5281/zenodo.7197359; The results were further compared with another 2D ILT algorithm, Upen2DTool  based onD, T1, and T2 peaks were assigned to water, fat, and a protein-associated peak , at several depths, without alteration to the samples. These measurements were made possible by using single-sided NMR because it can measure samples of any size. Based on previous research, the obtained ted peak . There ited peak .1H signal intensity. 1H NMR signal intensity of sample 1 evolved during maturation as a function of ripening time and distance from the surface  is close to the T2 values of the 2 casein-associated water peaks (7.2 and 16.2 ms) observed by T2 (see below). The dominant intermediate T2 peak, labeled W, was attributed to highly mobile water present in the gel structure of the cheese. The high mobility was confirmed by the D-T2 measurements described below. The T2 of the water peak (about 30 ms) was much shorter than that of corresponding peak (488 ms) observed in mozzarella cheese by g, the observed apparent relaxation time T2app in the CPMG experiment can be calculated using the following equation , Eq. [3] gives T2app = 36 ms, which is in good agreement with the T2 of peak W observed in our experiments. The peak with the longest relaxation time was assigned to signal from protons in the lipid phase, F .To gain information about the evolution of the heterogeneous cheese structure , the NMRractions . In thismponents . In the  studies . The sho studies , was ascequation :[3]1T2aphase, F . These pT2 can be prone to misinterpretation. In the early 2000s, T2 of the fat proton covers a wide range, which is overlaid with the water proton relaxation time. Moreover, dairy products consist not only of fat and water, but also contain protein and sugar and, depending on the preparation, the system may become more complex. To address this issue, 2D NMR correlation experiments can be used, such as T1-T2 and D-T2 methods. In correlation experiments, the data are resolved using 2 correlated variables, which can improve peak separation and identification. In T1-T2 correlation experiments, the T1:T2 ratio can be identified for each component, which reflects mobility, interactions, and the state of molecules  was interpreted to be water trapped in casein, with T1 = 160 ms and T2 = 2.4 ms. The T1:T2 ratio is high, about 65, because chemical exchange is a particularly efficient relaxation mechanism for T2 relaxation  = 2 × 10−9 m2·s−1 at room temperature; D decreases as molecular size increases, such as for protein or fat, and when mobility is restricted by the structure  was interpreted to arise from water. We anticipate that the signal of water trapped in casein was fused with the water signal in the D-T2 maps due to their similar D and T2 values; the exchange between the casein-trapped water and gel pore water pools are expected to be relatively fast in the diffusion delay time scale, leading to similar D values for both sites. The D associated with the WP peak decreased as ripening progressed due to more restricted diffusion in the casein gel network. The 2 peaks with significantly lower diffusion coefficients  are interpreted to originate fat globules, which are known to have D values around that range (z = (2ΔD)1/2 corresponding to D = 10−10 and 10−11 m2·s−1 (Δ = 5 ms) were 1 and 0.3 μm, respectively. Therefore, we interpreted that the lower diffusion coefficient peak F1 corresponded to smaller fat globules with the size <1 μm and the F2 peak arose from larger, >1 μm, fat globules. Similar size ranges have been observed by microscopy  and could be differentiated from the soft-ripening process in the central layers (4–5 mm) using


The current management of ST‐elevation myocardial infarction (STEMI) has reached remarkable improvement in outcomes through the wide diffusion of early primary percutaneous coronary intervention (pPCI) and of pharmacological therapy aimed to reduce the occurrence of coronary restenosis and left ventricular remodelling (LVR). In particular, the European guidelines recommend the dual antiplatelet therapy, beta‐blockers, angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor agonists (MRAs) in the treatment of STEMI patients with reduction of left ventricular ejection fraction (LVEF).In patients with symptomatic HF and reduced LVEF, the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan (SAC/VAL) has been found to decrease the risk of hospitalization for HF and CVD more effectively than enalapril. PARADISE‐MI  trial was designed to test these drugs in patients with acute myocardial infarction (AMI) and reduced LVEF. Unfortunately, the risk of primary endpoint (reduction of time‐to‐first CVD or development of HF) was not decreased in the SAC/VAL group.However, the right answer is probably that the results of PARADISE‐MI may be a type 2 error and that there may be a missed benefit of ARNI, at least in STEMI patients.P = 0.01], clinical endpoint committee (CEC)‐adjudicated total events , and investigator‐reported total events  were considered.In a recent research letter written by the same authors of PARADISE‐MI study, it emerged that the treatment with SAC/VAL reached a significant reduction of primary endpoint compared with ramipril group when investigator‐reported time‐to‐first event [hazard ratio, 0.85 , More intriguingly, by a deeper evaluation of primary composite outcome according to pre‐specified subgroups from overall population of PARADISE‐MI trial, we can observe a trend towards superiority for SAC/VAL compared with ramipril treatment in STEMI rather than non‐STEMI (NSTEMI) patients.FigureDuring STEMI, the potentially irreversible myocardial reperfusion injury is determined by micro‐vascular obstruction, which is dependent on non‐modifiable factors, such as genetic predisposition and pre‐existing coronary micro‐vascular dysfunction, and on modifiable factors, such as ischaemic injury, micro‐embolization of thrombotic debris, and direct reperfusion injury.Because the controversial efficacy of mechanical interventions (thrombus aspiration) and of pharmacological therapies (Gp IIb IIIa inhibitors and adenosine) in the treatment of coronary micro‐embolization, and given no proven treatment able to fight the inflammation determined by reperfusion, the role of drugs aimed to improve the myocardial cell survival and regulate the extracellular matrix (ECM) homoeostasis became pivotal to prevent post‐STEMI LVR.The use of drugs aimed to improve the survival of cardiac myocytes against reperfusion injury may be effective even if the start of this therapy is not immediate, as well as for SAC/VAL in PARADISE‐MI trial (on Day 4.3 since randomization).SAC/VAL is a first‐in‐class ARNI that simultaneously provides neprilysin (NEP) inhibition and angiotensin receptors‐1 (AT‐1Rs) blockade. NEP is a zinc‐dependent neutral endopeptidase required for degradation of peptides with known cardioprotective effects, including bradikynin (Bk), natriuretic peptides (NPs), substance P (SP), adrenomedullin (ADM), and apelins.Angiotensin II (Ang II) is also a NEP substrate. In this case, NEP inhibition should not exert a protective effect on ischaemic myocardium. Ang II stimulates NADPH‐oxidase activity through plasmatic AT‐1Rs, leading to superoxide generation and promotes reperfusion injury. Nevertheless, a growing body of studies supports a protective role for cardiac renin–angiotensin system against reperfusion injury. In fact, plasmatic AT‐2Rs stimulation by Ang II leads to the AT‐2Rs translocation from plasmatic to mitochondrial membrane, where they suppress the formation of reactive‐oxygen species.The early introduction of ARNI in the therapy of STEMI patients is further supported by the anti‐fibrotic properties of SAC/VAL. Myocardial fibrosis represents the non‐reversible phenomenon leading to LVR, and it is completed in a few months.In the pPCI era, the next therapeutic targets to prevent LVR in STEMI are represented by the improvement of myocardial cell survival against reperfusion injury and regulation of extracellular matrix homoeostasis. To this aim, SAC/VAL use is supported by large pathophysiological and little, so far, clinical evidence. Thus, we can speculate that the early initiation of SAC/VAL may reduce cardiovascular events compared with ACE‐inhibitors/ARBs, in STEMI with acute moderate LVEF reduction, not only through a better regulation of circulating volume but also through the reduction of the necrotic area and fibrosis inside the ischaemic myocardium leading to prevention of post‐infarction LVR. It is hopefully that this hypothesis will be tested in next randomized large clinical trials.All authors declare that they have no conflict of interest.


Permanent hemodialysis access comes with a myriad of problems on top of the well-known benefits; flow disturbances, risk of infection and revision being among them. All of these could eventually lead to impaired cardiac function. Even so, the relationship between impaired cardiac function due to arteriovenous access in patients undergoing hemodialysis has not been clearly described. This study aimed to analyze the relationship of flow in an artificial arteriovenous access with left and right ventricular function in patients with chronic kidney disease (CKD) undergoing hemodialysis at a referral hospital in Indonesia.This was a cross sectional study with consecutive sampling technique. Samples were patients with CKD undergoing hemodialysis at Dr. Soetomo General Hospital from December 2021to January 2022. A total of 47 patients who met the inclusion criteria underwent Doppler ultrasound to assess arteriovenous access flow and transthoracic echocardiography to assess left and right ventricle function.From 47 patients, 26 (55.3%) had high arteriovenous access flow. The clinical characteristics of the patients between the high and low arteriovenous access flow groups were not significantly different. We found that the value of left ventricular ejection fraction in the non-high-flow access group was significantly higher than the high-flow access group (p < 0.05). Other than that, the median right ventricle fractional area changes in the non-high-flow access group was also higher than the high-flow access group (p < 0.05).Arteriovenous access flow as measured by Doppler ultrasonography has a significant relationship with impaired left and right ventricular functions based on systolic function parameters from echocardiography. •There is an association between arteriovenous access flow and ventricular function.•The higher the access flow, the lower the left ventricular systolic function.•The higher the access flow, the lower the right ventricular systolic function.•It is important to periodically evaluate the access flow of hemodialysis patients. The global estimated prevalence of CKD is 13.4% 11.7–15.1%), and patients with end-stage kidney disease (ESKD) needing renal replacement therapy is estimated between 4.902 and 7.083 million [.1%, and Permanent hemodialysis access, in addition to providing benefits, also brings a series of problems, such as flow disturbances, risk of infection, and the need for revision . It willThe relationship between impaired cardiac function due to arteriovenous access in patients undergoing hemodialysis has not been clearly described. Heart failure itself is a comorbidity in hemodialysis patients, and up to half of all deaths in the hemodialysis population are due to CVD . DespiteImpaired cardiac function can present a difficult treatment dilemma. Ideally, clinicians should treat symptoms and prevent the development of heart failure while simultaneously maintaining adequate vascular access for hemodialysis. Previous studies have showed that there were significant correlation between artificial hemodialysis access flow with cardiac function in CKD patients undergoing hemodialysis. However, the studies are sparse and never been done in Indonesia before ,10. Eluc1.1This was a cross sectional study with consecutive sampling technique. Sampling was carried out on CKD patients undergoing hemodialysis who met the inclusion criteria at Dr. Soetomo General Hospital from December 2021 to January 2022. The inclusion criteria in this study were patients diagnosed with CKD and undergoing hemodialysis with AVF and AVG who were >18 years old and were willing to follow the study procedure by signing an informed consent. The exclusion criteria were CKD patients who had comorbid conditions, such as structural heart disease, hyperthyroidism, or pregnancy.The independent variable in this study was Qa from AVF and AVG measured using color Doppler ultrasound examination, categorized into two group: high flow group (Qa > 2000 ml/min) and non-high flow (Qa < 2000 ml/min). The outcome of this study was echocardiographic parameters of left and right ventricular function which include: (1) left ventricular systolic function using the teich and biplane method, (2) left ventricular diastolic function, (3) tricuspid annular plane systolic excursion (TAPSE), and (4) right ventricular fractional area change (FAC). For secondary analysis, we analyzed the effect of the Qa/cardiac output (CO), maximal tricuspid regurgitation velocity (TRVmax)/CO, and maximal tricuspid regurgitant pressure gradient (TRmaxPG)/CO ratio index against hyperdynamic condition using cardiac index (CI) parameters of more than 3.9/min/m2 .1.2www.researchregistry.com) (Unique Identifying Number: researchregistry7793) [This study was conducted in accordance with the Declaration of Helsinki and reported in line with the STROCSS 2021 criteria . Prior ttry7793) . All sub1.3t-test or Man-whiney was used for comparison between high flow group and non-high flow group where appropriate according to data distribution. The Chi-Square test or Fisher's Exact test where appropriate, was performed to determine associations. Pearson or spearman test was used to analyze correlation between the variables as needed. Two-tailed P value < 0.05 was considered statistically significant.Statistical analysis was performed using IBM SPSS Statistics version 16.0  to determine the relationship between Qa and left and right ventricular function, and CI. Ordinal and nominal data will be displayed with frequency and percentage, while interval or ratio data will be displayed by mean ± standard deviation (SD) for normal distributed data, and median and inter quantile range (IQR) for non-normal distributed data. Independent sample 1.4Patients and the public were not involved in this study.22.1A total of 47 patientsmet the inclusion criteria and underwent Doppler ultrasound examination to assess Qa and transthoracic echocardiography to assess left and right ventricle function. Baseline characteristic of this study includes gender, age, body height, body weight, history of hypertension, history of diabetes mellitus, history of stroke, history of hemodialysis and arteriovenous access location.There were more female patients included in this study, with an average age of 47.4 ± 10.8 years, weight 57.1 ± 11.2 kg, and height 159.2 ± 7.5 cm. The most common comorbidity found was hypertension (87.2%). The average duration of history of hemodialysis was 4.6 ± 3.5 years, with the majority of arteriovenous access located on lower arm (53.2%). It was also found that 26 (55.3%) subjects had high Qa .Table 1B2.2An analysis of the basic characteristic variables was performed on Qa to compared between the high flow and non-high flow . The res2.3p value 0.296 dan 0.697 respectively). Further analysis with pearson and spearman correlation also confirmed this finding by showing significant negative moderate correlation between Qa and EF either by Teich and by biplane with Qa   .Table 3A2.4Next, the diastolic function  test was compared based on the Qa category. The results showed that the E/e' in the non-high flow group was lower than the high flow group, however the difference was not statistically significant . Meanwhile, the median results of E/A and LAVI were relatively similar in the low-flow group compared to the high-flow group, which means there was no significant relationship between E/A and LAVI with Qa  .Table 4AThe diastolic function was then categorized based on the grades and compared between the two Qa groups. The calculation results showed that grades 1 and 2 diastolic dysfunction were more common in high flow conditions than low flow conditions, however the difference was not statistically significant, so Qa did not determine the degree of left ventricular diastolic dysfunction severity  .Table 5C2.5Next, the TAPSE & FAC analysis test were carried out based on the Qa category. The median results showed that the TAPSE value was relatively the same in the low flow group compared to the high flow group . Meanwhile, FAC was influenced by the Qa category, proved by the result of the median FAC value in the non-high flow access group which was significantly higher than the high flow group  . Further2.6A description of several ratio indices, i.e., Qa/CO, TRVmax/CO, and TRmaxPG/CO, were performed based on the category of hyperdynamic conditions using CI parameters of more than 3.9/min/m2 . The res3In this observational analytical study, evaluation of Qa and cardiac function by Doppler ultrasonography and transthoracic echocardiography were performed on a total of 47 CKD patients undergoing hemodialysis. There were 26 patients (55.3%) with a Qa reading of more than 2000 ml/min. These patients were classified as high-flow access and considered to be associated with impaired cardiac function in this study. The basic characteristics of the research subjects which include, age, gender, history of hypertension, history of diabetes mellitus, history of stroke, and duration of hemodialysis history had no significant difference and do not affect the Qa group category from our bivariate analysis.There was a significant difference, however, in the LVEF. Patients with high flow access had lower mean LVEF than those with low flow access. The correlation test also showed a moderate negative correlation, which means the higher the Qa was, the lower the LVEF. This result is in line with the findings of Saleh et al. (2018), where they found patients in the high-flow access group showed a significantly lower ejection fraction with an average value of 57.32% compared to 62.90% for the low access flow group .Our findings support the data from several studies from the United States and Europe which suggest that the mortality and prevalence of heart failure may be increased in patients with AVF access compared to patients receiving peritoneal dialysis. In AVF, connecting arteries to veins results in wasted blood flow because flow in the fistula does not contribute to tissue perfusion. Cardiac output and ventricular work increase in response to decreased arterial resistance, while venous return to the heart increases substantially, resulting in an increase in volume load. These changes can lead to a high-output heart failure in some patients . For thiUnlike the result of the LV systolic function, the results of the statistical analysis in LV diastolic function showed that there was no significant association between Qa and LV diastolic function, either by the parameters of the E/e' ratio, E/A ratio, and LAVI, as well as by using the grading parameters according to the guideline of American Society of Echocardiography (ASE) . For theIn addition to having an impact on the left ventricle, CKD and hemodialysis with arteriovenous access also have an impact on the right ventricle, as the increase in volume load from AVF/AVG flow results in an increase in the right ventricular pressure and volume, which in turn impairs function. Our result showed a significant association between Qa and right ventricular FAC parameters with a moderate negative correlation. There was also a significant difference in the right ventricular FAC value between the Qa group, where the FAC was significantly lower in the high-flow access group compared to the non-high-flow access group. These results are in line with a previous study by Reddy et al. (2017) in which there was a two-to threefold increase in the prevalence of right ventricular dilation and dysfunction after AVF/AVG creation. It may reflect a state of volume overload caused by excessive shunt flow from Arteriovenous access. The previous study demonstrated for the first time that worsening right ventricular dilatation was independently associated with increased mortality and progression of heart failure in patients with CKD undergoing hemodialysis .Basile et al. (2008) found that a limit of Qa > 2000 ml/min and the concept of increased cardio-pulmonary recirculation using a Qa/CO ratio with a limit of >20% could be associated with the risk of high-output heart failure . We perfSince there is a significant relationship between Qa and left and right ventricular functions, we argue that it is then very important to conduct periodic evaluations in CKD patients undergoing hemodialysis. Interventions and medications to reduce ventricular remodeling in the early phase of cardiac dysfunction have the opportunity to prevent more progressive damage due to impaired access and CKD itself. Anti-remodeling drug strategies to surgery to reduce excessive access flow might be an option in the treatment of cardiac dysfunction, and in some studies arteriovenous access modification has a good impact on ventricular remodeling .3.1The main limitations of this study are the small number of samples and the cross-sectional study design. Further research with larger study subjects with cohort study design is needed to confirm the findings of this study.4There is a significant relationship between Qa with left and right ventricular systolic functions using right ventricular FAC parameters in CKD patients undergoing hemodialysis. In contrary, there is no significant relationship between Qa and left and right ventricular systolic functions using the TAPSE parameter in CKD patients undergoing hemodialysis.www.researchregistry.com) (Unique Identifying Number: researchregistry7793). All subjects gave their informed consent prior to their inclusion in the study. All data that could reveal the identity of the subjects have been omitted.This study was conducted in accordance with the Declaration of Helsinki and reported in line with the STROCSS 2021 criteria. Prior to study initiation, approval by the Institutional Ethics Committee of Dr. Soetomo General Hospital has been received (0326//KEPK/XII/2021). This study has also been registered at the Research Registry :https://www.researchregistry.com/browse-the-registry#home/registrationdetails/624e534e3076fe001e912f2d/JNEP and IP are the guarantor for this study.All subjects gave their informed consent before their inclusion in the study. All data that could reveal the identity of the subjects have been omitted.Not commissioned, externally peer-reviewed.The authors have no conflicts of interest to declare.