Weaning a critically-ill patient from the ventilator is a crucial step in global management. This manuscript details physiological changes induced by altered heart-lung interactions during the weaning process, illustrates the main mechanisms which could lead to weaning failure of cardiac origin, and discuss a tailored management based on the monitoring of changes in central hemodynamics during weaning. The transition from positive-pressure ventilation to spontaneous breathing results in abrupt hemodynamic and metabolic changes secondary to rapidly modified heart-lung interactions, sudden changes in cardiac loading conditions, and increased oxygen demand. These modifications may elicit an excessive burden on both the respiratory and cardiovascular systems, result in a rapid and marked increase of left ventricular filling pressure, and ultimately result in a weaning-induced pulmonary oedema (WIPO). The T-piece trial induces the greatest burden on respiratory and cardiocirculatory function when compared to spontaneous breathing trial using pressure support ventilation with positive or zero end-expiratory pressure. Since LV overload is the mainstay of WIPO, positive fluid balance and SBT-induced acute hypertension are the most frequently reported mechanisms of weaning failure of cardiac origin. Although the diagnosis of WIPO historically relied on an abrupt elevation of pulmonary artery occlusion pressure measured during right heart catheterization, it is nowadays commonly documented by echocardiography Doppler. This non-invasive approach is best suited for identifying high-risk patients, depicting the origin of WIPO, and tailoring individual management. Whether this strategy increases the success rate of weaning needs to be evaluated in a population at high risk of weaning failure of cardiac origin. Weaning a critically-ill patient from the ventilator is a challenging process and a key step in overall therapeutic management since weaning failure is associated with a prolonged duration of mechanical ventilation and length of stay in the intensive care unit (ICU) . In turnWeaning from positive-pressure ventilation has been compared to an exercise stress test for the cardiovascular system . Indeed,Historically, the diagnosis of WIPO relied on an abrupt elevation of pulmonary artery occlusion pressure (PAOP) during right heart catheterization . CurrentInterruption of positive-pressure ventilation increases venous return, LV afterload and the work of breathing. Greater respiratory muscle oxygen consumption and cardiac workload may induce heart ischemia and decreased LV compliance . OverallThe transition from a positive intrathoracic pressure under mechanical ventilation to a negative pleural pressure generated by the respiratory muscles accounts for the consistent rise of PAOP during SBT . PreviouAmong patients undergoing ventilator weaning, three groups have been distinguished by an international consensus conference : simple No large-scale study assessing the prevalence of WIPO according to the different weaning groups is currently available. Most descriptive studies reported the rate of WIPO at the origin of weaning failure in patients with difficult or prolonged ventilator weaning . TypicalWIPO accounts for nearly 60% of weaning failure in patients with COPD (OR: 8.7 [2.0–37.3]), heart disease (OR: 4.5 [1.4–14.1]), or obesity (OR: 3.6 [1.2–12.6]) . Indeed,COPD patients are prone to develop WIPO for several reasons. First, the acute change of LV loading condition induced by SBT is exacerbated, since the hyperinflation and increased airway resistance during spontaneous ventilation require large negative inspiratory pressure to generate adequate tidal volumes . Second,In the WIND study, the 2,904 SBTs performed by physicians were almost equally distributed between T-piece ventilation (49.9%) and low pressure ventilation trials (47.5%), while other types of SBTs were seldom . In a phOverall, T-piece trial elicits the greatest burden on respiratory and cardiocirculatory function during SBT. Since patients at high risk of WIPO require a higher threshold for extubation, a successful T-piece trial appears to sensitively assess their ability to tolerate fully unsupported spontaneous breathing .p = 0.04 and 7.0 [5.0–9.2] vs. 5.6 [5.2–6.3]: p = 0.04, respectively). Similarly, Excessive rise in LV filling pressure during SBT in patients who develop WIPO is multifactorial. Although the leading mechanism at the origin of WIPO may vary, positive fluid balance frequently associated with hypervolemia is common . TypicalMitral regurgitation (MR) may participate in WIPO. Three mechanisms of MR may be distinguished during SBT: worsened functional MR, restrictive ischemic MR, eccentric MR secondary to a systolic anterior motion of the mitral valve with LV outflow tract obstruction . Abrupt Echocardiography study during SBT in COPD patients are scarce. The prevalence of elevated PAOP in these patients is high . In patiPassive leg raising before SBT has been proposed to predict WIPO , as wellEchocardiography is of major interest to early identify ventilated patients who are at high-risk of developing WIPO, before initiating SBT . This poDuring SBT, Since diuretics reduce circulating blood volume and may also reduce airway edema and resistance, they constitute the mainstay of WIPO management . In a raVasodilators can preferably be used in hypertensive patients who develop WIPO secondary to SBT-induced high blood pressure, including initial intravenous boluses to rapidly decrease systolic arterial pressure, hence LV afterload . NitrateBeta-blockers can also be advantageously used in the specific setting of LV outflow tract obstruction associated with an anterior systolic motion of the mitral valve and eccentric MR . The adrThe use of inotropes in patients developing WIPO appears counterintuitive since LV contractility does not seem to be hampered by SBT, even in patients with previous LV systolic dysfunction . MoreoveFinally, myocardial ischemia induced by SBT is seldom responsible for WIPO . NeverthSince the level of evidence of WIPO treatment is low for non-diuretics drugs and only based on physiology and small sample size, non-randomized interventional studies, a personalized approach in high-risk patient based on echocardiography monitoring is attractive to tailor therapy  Figure . PatientThe transition from positive-pressure ventilation to spontaneous breathing may elicit an excessive burden on both the respiratory and cardiovascular systems, and result in WIPO. The population at risk is broad and occult cardiac disease may be revealed at the time of SBT. Although positive fluid balance frequently participates in WIPO, alternative leading mechanisms may also be operant. Echocardiography is best suited for identifying high-risk patients, guiding early strategy to reduce LV overload, depicting the origin of WIPO, tailoring individual management, to ultimately increase the success rate of further SBTs and extubation. The effect of such strategy on patient-centered outcomes needs to be evaluated in a large population of patients at high risk of weaning failure of cardiac origin.


Coronary artery disease (CAD) is the leading cause of death followed by cancer, in men and women. With risk factors being endemic and the increasing costs of healthcare for management and treatment, myocardial perfusion imaging (MPI) finds a central role in risk stratification and prognosis for CAD patients, but it comes with its limitations in that the referring clinician and managing team must be aware of and use at their advantage. This narrative review examines the utility of myocardial perfusion scans in the diagnosis and management of patients with ECG alterations such as atrioventricular block (AVB), and medications including calcium channel blockers (CCB), beta blockers (BB), and nitroglycerin which may impact the interpretation of the exam. The review analyzes the current evidence and provides insights into the limitations, delving into the reasons behind some of the contraindications to MPI. Coronary artery disease (CAD) remains the leading cause of mortality in the United States (US), a trend that has persisted since 1990. CAD is responsible for a greater number of years of life lost due to premature mortality compared to the combined sum of lung, colon, breast, and prostate cancer. It is estimated that 10.9% of adults aged 45 or older and 17.0% of adults aged 65 or older in the US have CAD, respectively, with approximately 800,000 Americans experiencing a myocardial infarction (MI) each year. The economic burden of CAD is substantial, with estimated healthcare costs of $126.2 billion in 2010, which has been projected to increase to over $177 billion by 2040 . Althoug99mTechnetium-Sestamibi has been found to encompass a similar prognostic value compared to other methods. 99mTechnetium-Sestamibi offers clear advantages over 201Thallium-SPECT, particularly when gated. Functional perfusion imaging has a clear advantage in predicting cardiac events .,23.22,23The electrical impulse generated by the sinoatrial node must pass through the atria, the atrioventricular node, and the His–Purkinje system to reach the ventricles and trigger ventricular contraction, which is reflected as the PR interval and QRS complex on an ECG. If there is a delay in conduction within this system, this can result in an atrioventricular conduction block, leading to a prolonged PR interval on the ECG ,28,29. ABalanced ischemia is a condition characterized by a relatively equal reduction in blood flow in all regions of the myocardium during stress. This can be due to various factors such as coronary artery disease, which may lead to the narrowing or blockage of the coronary arteries. Balanced ischemia is often identified by SPECT imaging as a uniform decrease in radiotracer uptake throughout the myocardium, indicating an impaired perfusion to the entire heart. As it is hard to tell apart from a normal heart scan, a positive stress ECG should alert the physician conducting the examination. Prompt recognition and management of balanced ischemia are crucial to prevent further complications and optimize cardiac function ,37.Calcium, when it is in its ionized form (Ca2+), is widely recognized as a crucial second messenger in cells. The entry of Ca2+ into the cytoplasm is regulated by Ca channels, which allow Ca2+ to enter from external sources or be released from internal stores. Plasmalemmal ion channels, such as voltage-operated channels, receptor-operated channels, store-operated channels, and non-selective channels, are responsible for the entry of Ca2+ into the cell. Voltage-operated channels are further classified into three subtypes based on their conductance and voltage sensitivity, namely L (long-lasting), T (transient), and N  subtypes. Calcium antagonists primarily block the entry of calcium into cells by targeting the L subtype of the voltage-operated channels, thereby altering their opening mode to favor the short-lived channels and shifting them to a long-lived closed state . In clinBeta-blockers are a class of drug that is used in order to reduce ischemic effects by lowering oxygen consumption during both rest and stress ,49. The As a therapeutic agent, adenosine is employed for its antiarrhythmic properties in supraventricular tachycardia (SVT), and it can also function as a diagnostic tool depending on the type of SVT. The pharmacological effects of adenosine are mediated through purinergic adenosine receptors, including the A1, A2a, A2B, and A3 receptors, which are distributed across various systems such as the immune, nervous, circulatory, respiratory, and urinary systems. Notably, the receptors located in the cardiac atrioventricular (AV) nodal tissue and peripheral vasculature exhibit clinical effects when adenosine is administered ,58,59. Aage of the patient)). If the target heart rate is not reached at the highest dose, atropine can be additionally administered . The target heart rate can be achieved in over 90% of patients. The effects of dobutamine, which has a plasma half-life of 120 s, can be countered with a beta-blocker. The criteria for terminating the test and contraindications align with those for exercise testing [Dobutamine, a sympathomimetic agent, increases heart rate, blood pressure, and contractility, leading to an increase in myocardial oxygen consumption and reflexive enhancement of perfusion, potentially provoking ischemia in the presence of coronary stenosis. The stress is administered in 3 min intervals, starting with an initial infusion rate of 5 µg/kg/min and gradually increasing to 10, 20, 30, and 40 µg/kg/min, respectively. The target heart rate to be achieved is  is an inherited condition characterized by the presence of unexplained left ventricular hypertrophy, along with a non-dilated left ventricle and a preserved or an increased ejection fraction. Typically, the hypertrophy is uneven, with the basal interventricular septum showing the most pronounced thickening. Resting left ventricular outflow tract obstruction has been observed in approximately one-third of patients, while it was able to be induced in another one-third. In SEPCT imaging, it was found that it can disrupt the normal walls uptake, with the hottest pixels being in the septum, showing an apparent reduced perfusion in the rest of the left ventricle ,76.Dextrocardia is a rare cardiac congenital abnormality that presents itself with a right-sided heart mirroring normal anatomy . PatientThe presence of the pacemaker and LV leads in SPECT imaging may cause overestimations when applying CT attenuation correction (CTAC). However, a study found that the impact of these leads on SPECT findings was minimal. The overestimation was higher for ICD leads but remained at only 4%. The diameter of the leads and the composition of the materials used have been found to influence the levels of overestimation. Overall, CTAC was deemed useful despite the presence of these leads, as the leads did not significantly affect the SPECT results in both normal and high-resolution imaging. The study further clarified the limited impact of the leads on SPECT with CTAC .201Thallium. Functional abnormalities are yet to be studied with viability tracers such as 18F-FDG. The use of this tracer as a direct imaging agent for detecting exercise-induced myocardial ischemia shows great promise, as the differential glucose uptake between the normal and ischemic myocardium enables exercise 18 FDG to be used as a hot-spot imaging agent to detect this condition [vβ3, which is involved in endothelial cell survival and propagation and is present in response to angiogenic growth factors. Apoptosis has also been assessed using imaging, by labelling 99mTechnetium to annexin V, a protein expressed on the cell surface of apoptotic cells  and left bundle branch block (LBBB) when pharmacologic stress is conducted, to evaluate the presence and extent of myocardial ischemia. It can also help clinicians in assessing the efficacy of medical therapies, such as calcium channel blockers, beta-blockers, and nitroglycerin, in reducing myocardial ischemia. While there is still ongoing research on the clinical significance of perfusion defects in these patient populations, the information obtained from myocardial perfusion scans can aid in guiding clinical decision-making and optimizing patient care, knowing when to evaluate a patient undergoing therapy, and when to stop therapy to assess their baseline heart condition. This procedure still presents a limitation put forward in a recent trial, where there was no indication that an initial invasive approach compared to a conservative one could lead to lower event rates or a lower overall mortality . Therefo


Heart failure is a serious global health problem, and coronary artery disease is one of the main causes. At present, the treatment options for ischemic heart failure (IHF) are limited. This article mainly aims to explore the evidence of enhanced external counterpulsation (EECP) as a non-invasive cardiac rehabilitation method in patients with IHF and to make a preliminary exploration of its mechanisms.According to the existing evidence, the standard course of EECP is safe in patients with IHF and can significantly improve the quality of life of these patients. The effect of EECP on systolic function is still unclear, while EECP has a significant improvement effect on cardiac diastolic function. At the same time, this treatment can reduce the re-hospitalization rate and emergency visit rate of patients within 6 months. In terms of mechanisms, in addition to the immediate hemodynamic effect, existing evidence mostly suggests that its improvement of cardiac function may come from its upregulation of shear stress to improve myocardial perfusion.EECP is safe to use in patients with stable ischemic heart failure, and it can improve the performance status of patients and may be beneficial to cardiac function and reduce the short-term re-hospitalization rate. With the progress of population aging, heart failure has gradually become an important health problem in today’s world, causing huge social and economic burden. In recent years, although the incidence of heart failure has decreased compared with before under active prevention and control, the mortality rate is still on the rise . The 202There are only a few randomized controlled studies on the clinical efficacy of EECP in patients with IHF, most of which are cohort studies, and the sample sizes included are relatively small (see Table 2peak) was also observed in the EECP group 1 week after treatment, but this effect disappeared during follow-up [2peak by 1.25 ml/kg/min as exercise response. It was found that in subjects over 65 years old, both exercise response rates were significantly higher in the EECP group. The above differences may be due to weaker baseline exercise capacity in elderly patients, which may make it easier to demonstrate the benefits of intervention [In 2006, Arthur et al. published the results of the PEECH study, which included 130 IHF patients with NYHA class II–III, who were randomly assigned to the EECP group or the control group. It was found that the NYHA classification and quality of life of the EECP group were significantly improved after treatment. In terms of exercise tolerance, the total exercise time of the EECP group was significantly higher than that of the control, and this effect lasted for 6 months after treatment. Improvement in peak oxygen uptake  showed that LVEF improved significantly after standard EECP treatment  [Regarding changes in objective indicators of systolic function, left ventricular ejection fraction (LVEF) is the most common evaluation index. However, there is no unified conclusion on the effect of EECP on LVEF. Amr et al. included 42 patients with IHF after coronary artery bypass surgery, and no improvement in LVEF was found after 3 months of follow-up after the treatment . Yavari  < 0.01) . Fariba  < 0.01) . While i < 0.01) .The reasons for the different results above might be affected by the heterogeneity of the included patients, including the differences in the degree of coronary artery lesion, revascularization strategy, and baseline LVEF, which may affect the efficacy of EECP. In addition, for patients with preserved or mildly decreased ejection fraction, whether LVEF is an appropriate evaluation index is also worth exploring. In recent years, the development of cardiac speckle-tracking technology has been rapid. Its myocardial strain parameters can more sensitively and comprehensively evaluate myocardial systolic function than LVEF. A small amount of research has applied speckle-tracking technology to evaluate the clinical efficacy of EECP in CHD patients without heart failure and found significant improvement in global longitude strain (GLS) during EECP treatment , 19. TheP < 0.05) and E/Ea ; the above indicators improved significantly after EECP treatment. Other researchers evaluated patients with CHD without heart failure using E/A, left ventricular end-diastolic pressure, peak filling rate (PFR), and the time to PFR, and found that EECP has a potential positive effect on cardiac diastolic function.As for the impact of EECP on cardiac diastolic function, there are fewer relevant studies, but the conclusions are relatively consistent , 16, 20.In the PEECH study, the effect of EECP on short-term prognosis was evaluated; 9% of patients underwent EECP and 13.6% of controls were readmitted within 180 days . In a stGiven the hemodynamic changes during EECP treatment, an increase in the amount of blood returning to the heart might worsen congestive heart failure. Hence, the evaluation of the safety of EECP in IHF patients is extremely important. However, in clinical practice, no increase in heart failure exacerbation or thrombotic events was observed during or after EECP treatment. The safety of elderly subjects was consistent with that of the entire study population. However, discomfort such as skin and bone occurred significantly more frequently than in the control group , 10.At this stage, the mechanisms of EECP are mainly divided into immediate hemodynamic effects and long-term anti-ischemic mechanisms mediated by shear stress, and there are still other potential mechanisms that need to be explored  level. ADM is a vasodilator peptide which secreted by endothelium. Previous animal studies have found that the absence of ADM action could induce myocardial fibrosis and decrease LVEF, accompanied by a decrease in mitochondrial number, membrane potential, and respiratory function •. At theGiven the mechanisms of EECP, the primary concern for its application in patients with heart failure is safety assessment. Based on existing research results, the use of EECP in the stable stage of ischemic heart failure does not increase the risk of serious adverse events (including worsening heart failure and thrombotic events), but the discomforts of skin and bone may increase. In terms of effectiveness, EECP treatment can significantly improve NYHA classification and increase exercise time regardless of the cause of heart failure or baseline LVEF. At the same time, there is a clear improvement in diastolic function of the heart, while the effect on systolic function is not clear. There is an improvement in short-term prognosis indicators such as heart failure readmission after EECP treatment. In terms of exploring the mechanisms by which EECP improves heart failure, in addition to its immediate hemodynamic effects to reduce cardiac afterload and increase coronary perfusion, existing evidence mainly suggests that EECP can improve endothelial cell function to increase vasodilator release and promote neovascularization by upregulating shear stress and thus increasing myocardial contractility.Combining the above conclusions, it can be found that there are still many limitations in the exploration of EECP application in IHF: ① lack of large-scale RCT studies, existing research designs have shortcomings such as small sample size, non-blinding, high heterogeneity, which affect the reliability of results; ② lack of long-term follow-up observation limits the long-term evaluation of safety and efficacy of EECP in patients with IHF; ③ the evaluation indicators are relatively single, the comprehensive application of echocardiography, speckle-tracking imaging, cardiac magnetic resonance, and other methods can more comprehensively and sensitively evaluate changes in cardiac function; ④ in terms of exploring the mechanisms, it is currently mainly limited to its improvement in myocardial perfusion. Future research would explore whether EECP can directly enhance myocardial cell contractility to improve cardiac function.


In recent years, GLP-1 receptor agonists (GLP-1RA), and SGLT-2 inhibitors (SGLT-2i) have become available, which have become valuable additions to therapy for type 2 diabetes as they are associated with low risk for hypoglycemia and cardiovascular benefits. Indeed, SGLT-2i have emerged as a promising class of agents to treat heart failure (HF). By inhibiting SGLT-2, these agents lead to excretion of glucose in urine with subsequent lowering of plasma glucose, although it is becoming clear that the observed benefits in HF cannot be explained by glucose-lowering alone. In fact, multiple mechanisms have been proposed to explain the cardiovascular and renal benefits of SGLT-2i, including hemodynamic, anti-inflammatory, anti-fibrotic, antioxidant, and metabolic effects. Herein, we review the available evidence on the pathophysiology of the cardiological benefits of SGLT-2i. In diabetic heart disease, in both clinical and animal models, the effect of SGLT-2i have been shown to improve diastolic function, which is even more evident in HF with preserved ejection fraction. The probable pathogenic mechanisms likely involve damage from free radicals, apoptosis, and inflammation, and therefore fibrosis, many of which have been shown to be improved by SGLT-2i. While the effects on systolic function in models of diabetic heart disease and HF with preserved ejection fraction is limited and contrasting, it is a key element in patients with HF and reduced ejection fraction both with and without diabetes. The significant improvement in systolic function appears to lead to subsequent structural remodeling of the heart with a reduction in left ventricle volume and a consequent reduction in pulmonary pressure. While the effects on cardiac metabolism and inflammation appear to be consolidated, greater efforts are still warranted to further define the entity to which these mechanisms contribute to the cardiovascular benefits of SGLT-2i. At present there are a number of classes of pharmacological agents used for type 2 diabetes (T2D), with multiple agents available in each class . In receOf note, T2D is one of the main risk factors for CV diseases. It is directly associated with diabetic cardiomyopathy  and incrFour major CV outcome trials (CVOTs) – EMPA-REG (empagliflozin), CANVAS (canagliflozin), DECLARE-TIMI 58 (dapagliflozin), and VERTIS CV (ertugliflozin), investigated the CV benefits of SGLT-2i in patients with T2D . ReductiFaced with these promising results, dedicated trials in patients with HF were initiated –15. BaseBy inhibiting SGLT-2, SGLT-2i lead to excretion of glucose in urine with subsequent lowering of plasma glucose . HoweverA literature search was performed on PubMed for relevant articles and abstracts. The search string used was (“Sodium-Glucose Transporter 2 Inhibitors“[tiab] OR “Sodium-Glucose Transporter 2 Inhibitor“[tiab] OR “Sodium-Glucose Transporter 2 Inhibitors“[Mesh] OR “SGLT2-i“[tiab] OR “dapagliflozin“[tiab] OR “empagliflozin“[tiab] OR “canagliflozin“[tiab]) AND (“stroke volume“[mesh] OR “ejection fraction“[tiab] OR “Doppler“[tiab] OR “wedge“[tiab] OR “pulmonary artery pressure“[tiab] OR “end-diastolic volume“[tiab] OR “end-diastolic pressure“[tiab] OR “cardiac index“[tiab] OR “stroke volume“[tiab]) AND (mechanism*[tiab] OR pathway*[tiab]) AND (“Heart Failure“[Mesh] OR “heart failure”[tiab]). Papers were selected for inclusion in the present review according to their relevance, as judged by the authors. As a literature review, no ethics committee approval was needed.A number of studies have examined the effects of SGLT-2i on cardiac structure and function in animals and humans with diabetes Table .The effects of dapagliflozin on myocardial function have been evaluated in a rat model with streptozotocin-induced diabetes, wherein the heart developed diabetic cardiomyopathy with pronounced fibrosis and a decline in diastolic and systolic function . All of Adingupu et al. studied metabolic changes and CV function in ob/ob-/- mice, a model for obesity and reduced glucose tolerance characterized by systolic microvascular dysfunction . CompareCardiac contractility and CFVR were studied by Suhrs et al. in a randomized, placebo-controlled cross-over study in 13 patients with T2D treated with empagliflozin 25 mg or placebo for 12 weeks . No subs2 with empagliflozin compared to 0.01 g/m2 in patients receiving placebo.Shih et al. examined changes in left ventricular function in patients with diabetes who did not have symptomatic HF following 6 months of treatment with dapagliflozin . Both diKayano and colleagues investigated changes in diastolic function during exercise, measuring left ventricular filling pressure (LVFP) and right ventricular systolic pressure (RVSP) in 78 patients with T2D and poor glycemic control . ParticiDiastolic function has also been examined by Rau et al. who randomized 40 patients with T2D to empagliflozin or placebo for 3 months . EmpagliIkonomidis et al. investigated the effects of a number of glucose-lowering therapies on cardiac hemodynamic parameters . AltogetImpedance cardiography is a non-invasive method that allows calculation of stroke volume, cardiac output, and other hemodynamic variables . The tecAnimal and human studies in heart failure with preserved ejection fraction are listed in Table Habibi et al. reported that empagliflozin improves diastolic function in obese female db/db mice . In part2+ and Na+. Dapagliflozin further inverted endothelial activation, and reduced cardiac inflammatory markers such as NFkB and IL-6 as well as pro-fibrotic signaling via TGF-b.In a hypertensive model of HFpEF in rats, empagliflozin was associated with significantly decreased cardiac fibrosis in atrial and ventricular tissues, and the atrial and ventricular expression of several molecules including PPARα, natriuretic peptides, and TNF-α were normalized . In a siA study in a hypertension/hyperlipidemia-induced HFpEF pig model, dapagliflozin administered for 9 weeks significantly diminished cardiac concentric remodeling, although no improvements in diastolic function were observed . MoreoveLastly, HMGB1 appears to serve as a driver of inflammation for CV disease . In a moIn patients with T2D and stable HF with preserved EF, Soga et al. investigated the effect of dapagliflozin on left ventricular diastolic function . PatientSeveral animal studies have attempted to shed additional light on the mechanisms behind the cardiac benefits of SGLT-2i in patients with HF Table . In a diSGLT-2i inhibitors appear to be of benefit when given both before and after MI. For example, in another model of HFrEF due to ischemic cardiomyopathy, pressure-volume (P-V) relationship analysis was used to examine changes in intrinsic cardiac function in animals with experimental MI . FollowiThe effects of SGLT-2i have also been evaluated in non-diabetic experimental models. In one study, non-diabetic rats underwent sham surgery or permanent coronary artery ligation to induce MI . The aniMechanistic insights have also been provided. In a nondiabetic rat model of ischemic HF, animals were administered, or not, empagliflozin immediately after induction of MI . In animCardiac contractile function and myocardial substrate utilization has been assessed in lean swine that received canagliflozin or placebo 24 h before temporary occlusion of the circumflex coronary artery. Invasive study protocol was performed at baseline, during.Coronary occlusion and during 2 h of reperfusion . At the In an investigation in healthy normoglycemic rats, at 30 min after the administration of empagliflozin, increases in ventricular systolic pressure, mean pressure, and the max dP/dt were observed . EmpaglimTOR has also been implicated in a mouse model of cardiac dysfunction induced by sunitinib that was used to study the protective effects of empagliflozin . Mice trIn a model in rats in which mitral regurgitation (MR) induced HFrEF, animals were given no treatment or dapagliflozin for 6 weeks . DapagliIn another animal model of non-ischemic HFrEF, transverse aortic constriction (TAC) was used to induce cardiac remodeling . DapagliInflammation has been clearly linked in the CV benefits of SGLT-2i. In the same model of TAC-induced HFrEF, treatment with inhibitor empagliflozin confirmed the effects on lessened left ventricular enlargement . FurtherIn an animal model of diabetes using male BTBR ob/ob mice, dapagliflozin, ticagrelor, or the combination for were administered for 12 weeks, both agents decreased progression of diabetic cardiomyopathy as shown by amelioration in left ventricular end-systolic and end-diastolic volumes as well as LVEF . Both drLastly, changes in myocardial energetics were also observed in a nondiabetic swine model of HFrEF . In contSGLT-2i have been extensively studied in patients with HFrEF with or without diabetes. Cardiac energetics have been shown to be improved by SGLT-2i in patients with T2D . After tChan et al. published the results of a study in which they enrolled 665, 119, and 132 patients with T2D and preserved (≥ 50%), moderately reduced (40–50%), and reduced baseline LVEF (< 40%) who were receiving with SGLT-2i . In addi2 compared to placebo, and the LV end-diastolic volume index by 8.2 mL/m2 (P = 0.0042). No difference was seen in LV global longitudinal strain.The SUGAR-DM-HF trial randomized 105 patients with T2D/prediabetes and HFrEF (77.1% with NYHA II and 22.9% with NYHA III) to empagliflozin or placebo and followed for 36 weeks . In patiIlyas et al. investigated the effects of two weeks of therapy with dapagliflozin in 19 patients with T2D and HFrEF in a placebo-controlled crossover trial . While r2 consumption, oxygen uptake efficiency slope, and the 6-min walk test.In patients without diabetes and HFrEF, Santos-Gallego carried out a study in which 84 participants were randomized to empagliflozin or placebo for 6 months . Empagli2), left ventricular end-diastolic volume (-5.5 mL/m2), and left atrial volume (-2.5 mL/m2) compared with placebo after 12 weeks, although no change in LVEF was seen [In a post hoc analysis of the randomized Empire HF trial involving 190 patients with HFrEF (12.6% with T2D), empagliflozin was associated with significantly reduced LVESV (-4.3 mL/mwas seen . As notewas seen . Changeswas seen . The addThe effects of empagliflozin on the ratio of pulmonary capillary wedge pressure (PCWP) to cardiac index (CI) at peak exercise have been studied in 70 patients with HFrEF  . While nA secondary analysis of patients enrolled in the EMPA-TROPISM trial investigating empagliflozin in patients without diabetes and HFrEF evaluated the effect of SGLT2i in cardiac remodeling . EmpagliDiabetes mellitus, even in the absence of other risk factors such as arterial hypertension, obesity, and coronary artery diseaseis known to be associated with high risk for CV complications. The main cardiac morphofunctional alterations associated with diabetes are hypertrophy and diastolic dysfunction . A numbeIn a study of the effects of SGLT-2i in patients with or without established CV disease no significant changes in cardiac stroke volume of output were evident . FurtherIn contrast, diastolic function does appear to be directly influenced by SGLT-2i , 25, 28.The benefits of SGLT-2i have also been confirmed in the context of HFpEF both with and without diabetes. Animal models have largely confirmed these findings with improvement in LV diastolic function in animals with and without diabetes , 32. SimDiabetes and HFrEF are risk factors for each other and can bidirectionally independently worsen outcomes. Indeed, diabetes is a common concurrent diagnosis with HFrEF and increases the risk of HF by two- to four-fold . At the SGLT-2i appear to be associated with positive LV remodeling and with improvement in the LVEF along with reduced end-systolic volume , 59, altMetabolic changes have also been noted in addition to improvement in LVEF, which may lead to benefits in cardiomyocyte contractility .The effects of SGLT-2i have been more amply demonstrated in the context of HFrEF in the absence of diabetes. SGLT-2i have been shown to improve systolic function , 63 and Considering cardiac hemodynamics, SGLT-2i seem to be associated with improvements in systolic function, and as a consequence pulmonary hypertension, that appear to be rapid, in contrast to the effects on LVEF remodeling and mass , 66. SGLLarge CVOTs initially confirmed the CV benefits of SGLT-2i in patients with T2D –11. HoweIn diabetic heart disease, in both clinical and animal models, the effect of SGLT-2i have been shown to improve diastolic function, which is even more evident in HFpEF where it represents a key pathogenetic element. The probable pathogenic mechanisms likely involve damage from free radicals, apoptosis, and inflammation, and therefore fibrosis, many of which have been shown to be improved by SGLT-2i. While the effects on systolic function in models of diabetic heart disease and HFpEF is limited and contrasting, it is a key aspect in HFrEF, both with and without diabetes. The significant improvement in systolic function appears to lead to subsequent structural remodeling of the heart with a reduction in the LV volume and a consequent reduction in pulmonary pressure , 66, 75.


Cardiac haemodynamics is described by the Frank-Starling law, which states that the strength of the left ventricular (LV) systolic contraction is related to the LV diastolic filling, with other words LV stroke volume increases as LV volume increases due to the stretching of the myocyte. The purpose of the present study was to examine how the increasing LV volumes affect LV contractility represented by three-dimensional (3D) speckle-tracking echocardiography (3DSTE) -derived LV strains in healthy adults.This is post-hoc analysis of the MAGYAR-Healthy Study employing a novel method for technical analysis of echocardiographic datasets. The present study consisted of 301 healthy adults. Due to inferior image quality, 127 subjects have been excluded, therefore the remaining population included 174 subjects . All cases have undergone complete two-dimensional Doppler echocardiography extended with 3DSTE.LV global longitudinal (gLS) and area (gAS) strains were lowest in case of the highest LV end-diastolic volume (EDV). LV global radial (gRS) and 3D (g3DS) strains tendentiously increased with increasing LV-EDV. When segmental analysis was performed, increased LV-EDV was associated with increase of basal LV-RS and LV-3DS. Increased LV strains were associated with increased LV ejection fraction (EF) due to higher LV-EDV for LV-gRS (and LV-g3DS), lower LV-ESV for LV-gCS and lower LV-EDV and LV-ESV for LV-gLS (and LV-gAS). With increasing LV-gRS, LV-gCS and LV-g3DS, all LV strains increased except LV-gLS. With increasing LV-gLS, LV-gRS did not show any increase, LV-gCS and LV-g3DS were the highest when LV-gLS was the highest, while LV-gAS increased simultaneously. With increasing LV-gAS, all LV strains increased.There is a complex contractility pattern of LV segments/regions in response to elevated LV volumes in healthy circumstances. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Institutional and Regional Human Biomedical Research Committee of University of Szeged, Hungary (No.: 71/2011 and updated versions) and informed consent was given by all subjects.The present study consisted of 301 healthy adults, who were recruited for screening between 2011 and 2015 on a voluntary basis. Due to inferior image quality, 127 subjects have been excluded, therefore the remaining population included 174 subjects . All cases have undergone a physical examination, laboratory assessments, standard 12-lead electrocardiography (ECG) and two-dimensional Doppler echocardiography (2DE) with a negative result. No one was taking any medication regularly or had a known disease, pathological state or clinical condition, which could affect the findings. Together with 2DE, 3DSTE-derived data acquisition was also performed at the same time in accordance with our local practices 2.2For complete echocardiographic analysis, all healthy subjects have undergone 2DE. Cardiac chamber quantifications were performed according to recent guidelines including measurement of LV dimensions and volumes, determination of LV ejection fraction by the Simpson’s method, Doppler exclusion of valvular regurgitations or stenoses, and Doppler measurement of diastolic mitral inflow velocities and their ratio (E/A) 2.3Detailed LV analysis was performed in all cases including determination of LV volumes and strains, as well At second stage, offline data analysis was performed with a vendor-provided 3D Wall Motion Tracking software version 2.7 . Optimal apical longitudinal views were selected on apical 4-chamber (AP4CH) and 2-chamber (AP2CH) views and cross-sectional views at basal, midventricular and apical levels. For detailed LV analysis, septal mitral annular (MA)-LV edge, endocardial LV apical surface and lateral MA-LV edge were determined, then a sequential analysis was started creating a virtual 3D model of the LV. With this LV cast, LV volume changes could be determined during the cardiac cycle together with exact detection of LV-EF and objective features of LV contractility called as LV strains. Global , segmental (only for a certain segment), mean segmental  and regional  strains were calculated Strains were measured for featuring thickening and thinning of the myocardium , lengthening and shortening of the myocardium  and widening and narrowing of the myocardium . Based on these unidirectional/unidimensional strains, complex/multidimensional strains were also determined: area strain (AS) as a combination of LS and CS and 3D strain (3DS) as a combination of RS, LS and CS 2.4t-test was used, in case of non-normal distribution, Mann-Whitney-Wilcoxon test was performed. One-way analysis of variance (ANOVA) test with Bonferroni correction were used, where appropriated. For intraobserver and interobserver correlations, intraclass correlation coefficients (ICCs) were calculated. Statistical analyses were performed with SPSS software version 22 .Continuous variables are presented in mean ± standard deviation format, while categorical variables are presented in number/percentage format. The p < 0.05 was considered to be significant. Fischer’s exact test was used for all categorical variables. To test normality of distribution for continuous variables, Shapiro-Wilks test was performed: in case of normal distribution Student’s 33.12.All subject involved proved to be non-smoker with a family history of cardiovascular disorders in 40 out of 174 cases (23%). Systolic (123.1 ± 5.3 mmHg) and diastolic (76.1 ± 5.1 mmHg) blood pressures and heart rate (72.3 ± 2.4 1/s) were in normal ranges. Mean height, weight and calculated body surface area proved to be 171.1 ± 8.1 cm, 72.5 ± 11.2 kg and 1.86 ± 0.21 kg/m3.2Routine 2D echocardiographic data including left atrial diameter measured in parasternal long-axis view (36.6 ± 4.0 mm), LV end-diastolic diameter (48.1 ± 3.7 mm) and volume (106.8 ± 22.8 ml), LV end-systolic diameter (39.9 ± 25.0 mm) and volume (36.5 ± 9.2 ml), interventricular septum (9.0 ± 1.5 mm), LV posterior wall (9.1 ± 1.6 mm) and LV ejection fraction (65.9 ± 4.9%) were in normal range. Mean diastolic mitral inflow velocities (E and A) were 80.2 ± 17.5 cm/s and 64.6 ± 19.7 cm/s, respectively. No subject showed larger than grade 1 valvular regurgitation or had valvular stenosis on any valves.3.3–subjects having less than (mean – 1SD) of the above mentioned parameters ,–subjects having larger than (mean + SD) of the above mentioned parameters ,–subjects having larger/equal than (mean – 1SD) and lower/equal than (mean + 1SD) of the above mentioned parameters.The mean ± SD of LV-EDV, LV-ESV, LV-gRS, LV-gCS, LV-gLS, LV-gAS and LV-g3DS of adult healthy subjects proved to be 86.1 ± 23.2 ml, 36.2 ± 10.6 ml, 25.4 ± 9.4%, −27.7 ± 5.0%, −16.1 ± 2.5%, −40.4 ± 4.9% and 28.0 ± 9.0%, respectively. The population of healthy cases were classified into the following subgroups:3.4The mean data acquisition time together with complete 3DSTE-derived LV analysis did not take more than 15 min in any of cases.Increasing LV-EDV was associated with increasing LV-ESV and LV mass with preservation of LV-EF. Similar happens with increasing LV-ESV as seen in case of LV-EDV with reduction of LV-EF. LV-gLS and LV-gAS were lowest in case of the highest LV-EDV. LV-gRS and LV-g3DS tendentiously increased with increasing LV-EDV. With increasing LV-ESV lower LV-gLS, LV-gCS and LV-gAS could be detected .Table 1LWhen segmental analysis was performed, increased LV-EDV was associated with increase of basal LV-RS and LV-3DS, decrease of midventricular LV-LS and LV-AS and reduction of apical LV-CS. Increased LV-ESV showed associations with reduced LV-CS in all regions, decrease of midventricular LV-LS and deterioration of LV-AS in all regions .Table 2LIncreased LV strains were associated with increased LV-EF, but due to higher LV-EDV for LV-gRS (and LV-g3DS), lower LV-ESV for LV-gCS and lower LV-EDV and LV-ESV for LV-gLS (and LV-gAS). Increased LV-gLS and LV-gAS were associated with reduced LV mass , Table 4With increasing LV-gRS, LV-gCS and LV-g3DS, all LV strains increased except LV-LS. With increasing LV-gLS, LV-gRS did not show any increase, LV-gCS and LV-g3DS were the highest when LV-gLS was the highest, while LV-gAS increased simultaneously. With increasing LV-gAS, all LV strain increased , Table 43.5All measurements were peformed 5 times in all cases. Adequate simultaneous LV volumetric and strain measurements could be performed in 174 out of 301 assessments .3.6Intraobserver ICCs for LV-EDV, LV-ESV, LV-RS, LV-CS, LV-LS, LV-3DS and LV-AS proved to be 0.91, 0.90, 0.85, 0.81, 0.82, 0.80, and 0.83, respectively. Interobserver ICCs for the same parameters were 0.92, 0.91, 0.82, 0.78, 0.79, 0.78, and 0.80, respectively.4Strain and strain rate are measures of deformation featuring left ventricular (LV) function. Deformation represented by strain reflects the change in dimensions of myocardial fibres over the cardiac cycle, strain rate is the change in strain with respect to time 2DSTE is a widely used echocardiographic technique for LV-gLS assessment with a significant prognostic impact 3DSTE is a novel imaging method capable of simultaneous assessment of LV volumes (and LV-EF) and strains from the same acquired 3D echocardiographic dataset allowing the examination of their dependence on each other The main finding of the present study is that increased LV-g3DS, which represents the sum of contractions in all directions, could be detected in healthy subjects with elevated LV-EDV. Segmental analysis showed increase of LV-RS and LV-3DS of basal segments, which seems logical due to its adjacent localization to LV inflow mitral annulus, so this area is affected/stretched firstly by LV volume in diastole. Elevated LV-EDV is accompanied with non-significant tendentious increase of LV-gRS, representing radial contraction of the myocardium, and significant reduction of LV-gLS representing longitudinal myocardial contraction, mainly located in the midventricular region. It should be noted that LV-EF remains preserved. With increasing global LV strains, LV-EF showed simultaneous increase due to elevation of LV-EDV for LV-gRS, reduction of LV-ESV for LV-gCS and reduction of both LV volumes but in different degrees for LV-gLS. With increasing LV-gRS and LV-gCS, all other strains increased simultaneously except LV-gLS, which remained unchanged.These results suggest a complex contractility pattern of LV segments/regions in response to higher LV volumes. It seems to be important which myocardial areas  are stretched firstly in response to elevated LV volumes making these areas responsible for elevated contractions. Longitudinal contraction, however, seems to compensate for these movements making LV-EF constant. However, further clinical and experimental studies are warranted to confirm our findings, even in different pathological states with higher LV volumes.4.1Although significant improvement in 3D echocardiographic technology has been performed in the last decade, image quality for 2DE is still better than that of 3DSTE due to limited temporal and spatial resolution. During 3DSTE analysis, 4–6 cardiac cycles and ECG-gated capture are required for optimal virtual 3D images, which make an opportunity for stitching artifacts. Moreover, respiratory motion and rhythm disturbances make data acquisition and imaging difficult or impossible. This sort of limitations could significantly affect the findings 5There is a complex contractility pattern of LV segments/regions in response to elevated LV volumes in healthy circumstances.Attila Nemes: Conceptualization, Writing – original draft, Writing – review & editing. Árpád Kormányos: Methodology, Investigation, Data curation. Zoltán Ruzsa: Writing – review & editing. Alexandru Achim: Writing – review & editing. Nóra Ambrus: Writing – review & editing. Csaba Lengyel: Writing – review & editing.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Undiagnosed congenital heart disease and management of pediatric cardiogenic shock presents a diagnostic challenge for the emergency clinician. These diagnoses are rare and require a high index of suspicion given the overlap with more common pediatric pathology. Point-of-care ultrasound can assist in differentiating these presentations. We present a case of neonatal cardiogenic shock secondary to a previously undiagnosed congenital heart disease, specifically Shone complex, detected using point-of-care ultrasound.A six-week-old female presented with severe respiratory distress and was found to be in cardiogenic shock secondary to a previously undiagnosed congenital heart defect.Initial diagnosis of congenital heart disease is uncommon in the emergency department, but it should be recognized by clinicians given the high associated morbidity and mortality. Point-of-care ultrasound is a powerful tool to assist in evaluating for cardiac abnormalities as an etiology for undifferentiated shock in the pediatric population. Congenital anomalies are the leading cause of infant mortality in the United States with congenital heart disease accounting for 30–50% of these deaths.3Early use of point-of-care ultrasound in this patient population can provide invaluable information for the emergency clinician. Our case highlights the utility of point-of-care ultrasound to identify a previously undiagnosed congenital heart defect in a neonate presenting in cardiogenic shock. Specifically, our case highlights Shone complex, a rare congenital heart disease comprised of four left-sided heart defects including a parachute mitral valve, subaortic stenosis, a supravalvular mitral ring, and coarctation of the aorta.4A six-week-old female presented to our ED via ambulance from her pediatrician’s office for respiratory distress. She had no known past medical history and was born at 38 weeks via induced vaginal delivery with routine prenatal care. Her mother described a history of increased work of breathing, wheezing, and grunting respirations since birth, which had noticeably worsened in the prior week. The patient had mild associated congestion and rhinorrhea, but her mother denied other infectious symptoms. At the pediatrician’s office, the patient was found to have an oxygen saturation of 70% and was placed on a non-rebreather with minimal improvement.Her initial vital signs on arrival to the ED showed hypothermia with a temperature of 35.2° Celsius, a tachycardic heart rate of 169 beats per minute, tachypnea with a respiratory rate of 50 breaths per minute, and persistent hypoxia at 68% despite oxygenation by non-rebreather. Obtaining an accurate blood pressure was challenging, but the highest measurement was 38/23 millimeters of mercury. Physical examination was notable for an ill-appearing, mottled, neonatal female. Her heart and lung sounds were diminished on auscultation, with diffuse rales that were more prominent in the right lung. She was noted to have absent femoral pulses.Given the patient’s poor oxygen saturation and increased work of breathing, she was transitioned to high-flow nasal cannula. A chest radiograph was obtained and demonstrated cardiomegaly with pulmonary interstitial edema .Focused point-of-care echocardiography was performed, which showed poor left ventricular contractility with an ejection fraction visually estimated to be less than 15%, restricted motion of the mitral valve leaflets with abnormal valve morphology, and a mitral regurgitation jet . These fWhat do we already know about this clinical entity?Undiagnosed congenital heart disease can be a diagnostic challenge given the overlap with more common pediatric pathology.What makes this presentation of disease reportable?Cardiogenic shock from an undiagnosed congenital heart disease such as Shone complex is a rare but important consideration in the undifferentiated sick neonate.What is the major learning point?Point-of-care ultrasound is a powerful tool to assist in evaluating for cardiac abnormalities as an etiology for undifferentiated shock in the pediatric population.How might this improve emergency medicine practice?Point-of-care ultrasound in the sick pediatric patient can provide real-time diagnostic information and facilitate early collaboration with consultants.Ultimately her oxygenation and work of breathing failed to improve on high-flow nasal cannula, and she was intubated. Fentanyl was given for induction and sedation, but paralytics were avoided to ensure preservation of her respiratory drive.Cardiology was consulted and a complete echocardiogram was performed, which confirmed the diagnosis of congenital heart disease, more specifically an incomplete Shone complex. We considered initiation of alprostadil in case of a ductal-dependent lesion, and this was eventually administered after transfer to the pediatric intensive care unit. Her clinical course was complicated by significant end-organ damage including acute renal failure requiring continuous renal replacement therapy and seizures. She underwent coarctation repair several days later, which she tolerated well. Her ejection fraction, renal failure, and seizures improved, and she was discharged home one month after admission.Shone complex is a rare congenital heart disease comprising four left-sided heart defects including a parachute mitral valve, subaortic stenosis, a supravalvular mitral ring, and coarctation of the aorta. It is estimated that Shone complex comprises 0.6–0.7% of all congenital heart disease.8While the definitive diagnosis of Shone complex is well outside the scope of point-of-care ultrasound, some defining sonographic abnormalities can be striking and readily appreciated. Our point-of-care echocardiography was performed using the phased array probe placed in the standard positioning. There are no differences in probe placement between the adult and pediatric populations. The “parachute” shape of the mitral valve has a distinct sonographic appearance and may markedly restrict the movement of the valve leaflets, which is easily appreciated on dynamic imaging . Mitral 7In our case, a previously healthy six-week-old with reported routine prenatal care presented in decompensated cardiogenic shock. She was ultimately found to have an incomplete form of Shone complex with a bicuspid aortic valve, a parachute mitral valve, and critical postductal coarctation of the aorta. She did not have subaortic stenosis or a supravalvular mitral ring. Her case proved to be a diagnostic challenge as we began with a working diagnosis of bronchiolitis, prompting the initiation of high-flow nasal cannula. We additionally considered sepsis, toxin-mediated, congenital metabolic disorders, and non-accidental trauma as other etiologies for her decompensation.The cardiomegaly and interstitial prominence on her chest radiograph initially raised our concern for underlying heart failure. However, the chest radiograph alone did not provide enough diagnostic information for proper management. In the acute setting, the anatomic, physiological, and hemodynamic information that functional echocardiography provides can be used in targeting specific interventions and evaluating response to treatment.In general, pediatric cardiogenic shock with left ventricular systolic failure, such as in Shone complex, is managed with inotropes to increase contractility and reduce afterload. Diuretics may also be used to decrease both pulmonary vascular congestion and preload.11The decision to intubate congenital heart patients is debated given the risk of decreasing preload and worsening cardiac output. In severe cases, intubation and positive-pressure ventilation may assist in decreasing left ventricular transmural pressure and afterload as well as the metabolic demands of respiratory muscles. Our decision to proceed with intubation was made in conjunction with our pediatric intensivists and cardiology colleagues as sedation and intubation can cause rapid deterioration in which mechanical cardiac support may be needed.Delayed diagnosis of congenital heart disease is rare but carries a high risk of morbidity and mortality. These cases can be diagnostic challenges given that heart failure and cardiogenic shock is rare in the pediatric and neonatal population. Symptoms can also overlap with more common conditions including bronchiolitis or pneumonia. Emergency physicians should be aware of these lesions and the role of point-of-care ultrasound to assist with diagnosis.VideoNarrated video describing the chest radiograph with cardiomegaly and pulmonary interstitial edema. Video clip of the point-of-care parasternal long-axis view demonstrates abnormal mitral valve morphology with tethering and restricted motion of the mitral valve leaflet (white arrow). Point-of-care apical four-chamber view demonstrates color flow Doppler with a mitral regurgitant jet (white arrow). In the final clips, a cardiology-performed echocardiogram in the parasternal long-axis and short-axis views reveal a “parachute” mitral valve (white arrow) and bicuspid aortic valve (white arrow), respectively. The suprasternal aortic view reveals coarctation of the aorta (white arrow).


What Is Already Known and How This Shapes the FutureHighly controlled experimental studies have illustrated the importance of ischaemia time in relation to myocyte necrosis in acute myocardial infarction. However, in humans, the situation is more complex and the relationship between clinical outcomes and ischaemia time is non-linear over a time window that is relevant to clinical presentation.Emerging techniques can characterise myocardia in individual patients, providing enhanced understanding of the heterogeneity of the response to ischemic injury.Assessments of microvascular function, including secondary changes such as intramyocardial haemorrhaging, should inform decision making regarding additional therapies.Early prediction of the nature and extent of myocardial recovery vs. irreversible injury would be useful for prognostic and therapeutic purposes in addition to guiding clinical pathways and safe resource allocation.Integrating knowledge of the status of the myocardium and the stages of activation of systemic responses should allow the development and application of therapies based on mechanistic characterisation of upstream signalling pathways and the downstream consequences of effector cells, e.g., of the innate immune system.The past decade has seen a marked expansion in the understanding of the pathobiology of acute myocardial infarction and the systemic inflammatory response that it elicits. At the same time, a portfolio of tools has emerged to characterise some of these processes in vivo. However, in clinical practice, key decision making still largely relies on assessment built around the timing of the onset of chest pain, features on electrocardiograms and measurements of plasma troponin. Better understanding the heterogeneity of myocardial injury and patient-level responses should provide new opportunities for diagnostic stratification to enable the delivery of more rational therapies. Characterisation of the myocardium using emerging imaging techniques such as the T1, T2 and T2* mapping techniques can provide enhanced assessments of myocardial statuses. Physiological measures, which include microcirculatory resistance and coronary flow reserve, have been shown to predict outcomes in AMI and can be used to inform treatment selection. Functionally informative blood biomarkers, including cellular transcriptomics; microRNAs; extracellular vesicle analyses and soluble markers, all give insights into the nature and timing of the innate immune response and its regulation in acute MI. The integration of these and other emerging tools will be key to developing a fuller understanding of the patient-level processes of myocardial injury and repair and should fuel new possibilities for rational therapeutic intervention. Acute myocardial infarction (AMI) occurs when sustained interruption to the perfusion of the myocardium results in cell death and tissue necrosis. Whilst this is the primary event, it has become increasingly clear that several inter-related processes, which are relevant to myocardial injury and recovery, are set in train by initial ischemic insults. Appreciation of these processes is necessary, since they introduce patient-level heterogeneity that has important implications for selecting effective treatments that optimise benefits and minimise harm. After 40 min of ischemia, myocyte necrosis was subendocardial but with increasing duration of coronary occlusion, irreversible injury progressed as a wavefront toward the subepicardium. . Thi. Thi4]. However, as shown in time is muscle” or “time is brain” when managing patients with acute MI or ischaemic stroke [-omics” [Approaches to management have emerged, reflecting the well-worn adage that “c stroke . However[-omics” ,17, micr[-omics” ; (ii) di[-omics” ; and  of AMI and to guide early intervention therapies in those with non-Q-wave AMI . HoweverSometimes, at infarct edges, a mixture of necrotic tissue and viable myocardium exists as isolated islands or peninsulas, and this area has been termed the “border zone” . The disChanges in the structure of the myocardium, including at the cellular level, are not uniform in response to prolonged ischaemia or reperfusion injury ,42. In oVolumetric changes within the structure of the myocardium, including the distribution of water, has enabled the use of late gadolinium enhancement (LGE) as an in vivo surrogate of infarct size ,44,45,46Importantly, microvascular dysfunction can be quantified invasively at the time of coronary angiography through the application of pressure/flow guidewires and Doppler thermodilution techniques ,57. BothOedema-sensitive imaging (such as T2-weighted sequences) offers the ability to identify a volume of myocardium that has recently been subject to significant ischaemia, even when normal perfusion has been subsequently restored (either spontaneously or after treatment). In some sense, oedematous myocardia bear the memory of ischaemia. Thus, they can be used to determine the “volume at risk”. To date, this application has remained largely confined to calculating myocardial salvage indices, with limited data on its prognostic value ,64,65,66Crucially, T1 mapping techniques have enabled us to differentiate reversible versus non-reversible myocardial injury acutely following MI . Cut-offRecently, a novel quantitative imaging biomarker of microvascular function was systemically used to assess the extent of acute infarction . The absLastly, troponin is a widely used clinical biomarker as a surrogate of infarct size but peaks only after injury has occurred. Furthermore, after successful revascularisation, a rapid washout can produce a misleadingly high peak (but narrow profile) that does not relate to the long-term outcome . While 7In a clinical setting, early uncertainty about whether a myocardium will recover from an ischemic insult or not will constrain the scope of tailored therapy. Thus, novel imaging biomarkers of the sort described above could provide opportunities to characterise patients and identify those with reversible myocardial injury. The overall emphasis is a move away from a one size fits all approach and estimation of infarct progression based only on the presumed time of ischaemia. Characterising the myocardium, including early indications of reversible vs. irreversible injury (within 3 h of primary PCI), is of prognostic relevance and may set the stage to test new therapeutic options in better stratified populations. Microvascular dysfunction is also a major challenge and various techniques have highlighted adverse outcomes in patients with suboptimal microcirculation function ,76,77. PAdditional complexity can occur when the failure of an endothelial barrier leads to an intramyocardial haemorrhage (IMH) ,78,79,80Carrick et al. showed that all patients with IMHs in their study also had evidence of MVO ,83. TherInfarct recovery is a complex process that is related to not solely the initial insult of interrupted perfusion but also secondary processes that are variable in different patients, including inflammatory cellular infiltration, the resorption of oedema, the replacement of necrotic myocytes with fibrous tissue and angiogenesis . Even reUsing quantitative T1 and T2 mapping techniques, new insights into infarct recovery have also been obtained. Absolute T1 values at 6 months have remained relatively higher in areas of previous infarction, but not in salvageable myocardia. These areas of high T1 values likely reflect the replacement of myocytes with fibrous tissue . SimilarBesides MRI-based observations, the measurement of invasive indices of coronary physiology has also provided similar evidence of functional recovery of coronary microcirculation, depicted as a progressive normalisation of vasodilatory capacity in response to vasodilating agents such as adenosine. Revascularisation itself can affect coronary microvascular vasodilatory functions both positively and negatively, as reflected by a change in the IMR. Approximately 40% of patients have shown incomplete recovery or even worsening of microvascular functions after revascularisation . A largeCuculi et al.  have gonA vigorous inflammatory cell response is a cardinal feature of AMI. Studies in animal models have shown that aspects of cellular inflammation are involved in the propagation of injury as well as its resolution, its repair and scar formation ,105,106.Neutrophils are the first cells to increase in peripheral blood following AMI ,108. In Systemic activation is evidenced by the increased plasma levels of circulating inflammatory cytokines  and endoEVs are submicron-sized lipid envelopes that carry surface proteins, which enable receptor-mediated signalling with cells locally in tissues or distally from their sites of origin through liberation into peripheral blood. Plasma EVs are elevated at the time of presentation of AMI and correlate with the extent of myocardial injury as determined with T2W MRI . Plasma The expanding understanding of the means by which the ischemic myocardium signals to remote reserves and the appreciation that responding leukocytes show particular patterns of transcriptomic response opens the possibility to map the systemic inflammatory statuses of patients in response to MI with increasing precision and to combine these with the characterisation of the status of the myocardia themselves. With greater understanding of the processes described above, it may be possible to augment current tools to gain a better understanding of patient-specific clinical statuses, far enhancing currently used biomarkers such as the ECG and serum troponin . The meaAs illustrated in With better understanding of underlying biological processes and technological advances to rapidly profile clinical samples, it may be possible to diagnose patients sooner, obtain mechanistically relevant characterisation, stratify the patients’ risk, institute specific bespoke therapies and obtain a better understanding of prognosis. These tools and their successors therefore have the potential to improve care from the current “one size fits all” approach to a more personalised approach, improving safety and reducing risks, thereby ultimately improving clinical outcomes.


Acute myocardial edema (AME) is increased water content in the myocardium and represents the first and transient pathophysiological response to an acute myocardial injury. In-vivo and non-invasive evaluation is feasible with cardiac magnetic resonance (CMR), which is a powerful imaging technique capable of tissue characterization. In the clinical setting, early demonstration of AME has a recognized diagnostic value for acute coronary syndromes and acute myocarditis, although its prognostic value is not well established. This article provides a comprehensive narrative review on the clinical meaning of AME in heart diseases. In particular, the available evidence of a possible favourable prognostic value in several clinical scenarios is addressed. Physi virtual . The inc virtual . AME is a transient phenomenon, resolving quickly in absence of necrosis and/or fibrosis. Accordingly, it may predict reversibility and healing of the myocardial injury . The in This article provides a comprehensive narrative review on the clinical meaning of AME in heart diseases. In particular, the available evidence of a possible favourable prognostic value in different clinical scenarios, including acute coronary syndromes, acute myocarditis, Tako-Tsubo syndrome (TTS) and resuscitated sudden cardiac death, will be addressed. AME, in the context of acute coronary syndromes, is seen in almost all patients. In line with the ischemic wave-front phenomenon, it spreads from the subendocardium to the whole wall thickness of the myocardium supplied by the occluded artery. The possibility of its detection with T2 sequences is crucial for diagnostic and prognostic assessment. In particular, for this latter, the hyperintense myocardium in such sequences defines the so-called “area at risk” ,11. ThisThe detection of AME is a cornerstone of non-invasive diagnosis of clinically suspected acute myocarditis ,22,23. IAME is a relevant finding in the diagnosis of TTS, helping the differential diagnosis  with botIn summary, patients diagnosed with TTS syndrome usually have a good outcome, characterized by resolution of AME, recovery of ventricular function and ECG abnormalities.Recent studies pointed to the presence of AME in patients with resuscitated out of hospital cardiac arrest (OHCA) . The patCMR is a cornerstone imaging technique in cardiomyopathies ,50, and AME was detected by CMR also in autoimmune diseases with possible cardiac involvement. Mavrogeni and colleagues demonstrated the presence of edema in over one-half of a cohort treatment of naïve patients with a broad spectrum of connective tissue diseases and without cardiovascular disease. Re-evaluation of the patients after 6 months of adequate disease-modifying treatment showed a significant reduction of AME . Signs oSimilarly, myocardial edema was detected in cardiac amyloidosis (CA), both light chain (AL) and transthyretin (ATTR). In a study by Ridouani and colleagues of about 44 patients with CA, myocardial native T2 was significantly increased, especially in AL-CA . FurtherAME was also detected in heart transplant recipients with ongoing acute rejection confirmed by biopsy ,63,64. TMyocardial edema was recognized in drug induced myocarditis as well, associated with immune checkpoint inhibitor (ICI) drugs and in the context of drug rash with eosinophilia and systemic symptoms (DRESS) syndrome ,66. AME Eventually, AME was also detected in patients after COVID-19 infection, in absence of any clinical clues for acute myocarditis ,70. Its There are some gaps of evidence that are worth addressing in future research. First, most of available studies assessed AME using T2-short tau inversion recovery imaging. Nevertheless, this technique is being replaced by T2 mapping, since its better reproducibility and spatial resolution. Indeed, few data are available about accuracy of AME detection with a combination of the two techniques. Second, the lack of standardized timing of CMR execution after acute injury could compromise the possibility of detection of AME, which is a transient phenomenon. This is particularly relevant in acute coronary syndromes, as previously described. Third, there is a scarcity of correlation studies between CMR detection of AME and histology. This could be not only of scientific interest but could also shed further light upon the prognostic significance of edema.Multiple techniques are being considered to sort some relevant limitations in edema detection. As already reported, the pattern analysis is crucial to recognize the correct aetiology underlying AME. In this perspective, a layer-by-layer myocardial T2 analysis could be useful. Single-breath fat saturated dark-blood cardiac T2 mapping would improve accuracy of myocardial T2 mapping, by limiting partial-voluming related to both fat and blood, without significant loss of signal-to-noise ratio . Other tAnother technique that could improve the detection of AME with better sensitivity is diffusion-weighted imaging because of its contrast mechanism . This haAcute myocardial edema is a hallmark of myocardial injury, whatever the underlying etiology. The progress in cardiovascular magnetic resonance techniques, particularly with T2 weighted sequences and T2 mapping, allows its detection in multiple clinical scenarios. Generally, its presence owns a favourable prognostic meaning in widespread common cardiac conditions, such as acute coronary syndromes, acute myocarditis, TTS and OHCA  (Figure By contrast, in the context of systemic disorder as autoimmune diseases or cardiac amyloidosis, its presence is a signal of none or non-optimal treatment. Further studies are needed to overcome current limitations in the assessment of AME and to elucidate the prognostic meaning in less explored fields, such as persistent edema, autoimmune disease, cardiomyopathies and heart transplantation.


Dilated cardiomyopathy (DCM) is characterized by systolic dysfunction and is usually idiopathic. A rare cause of reversible DCM is hypocalcemia. Calcium plays a key role in myocardial contraction. Hypocalcemia can lead to a decrease in contraction, left ventricular systolic dysfunction, and heart failure with reduced ejection fraction (EF). Hypocalcemia-related reversible DCM reports are rare. Herein, we present two cases with heart failure caused by hypocalcemia developed due to hypoparathyroidism. The first case presented with severe heart failure and an extremely low serum calcium level (4.4 mg/dL) due to idiopathic hypoparathyroidism. The second case, which was also admitted with heart failure due to hypocalcemia, had iatrogenic hypoparathyroidism due to a subtotal thyroidectomy. In both cases, patients had reduced left ventricular systolic functions . After calcium replacement and heart failure treatment, calcium levels were normalized. A significant and rapid improvement in heart failure was achieved in both cases . Serum calcium levels should always be measured in patients with heart failure, and the etiology of hypocalcemia should be sought. In addition to the standard pharmacotherapy of heart failure with reduced EF, calcium supplementation is essential for treating these patients. There may be various diseases in etiology, but sometimes no cause could be found and, in this case, it is referred to as idiopathic DCM . Calciumay occur . Cases oay occur -6. HereiCase 1: A 41-year-old woman was admitted to the emergency room with leg swelling, shortness of breath, numbness, and hand cramps. The calcium level was 4.4 mg/dL, and the patient was treated with intravenous calcium and diuretics. She was hospitalized for treatment and further evaluation. Medical history revealed bronchial asthma, bilateral cataract surgery, and a right ankle fracture.Physical examination findings were a weight of 103 kilograms, a height of 155 centimeters, dry skin, fragile nails, teeth hypoplasia, a positive Chvostek sign, blood pressure of 143/78 mmHg, a positive S3, generalized edema, fine inspiratory crackles bilaterally in lungs until middle zones, eczematous lesions on her skin, and alopecia totalis. Laboratory results showed microcytic anemia; creatinine, 0.6 mg/dL; albumin, 3.27 g/dL; calcium, 5.9 mg/dL; phosphorus, 4.3 mg/dL; LDH, 817 U/L; CK, 869 U/L; TSH, 2.9 mIU/L; fT4, 19.5 pmol/L; anti-TPO, 200 IU/mL; PTH, 12.7 pg/mL,; HbAa1c, 7.4%; c-peptide, 5.03 ng/mL; microalbumin/creatinine, 10.6 mg/g; pro-BNP, 1704 pg/mL; and hsTroponin T, 10.66 pg/mL (< 14) .An electrocardiogram (ECG) showed sinus tachycardia. A transthoracic echocardiogram (TTE) revealed reduced left ventricular systolic dysfunction (ejection fraction [EF] was measured as 33% using Teichholz's method) and global left ventricular hypokinesis  and B. ACalcium, cholecalciferol, magnesium, and calcitriol for hypoparathyroidism and intravenous furosemide for generalized edema were initiated. After the fifth day, the patient's weight was 88 kg; her edema decreased; and calcium was 9.3 mg/dL. Ramipril and carvedilol were started for heart failure.Further investigation for autoimmune polyglandular syndromes showed no features. Therefore, the patient was diagnosed with idiopathic hypoparathyroidism. A spine X-ray revealed paravertebral ligament calcification. There was no evidence of nephrolithiasis, nephrocalcinosis, or basal ganglia calcifications. The patient's bronchial obstruction ameliorated after calcium replacement.She was discharged from the hospital with calcium 2,000 mg/daily, calcitriol 1 mcg/daily, magnesium 365 mg/daily, and cholecalciferol 1,600 IU/daily for the treatment of hypoparathyroidism. The follow-up evaluation showed normocalcemia and normophosphatemia with pro-BNP 300 pg/mL . After aCase 2: A 58-year-old woman was admitted to the emergency department with swelling in the legs, shortness of breath (NYHA class III), numbness and cramping in the hands, and around the mouth. Her medical history revealed iatrogenic hypoparathyroidism due to a subtotal thyroidectomy (45-years-ago) and bilateral cataract surgery (15-years-ago). She took an oral calcium replacement. However, in recent years, her treatment has been erratic, and she was admitted to emergency departments periodically for contraction complaints and to receive IV calcium replacement therapy. Recently, she was diagnosed with heart failure.Physical examination findings were a weight of 120 kg, a height of 158 cm, positive Chvostek and Trousseau signs, and carpopedal spasms in both hands. Moreover, her blood pressure was 143/78 mmHg, with a heart rate of 101 beats per minute, pitting (+) pretibial edema, and fine inspiratory crackles bilaterally in lungs.An electrocardiogram showed sinus rhythm, a right bundle branch block, and QT interval was 508 ms, corrected for heart rate due to Bazett's formula . LaboratParenteral calcium was started for symptomatic hypocalcemia. After the symptoms resolved, treatment was changed to oral calcium 3000 mg/daily, cholecalciferol 2400 IU/daily, magnesium 365 mg/daily, and 1 mcg calcitriol/daily. She was given a phosphorus-restricted diet and phosphorus-binding agents for the hyperphosphatemia.TTE disclosed moderately reduced left ventricular systolic dysfunction (EF was measured as 42% using a biplane Simpson's method), global left ventricular hypokinesis, left atrial dilatation, grade II mitral regurgitation (secondary to annular dilatation), mild tricuspid regurgitation, and pulmonary hypertension (an estimated pulmonary artery systolic pressure of 37 mmHg). Ramipril 5 mg/daily, carvedilol 6.25 mg/daily, and intravenous furosemide were initiated. Her dyspnea and findings of congestion resolved within days after the normalization of calcium levels. ECG showed sinus rhythm and a corrected QT interval of 438 ms . No nephControl TTE revealed left ventricular systolic function at the lower limit of normal (EF was measured as 50% using a biplane Simpson's method), mild mitral regurgitation, trace tricuspid regurgitation, and an estimated pulmonary artery systolic pressure of 25 mmHg .This report of two cases with hypoparathyroidism illustrates one of the few reversible causes of heart failure. Both cases had profound symptoms and signs of congestion, and the patients recovered shortly after a combination of calcium replacement and heart failure therapy.Dilated cardiomyopathy is a condition characterized by systolic dysfunction and can be reversible caused by, for example, alcoholism, postpartum cardiomyopathy, and hypothyroidism. A cause of reversible DCM is hypocalcemia due to hypoparathyroidism. Hypocalcemia-related reversible DCM reports are rare .Parathyroid hormone (PTH) regulates calcium metabolism through several routes, including the bone resorption by osteoclast activation, the renal absorption of calcium in distal tubule, stimulation of 1-α hydroxylase, and the inhibition of proximal tubular transport of phosphates. PTH is important for calcium balance and homeostasis. After all, PTH deficiency results in hypocalcemia . The mosIntracellular calcium plays a key role in the cardiac muscle's systolic and diastolic functions. Chronic and severe hypocalcemia can lead to a decrease in myocardial contractibility and may lead to left ventricular systolic dysfunction and heart failure with reduced EF . RecentlIn our report, we presented two cases of heart failure secondary to hypocalcemia. The cause was idiopathic hypoparathyroidism in the first case and iatrogenic hypoparathyroidism due to previous thyroid surgery in the second case. In both cases, myocardial contractility was impaired, and pro-BNP levels were elevated, consistent with the findings of heart failure. We presumed that DCM developed because of hypocalcemia, which was not treated for a long time. After a combination of heart failure therapy and calcium replacement, left ventricular systolic functions recovered in both patients, and pro-BNP levels decreased within days.Patients with chronic hypocalcemia may have subjective symptoms, which are not specific to hypocalcemia, such as chronic fatigue and muscle weakness. It may be difficult to diagnose hypocalcemia in the absence of tetani. Both cases that we presented had a history of cataract surgery. It is well known that hypoparathyroidism is an essential cause of lenticular cataract, especially in younger patients. Ophthalmologists should be aware of metabolic disorders accompanied by cataract, so that some cases can be diagnosed earlier.Sometimes the patient's initial presentation can be due to heart failure. Diuretic treatment could be started without knowing the serum calcium levels. Specifically, furosemide could decrease the serum calcium level by increasing the calcium excretion in urine, which can lead to worsening symptoms. Hypocalcemia-induced heart failure is resistant to diuretic treatment but rapidly responds to calcium replacement and normalization of the serum calcium levels .Acute coronary syndrome should be a differential diagnosis, as newly diagnosed heart failure with reduced EF may be the first presentation of the myocardial infaction . DiabetiIn conclusion, hypocalcemia is a reversible cause of heart failure. Serum calcium levels should always be measured in patients with heart failure, and the etiology of hypocalcemia should be sought. In addition to the standard pharmacotherapy of heart failure with reduced EF, calcium supplementation is essential for treating these patients.


Background: The hemodynamic definition of PH has recently been revised with unchanged threshold of peak tricuspid regurgitation velocity (TRV). The aim of this study was to evaluate the predictive accuracy of peak TRV for PH based on the new (>20 mmHg) and the old (>25 mmHg) cut-off value for mean pulmonary artery pressure (mPAP) and to compare it with the mean right ventricular–right atrial (RV–RA) pressure gradient. Methods: Patients with advanced heart failure were screened from 2016 to 2021. The exclusion criteria were absent right heart catheterization (RHC) results, chronic obstructive pulmonary disease, any septal defect, inadequate acoustic window or undetectable TR. The mean RV–RA gradient was calculated from the velocity–time integral of TR. Results: The study included 41 patients; 34 (82.9%) had mPAP > 20 mmHg and 24 (58.5%) had mPAP > 25 mmHg. The AUC for the prediction of PH with mPAP > 20 mmHg was 0.855 for peak TRV and mean RV–RA gradient was 0.811. AUC for the prediction of PH defined as mPAP > 25 mmHg for peak TRV was 0.860 and for mean RV–RA gradient was 0.830. A cutoff value of 2.4 m/s for peak TRV had 65% sensitivity and 100% positive predictive value for predicting PH according to the new definition. Conclusions: Peak TRV performed better than mean RV–RA pressure gradient in predicting PH irrespective of hemodynamic definitions. Peak TRV performed similarly with the two definitions of PH, but a lower cutoff value had higher sensitivity and equal positive predictive value for PH. Pulmonary hypertension is defined as an increase in mean pulmonary artery pressure (PAP) at rest. The diagnostic threshold of mean PAP has recently been lowered from 25 mmHg to 20 mmHg . The decAdvanced heart failure patients are usually included in pulmonary hypertension clinical group 2, due to left heart disease . Right hCurrent guidelines recommend the use of peak tricuspid regurgitation velocity (TRV), with a threshold of >2.8 m/s, instead of estimated systolic PAP in assessing the probability of the presence of pulmonary hypertension ,12. In fThis study aimed to evaluate the predictive power of peak TRV for identifying patients with pulmonary hypertension classified according to the new (>20 mmHg) and the old (>25 mmHg) cutoff values of mean PAP and to compare the results with the mean right ventricular–right atrial (RV–RA) gradient, which ideally correlates better with mean PAP.All consecutive patients with advanced heart failure undergoing right heart catheterization as part of the screening for heart transplantation eligibility from 2016 to 2021 at the University Hospital of Siena were retrospectively reviewed. The exclusion criteria were: right heart catheterization unavailability, chronic obstructive pulmonary disease, any septal defect, inadequate acoustic window or undetectable tricuspid regurgitation (TR). The study was conducted in accordance with the Declaration of Helsinki, and approved by the local Ethics Committee.Baseline characteristics, laboratory tests, echocardiographic and right heart catheterization data were retrospectively collected in a dedicated database.All echocardiographic examinations were performed by experienced operators using GE Vivid E80/E95 echocardiographs equipped with an adult 1.5–4.3 MHz phased array transducer, with an ECG continuously monitored, according to the American Society of Echocardiography/European Association of Cardiovascular Imaging recommendations ,21. Comp2). Systolic PAP was calculated by adding the maximum RV–RA pressure gradient to mean RA pressure. Diastolic PAP was derived from mean PAP and systolic PAP using the formula: diastolic PAP = 1.5 × [mean PAP—(systolic PAP/3)] [The mean right ventricular–right atrial (RV–RA) pressure gradient was retrospectively obtained from VTI of TR. The mean PAP was obtained by adding the mean RV–RA pressure gradient to estimated mean RA pressure . The max PAP/3)] . All oth PAP/3)] ,21. PartFor speckle-tracking echocardiography analysis, endocardial borders and myocardium of all segments from the apical views  had to be clearly visualized throughout the whole cardiac circle. Analysis was retrospectively performed offline using EchoPAC software v204  and conventional protocol [Right heart catheterization was performed on the same day as the echocardiographic examination, just after it. A pulmonary artery Swan–Ganz catheter was used to obtain mean RA pressure, diastolic, systolic and mean PAP and pulmonary arterial wedge pressure (PAWP), using conventional technique . Pressurp-value < 0.05 was considered statistically significant. Analysis was performed using SPSS, version 26 .Continuous data are presented as mean and standard deviation or as median and interquartile range, as appropriate. The Kolmogorov–Smirnov test was used to verify normal distribution of variables. Categorical data are summarized as absolute and relative frequencies. To assess the predictive performance of the echocardiographic variables for PH, Receiver Operating Characteristic (ROC) curves were created, and the Youden index was used to determine the best cutoff values. To evaluate the strength of the relationship between echocardiographic and RHC data, a correlation analysis using Pearson’s correlation coefficient was performed. To evaluate agreement between the two methods, a Bland–Altman analysis was carried out. A In the first instance, 91 patients were recruited in the study. Thirty-seven patients were excluded from the analysis because right heart catheterization was not performed at the time of data collection, 1 patient because of an interatrial septal defect, 3 patients because of chronic obstructive pulmonary disease and 9 patients because of inadequate acoustic window or undetectable TR. The final population included in the analysis was comprised of 41 patients.The median age of patients was 58 years (IQR: 52–62), who were mostly men (82.9%). The etiology of heart failure was predominantly nonischemic (61.0%). Most patients had ICDs (85.4%). The median NT-proBNP was 1522 pg/mL (IQR: 649–2550). Most patients were in NYHA class II  or III . The complete patient’s baseline characteristics are presented in The mean left ventricular end-diastolic diameter was 68 ± 11 mm, and the median left ventricular ejection fraction (LVEF) was 28% (IQR: 23–35). The median right ventricular mid-end-diastolic diameter was 31 mm (IQR: 29–34), and the median fractional area change (RVFAC) was 38% (IQR: 33–45). Most patients had mild TR (51.3%), while the minority had severe TR (19.5%). Twelve patients had moderate TR (29.2%). The median peak TRV was 2.5 m/s (IQR: 2.2–3.0), and the median RV–RA gradient was 18 mmHg (10–24). The complete echocardiographic measurements are shown in The mean RA pressure was 7.5 ± 4.1 mmHg. The mean systolic PAP was 39 ± 12 mmHg. The mean PAP was 27 ± 9 mmHg. The median PAWP was 17 mmHg (IQR: 10–22). The median pulmonary vascular resistance was 2.51 WU (IQR: 1.95–2.98). Thirty-four patients (82.9%) had mean PAP > 20 mmHg, and 24 patients (58.5%) had mean PAP > 25 mmHg. The complete right heart catheterization measurements are reported in According to the new definition of PH (mPAP > 20 mmHg), the area under the ROC curve (AUC) for peak TRV in predicting PH was 0.855, for mean RV–RA gradient was 0.811, for estimated sPAP was 0.834 and for estimated mPAP was 0.758 . Accordip < 0.001. The correlation between mean RV–RA gradient and RHC-derived mPAP was r = 0.573, p < 0.001. The correlation between echocardiography-estimated PA pressures and RHC-derived PA pressures was: mPAP, r = 0.608, p < 0.001; sPAP, r = 0.616, p < 0.001 and dPAP, r = 0.576, p < 0.001.The correlation between peak TRV and RHC-derived sPAP was r = 0.624, The absolute mean difference between mean, systolic and diastolic PA pressures by RHC vs. echocardiography was −1.3 ± 9.8 mmHg, 2.4 ± 12.7 mmHg and −2.3 ± 8.2 mmHg, respectively. The main findings of this study can be summarized as follows: (1) Peak TRV performed similarly in predicting pulmonary hypertension according to the two hemodynamic definitions , but a lower cutoff value of 2.4 m/s had higher sensitivity and equal positive predictive value when applying the new definition of pulmonary hypertension, compared with the currently used threshold; (2) Peak TRV performed better than the mean RV–RA pressure gradient in predicting pulmonary hypertension for both old and new definitions; and (3) Estimation of pulmonary artery pressures using echocardiographic methods mainly based on TR analysis is modestly accurate when compared to right heart catheterization.In the context of the evaluating pulmonary circulation hemodynamics, Doppler echocardiography still remains the first-line noninvasive investigation, being patient-friendly and an easy bed-side test . HoweverPeak TRV is calculated from TR evaluated with CW Doppler interrogation of the tricuspid valve in apical four-chamber view. Applying Bernoulli’s equation, maximum and mean RV–RA gradients can be calculated from the same acquisition, considering peak TRV and from VTI calculation, respectively. Therefore, not only systolic PAP may be estimated from TR and estimated RA pressure, but also mean PAP and, consequently, diastolic PAP. Therefore, the aim of this study was to, firstly, evaluate if peak TRV performed well even according to the new hemodynamic definition of pulmonary hypertension, and, secondly, to evaluate if other TR-derived parameters could potentially perform better than peak TRV in predicting pulmonary hypertension.Regarding the first question, in this study, we have shown that peak TRV performs well independently of the pulmonary hypertension definition used in an advanced heart failure population, with similar predictive performance according to the two definitions. However, in our study population, a lower cutoff value for peak TRV had a higher sensitivity but equal positive predictive value for pulmonary hypertension when the new hemodynamic definition is used as compared to the currently recommended threshold. As a first-line tool to assess the probability of pulmonary hypertension, sensitivity should be preferred over specificity to allow a higher detection of patients affected by pulmonary hypertension. Indeed, for the same reason, recent guidelines have lowered the cutoff of mean PAP from 25 to 20 mmHg to make a diagnosis of pulmonary hypertension. The information coming from additional echocardiographic parameters and second-level examinations with higher specificity will allow for recognizing false-positive patients resulting from the first assessment.As already mentioned, peak TRV may be used to derive maximum RV–RA pressure gradient when using the modified Bernoulli’s equation, which ideally better reflects systolic PAP rather than mean PAP. In fact, mean PAP may be better reflected by mean RV–RA pressure gradient. Therefore, we evaluated the predictive performance of mean RV–RA pressure gradient for pulmonary hypertension, which, however, proved to be less accurate than peak TRV in predicting the presence of pulmonary hypertension, irrespective of the used definition, new or old. Also, estimated pulmonary artery pressures through adding estimated RA pressure to maximum and mean RV–RA pressure gradients, namely, systolic PAP and mean PAP, were generally inferior to peak TRV in predicting pulmonary hypertension. Curiously, in our study population, systolic PAP performed better then peak TRV in the prediction of pulmonary hypertension according to the old definition, but these data were not confirmed when using the new hemodynamic definition.Finally, correlation analysis and Bland–Altman analysis showed only modest agreement between echocardiographically estimated PAPs and right heart catheterization-derived PAPs. The largest absolute mean difference and the highest dispersion were observed for systolic PAP. Therefore, the consistency of results regarding peak TRV further support its use results to assess the probability of having pulmonary hypertension instead of mean RV–RA pressure gradient and estimated systolic PAP and mean PAP, as recommended by current guidelines. However, our results pose an issue on the threshold of peak TRV when the new hemodynamic definition is used, at least in an advanced heart failure population. In fact, lowering the cutoff of peak TRV in light of the new hemodynamic definition of pulmonary hypertension should be taken into consideration due to the higher sensitivity and equal positive predictive value as compared to the current threshold. The results of this study provide new findings regarding the accuracy of commonly used echocardiographic tools according to both the new and the old hemodynamic definition of PH in patients with AHF, who are evaluated for heart transplantation. This is particularly valuable since PH is a key element to assess during the heart transplantation evaluation protocol. The results may appear to be in contrast to previous studies with similar purposes, even though a direct comparison cannot be made because of the significantly different populations .This study is a single-center and data analysis was retrospective in nature, which are known for their limitations. The included patients are part of a very selected and restricted population of subjects with advanced heart failure, which may limit the extent of applying the results to the general population. However, since analyses were performed between measurements with the two methods in the same individual, the above concern is only modest. Even though the included patients belong to those with AHF, considered for heart transplantation, one of the main limitations of the study remains the relatively small sample size, which may limit the broad implication of the results. Also, because of the retrospective design of the study, we did not perform a sample size calculation and performed the analysis with the available data at our institution, which thereafter proved sufficient for the purpose of the study. We selected a population of patients with advanced heart failure because of the high prevalence of pulmonary hypertension in this group and the routine performance of right heart catheterization to assess eligibility for heart transplantation. Estimation of pulmonary pressures from TR can be affected by both TR degree and right ventricular impairment, both conditions are frequently seen in this study population of AHF patients. Despite this being a limitation, it allows for exploring the validity of the commonly used echocardiographic tools in screening for PH even in this special population of patients. Being a retrospective study, there were not enough echocardiographic exams with a CW Doppler registration at the pulmonary valve level, in order to estimate pulmonary artery pressures using pulmonary regurgitation signals. Moreover, the lack of pulsed-wave Doppler acquisitions of right heart including RV filling time and pulmonary acceleration time should be mentioned.Peak TRV performed better than other echocardiographic variables for the prediction of pulmonary hypertension according to the new hemodynamic definition. Also, peak TRV performed similarly with the old definition of pulmonary hypertension, but a lower cutoff showed higher sensitivity and equal positive predictive value for pulmonary hypertension as compared to the current one.