The incidence of the no-reflow (NR) phenomenon varies depending on the diagnostic criteria used. If just the angiographic criteria are considered , it will be found that the incidence of NR is quite low; on the other hand, when the myocardial NR is taken into account , the real incidence is higher. Thus, the early establishment of a diagnosis of NR and the administration of specific treatment can lead to its reversibility. Otherwise, regardless of the follow-up period, patients with NR have a poor prognosis. In the present work, we offer a comprehensive perspective on diagnostic tools for NR detection, for improving the global management of patients with arterial microvasculature damage, which is a topic of major interest in the cardiology field, due to its complexity and its link with severe clinical outcomes. The no-reflow (NR) phenomenon is highlighted when, following a myocardial infarction (MI), after the efficient unclogging of the epicardial coronary artery involved in the infarction, inadequate myocardial infusion is observed. Although effective methods of vascular permeabilization (such as coronary angiography) are currently available, the incidence of the phenomenon remains high, being found in 0.6 to 3.2% of patients who have had percutaneous coronary intervention (PCI) ,2,3.a NR phenomenon identified by angiography, expressing the degree of TIMI and MBG flow;a myocardial NR that may occur in patients who have obtained excellent resumption of intracoronary flow, but in whom the quality of reperfusion in the microcirculation is poor .Coronary NR, detected angiographically, occurs when the degree of thrombolysis in myocardial infarction (TIMI) flow and the myocardial blush grade (MBG) is ≤2, and has been found in 2% of patients who underwent interventional myocardial revascularization. The two types of NR are as follows:Estimation of the incidence of the phenomenon evaluated only according to angiographic criteria underestimates its presence, because these instances are limited only to coronary NR. However, taking into account the quality of myocardial reperfusion , there is a significant increase in the incidence of this phenomenon, which can be found in a third of patients with acute MI (AMI) .The illusion of myocardial reperfusion following myocardial revascularization, as well as the prognosis of these patients, is of real interest in assessing the quality of coronary microcirculation reperfusion, beyond simply assessing the resumption of optimal epicardial coronary flow. In order to achieve a reliable assessment of the quality of coronary reperfusion, several imaging techniques are available to cardiologists: post-stent angiographic evaluation, electrocardiogram (ECG), and more recently new imaging techniques including myocardial contrast echocardiography (MCE), cardiac magnetic resonance imaging (CMRI), and positron emission tomography (PET) .NR becomes more frequent as the duration of myocardial ischemia becomes longer. At the myocardial level, NR does not occur unless the reperfusion of the coronary artery responsible occurs before the installation of irreversible myocardial lesions . As a consequence, after the onset of myocardial necrosis, the phenomenon of NR is expected to occur .A dynamic process can evolve after myocardial reperfusion, worsening the ischemic lesions. The prognosis of patients with NR is unfavorable, as they are prone in the short term to the occurrence of malignant rhythm disorders and sudden cardiac death, and in the long term to the occurrence of heart failure. Recently, there have been significant improvements in technique and pharmacotherapy that have significantly changed the prognosis of patients . PublishDespite significant advancements in the prevention and treatment of cardiovascular disorders, women continue to be underdiagnosed and undertreated, with greater rates of hospitalization and death than males .Due to the multifactorial nature of the phenomenon, different therapy approaches are required. The use of vasodilators such as verapamil, adenosine, nitrates, nicardipine, sodium nitroprusside and papaverine is common in today’s pharmacological therapy; however, a vasoconstrictor-like epinephrine may also play a significant role . FurtherPoor cardiovascular outcomes are the leading cause of death in many nations, responsible for almost one-third of all deaths worldwide. More effective diagnostic methods and non-invasive imaging approaches are essential in providing detailed information about different pathologic conditions. Nanotechnology contains nanoscale structures with unique physicochemical features that make them desirable for improving present diagnosis procedures, and may play a beneficial role in diagnosing NR in conjunction with imaging techniques .Detection of NR after PPCI in patients with segment elevation myocardial infarction (STEMI) is essential because it represents the failure of myocardial reperfusion, despite recanalization of the infarcted epicardial coronary artery. Although the incidence of NR today is low, many of these patients have not been diagnosed correctly, and the prognosis is unfavorable, both in the short and long term, compared to those who do not develop the pathology .In the aforementioned context, this narrative review highlights the updates available for NR diagnosis and treatment in patients with STEMI, a phenomenon often ignored or underestimated, although there are many diagnostic methods available to specialists in the field. Our study also provides a very well documented pathogenesis of NR and a relevant and necessary update in the field of NR diagnostics methods, very useful for cardiologists and other medical specialists.This paper identified and filtered academic publications focusing on the NR phenomenon between 1992–2022, following a comprehensive search of the literature (the main platform for the key word search was PubMed) in the topic of the management of NR, highlighting and detailing the most important diagnostic methods available for use in the field of cardiology . However, the exact mechanisms have not been fully elucidated and require further research ,35. The Predictors of NR can be divided into two categories: classical cardiovascular risk factors and angiographically demonstrated predictors. It has been found that NR is more common in patients with several associated cardiovascular risk factors. Thus, patients who are older, obese, dyslipidemic, diabetic, hypertensive, or smokers who developed STEMI are more prone to NR after myocardial revascularization due to pre-existing microvascular endothelial dysfunction .A direct proportional relationship of the involvement of visceral obesity in the development of atherosclerosis has been detected by measuring body mass index, explained mainly by the production of proinflammatory elements and other enzymes with an unfavorable effect on the vascular endothelium .The impact of dyslipidemia is due to the increase in plasma total cholesterol level, which is the main risk factor in triggering the atherogenesis process. The first changes that appear in the arterial wall are prominent yellow lipid streaks on the surface of the vascular endothelium, formed predominantly by foam cells. The next changes are the appearance of fibrous atheromatous plaques which can cause partially or totally occlusive vascular lesions. They may have a fibrous consistency with a lower lipid content, or a soft consistency due to a high lipid content ,39.As changes continue, atheroma plaque complication may be observed, including cracking, rupture or ulceration of the atheroma plaque which can lead to the development of local hemorrhaging and thrombosis. Depending on the size of the thrombi, they may partially or totally obstruct the vascular lumen, leading to AMI. Low-density lipoprotein cholesterol indirectly contributes to the instability of atheromatous plaques, carrying an increased atherogenic risk, which will contribute to the development of the vulnerable atheromatous plaque and finally to its rupture, obstructing of the vascular lumen and the development of AMI ,41,42.Regarding the role of diabetes mellitus in determining ischemic lesions and the occurrence of NR, it has been observed that both insulin- and non-insulin-dependent diabetes mellitus are associated with an increased risk of ischemic cardiovascular disease . HoweverHypertension is a particularly important risk factor for cardiovascular disease. However, it is also a controversial factor, as hypertension facilitates the action of other factors causing endothelial dysfunction .It has also been observed that following epicardial coronary artery re-permeabilization in the development of AMI by PPCI, NR was more frequently encountered in patients with late presentation to the medical unit where PCI was performed. This is explained by the enlargement of the ischemic zone and the appearance of myocardial necrosis, which leads to the occurrence of the phenomenon. Also, the infarcted anterior territory as well as the anterior descending artery are more frequently incriminated in the occurrence of NR, as well as the implantation of an increased number of stents for revascularization of the involved coronary artery ,47.Regardless of the type of NR phenomenon, its occurrence is determined by multifactorial causes including non-modifiable and modifiable cardiovascular risk factors, as well as the location of STEMI involving the anterior descending artery as the responsible artery, revascularization time, and intracoronary drug management of the coronary NR . The preDue to the wide range of current approaches for evaluating the clinical NR phenomenon, it is essential to assess the mechanisms and limitations of the most frequently used diagnostic tools.There are available several methods available to diagnose NR; we initially consider the classical methods, including electrocardiogram (ECG), coronary angiography, TIMI-flow grade, corrected TIMI frame count (CTFC), MBG and TIMI myocardial perfusion grade (TMPG) .The ECG is a standard method of assessing the NR process, which is defined as prolonged ST elevation despite opening the epicardial coronary artery in the setting of a STEMI ,51,52. FLong-term mortality following PPCI is predicted by persistent ST elevation and MBG grades 0 to 1, while CTFC is a weaker predictor. Concomitant use of these features may improve their predictive power .ST resolution can be obtained in simply and quickly; however, in some cases it can be an ineffective tool for diagnosing the NR phenomenon. In a comparative study, incomplete ST resolution was correlated to baseline LV function, but not to changes over time . MoreoveIt has been shown that a rapid reduction in ST elevation after reperfusion therapy is correlated with early, complete, and quick restoration of cardiac tissue perfusion. Furthermore, successful tissue perfusion is also associated with early T-wave inversion. Following cardiac reperfusion therapy, sustained elevation of the ST segment is linked with poor clinical and functional results. Thus, ST segment monitoring is an effective and inexpensive approach to assess myocardial reperfusion .Using TIMI flow grades, angiographic and clinical outcomes following PPCI are commonly correlated with thrombolysis. The hypothesis is that contrast fluidity in the epicardial coronary artery represents spontaneous coronary circulation and myocardial perfusion, as well as the efficacy of coronary intervention .NR can be evaluated without additional cost by using simple angiographic procedures at the time of PCI. The CTFC is the number of cine frames between contrast injection and the frame in which contrast reaches a standardized distal marker in the culprit artery, and is generally used to show enhanced therapeutic flow. TIMI flow grade is exclusively sensitive to epicardial blood flow and has low sensitivity to microvascular blockage. The quantity of contrast that passes through and opacifies cardiac tissue is measured by myocardial perfusion grade, and more frequent MBG. MBG b3 was found in 18–37% of patients with normal TIMI grade 3 flow after PPCI for MI ,60.Existing medical evidence suggests the use of “angiographic criteria” to identify NR, such as TIMI flow grade b3 or TIMI flow grade 3 plus MBG b3. By TIMI flow grade, the incidence of NR after PPCI was 12–37% and by MBG was 29–63% ,62,63.TIMI flow grades are provided on a scale of 0 to 3. Improved clinical outcomes and decreased mortality have been linked to higher TIMI flow grades. During coronary angiography, TIMI blood flow grades are used to assess the quality of coronary flow ,65.This method assesses the clearance of radiographic dye in the coronary arteries. Patients with TIMI 0 or 1 flow are considered to have experienced failed reperfusion  trial, the degree of MBG and the ST-segment resolution 4 h after PPCI are commonly discordant (in around 40% of cases), which may limit their use. ST resolution was a more accurate indicator of clinical outcomes at one month and at one year after multivariable adjustment; however, both factors in combination appeared to have added predictive value .TMPG, which is similarly rated on a scale of 0 to 3, is another way to assess myocardial perfusion. TMPG grade 3 blush represents the start of blush clearance during washout ; TMPG grade 2 blush clears mildly or not at all during three cardiac cycles of washout; TMPG grade 1 blush indicates the presence of myocardial blush without clearance from the microvasculature ; grade 0 blush indicates no perfusion at tissue level ,76.TMPG is a densitometric method for grading the evolution of contrast media at the myocardial level . To grade NR, it can be combined with the TIMI flow grade .MBG, on the other hand, assesses the intensity of the blush in the distribution of the culprit artery compared to the contrast density in unaffected areas. Independent of epicardial blood flow restoration, impaired reperfusion as defined by the TMPG grading system is linked to a higher risk of mortality .TMPG had the highest correlation with MVO when assessed by cardiac magnetic resonance imaging (CMRI) on the third day post-STEMI in a study of patients receiving PPCI, but MBG had no correlation with CMR-derived evaluation of MVO .The clinical status of patients with NR phenomenon has improved lately due to advances in medical imaging technologies that have had a significant impact on diagnostic assessment. The methods available for establishing the diagnosis of NR include cardiac magnetic resonance imaging (CMRI), myocardial contrast echocardiography (MCE), single photon emission computed tomography (SPECT), and positron emission tomography (PET).The gold standard for assessing and diagnosing NR phenomenon is CMRI. Regardless of the extent of the infarct, an increased degree of MVO observed by CMRI predicts a worsened outcome in terms of LV remodeling, mortality, and heart failure hospitalizations. The extent of MVO measured by CMRI several days after PPCI is associated with heart failure hospitalizations and mortality after 12 months of the infarction ,80.Late gadolinium enhancement (LGE) and first pass perfusion are two gadolinium-based approaches for detecting MVO. Both procedures involve the injection of gadolinium, an extracellular substance that rapidly extravasates into the interstitial space. Gadolinium clearance in normal tissue is relatively quick (1–2 min), whereas clearance from infarcted tissue is significantly slower (approximately 30 min). In the late contrast enhancement procedure, imaging is performed 10–15 min after intravenous gadolinium administration. As a result, relative to normal cardiac tissue, infarcted myocardium appears hyper-enhanced or “bright”, while MVO shows a central hypo-enhanced zone within the hyper-enhanced area. This is known as ‘late MVO’, and it is caused by severe damage to the microvasculature, which prevents gadolinium from accessing the area ,81.The first pass perfusion technique is another gadolinium-based approach for MVO detection. For the first 50 heart beats, first-pass perfusion imaging is performed simultaneously with contrast injection, producing at least three short axis slices. Shortly after contrast injection, normal and infarcted myocardium show a uniform increase in signal intensity, whereas MVO appears as a lowered signal intensity (hypo-enhancement) in the core structure of the infarct persisting for more than 2 min. This is referred to as “early MVO”. The superiority of one methodology over another for quantifying MVO is still a point of contention. Several experimental studies observed certain differences in sensitivity between early and late MVO ,82.Late MVO, on the other hand, is considered less sensitive than early MVO because small ‘no-reflow’ areas are rapidly increased due to extracellular contrast medium diffusion from surrounding regions with normal microvasculature. As a consequence, late MVO detection may underestimate the degree of MVO .Early MVO, however, had shortcomings such as insufficient LV coverage, low signal-to-noise ratio, and low spatial resolution. An imaging method that integrates early imaging with total LV coverage was proposed in an experimental study .The medical evidence showed that the presence of MVO, rather than its extent, is the most accurate indicator of changes in global functionality and LV end-systolic volume at follow-up .CMRI is frequently performed within the first week (day 3–5) of an AMI ,85. An eGas-filled microbubbles are used in MCE, which are particularly effective at scattering ultrasonography. These microbubbles are small (maximum 5 μm) and do not obstruct capillaries. They can be used to detect microvascular perfusion, myocardial blood volume and capillary flow, or to identify molecular events occurring on the microvascular endothelium or within the cellular components of blood present within the microvasculature, even though they remain entirely within the vascular space .Microbubbles are used to assess microvascular perfusion because their intravascular rheology matches that of erythrocytes. Microbubbles are introduced as a continuous infusion, and steady state is reached after 2–3 min, when their concentration in any blood pool, such as the LV cavity or myocardium, is constant and proportional to the blood volume concentration of that pool. When the acoustic intensity obtained from the myocardia after background subtraction is normalized to the LV cavity, the myocardial blood volume fraction is determined. Because capillary blood accounts for 90% of myocardial blood volume fraction at end-systole, a single end-systolic MCE image can be used to measure capillary density in various myocardial areas .Two semi-quantitative assessment procedures were used. Firstly, a perfusion score was assigned, ranging from 1 to 3, based on the change in the myocardial signal intensity throughout the replenishment curve as well as the degree of opacification at peak contrast effect. Secondly, in each apical view, the endocardial length of the transmural contrast defect (score = 3) was quantified, averaged, and reported as a percentage of the LV endocardial length. Despite the achievement of epicardial patency, persistent contrast deficiencies were linked to MVO ,90,91.Low flow through an open infarct-related artery may also be evaluated using the microbubble destruction technique, in the same way as collateral flow. Lower amounts of anterograde flow lead to a slower filling of myocardium compared with normal conditions. If the capillary blood volume is basically intact  and the myocardium fills up in less than 15–20 s on MCE, the myocardium is viable, and revascularization will improve its functionality. These results have been confirmed and validated in a clinical investigation of AMI patients ,92.p = 0.031 and p = 0.027, respectively) but had no correlation with MBG (p = 0.067). There were considerably more segments with a perfusion deficiency on MCE among individuals with anterior AMI than in patients with inferior AMI (p = 0.0001). Angiographic methods of perfusion evaluation, such as TMPG and CTFC, correlated with MCE results. A larger amount of perfusion deficiency was associated with anterior AMI. MCE results were significantly linked to systolic LV function recovery and clinical conditions at six-months follow-up [PPCI was successful in 100 patients diagnosed with a first STEMI and single-vessel illness. The regional contrast score index, TIMI, CTFC, TMPG, and MBG were all assessed. On MCE, 168 of the 717 asynergic segments showed a lack of perfusion. Regional contrast score index was significantly linked with TMPG and CTFC /123 I-beta-methyl iodophenyl pentadecanoic acid (I-BMIPP) SPECT scan within one week of initial AMI. On each SPECT image, LV myocardium was separated into 17 segments and the accumulation of tracer in each segment was scored using a five-point scoring system based on American Heart Association criteria. Summing the values for all 17 segments generated the total severity score. The mismatch ratio between myocardial perfusion and metabolism was calculated using the total severity scores of 201TlCl and 123I-BMIPP. The patients enrolled in the study were classified according to TIMI flow grade. The dual-isotope myocardial SPECT of 201TlCl/123I-BMIPP indicated the biochemical degree of the NR phenomenon, whereas coronary angiography had shown clearly recanalized vascular flow. Therefore, myocardial dual-isotope SPECT may be beneficial in evaluating reperfusion treatment .123I-BMIPP was used to visualize myocardial fatty acid metabolism, reflecting the memory at the onset of MI. The discrepancy between blood flow and metabolism after PCI indicates the volume of reperfused myocardium and enables severe myocardial damage without decreased flow  to be identified. Therefore, to evaluate the usefulness of 201TlCl/123 I-BMIPP dual-isotope myocardial SPECT for identifying NR, the relationship between perfusion metabolism mismatch and the degree of reflow after PCI were investigated . The “noPlanar images are utilized to develop a three-dimensional representation of myocardial perfusion in SPECT, a method which is more frequently applied and available in clinical practice today. SPECT can collect successive slices of normal and pathological areas without overlap, and with better resolution than planar imaging. SPECT imaging has been validated for the identification of coronary artery disease in several large-scale investigations; nonetheless, there are certain limitations to this imaging method. These include abnormalities generated by motion, attenuation, or extracardiac activity, all of which have an impact on image quality and reader variability. Furthermore, SPECT imaging commonly employs technetium-99m (Tc-99m) tracers, which have a poor first-pass extraction rate, resulting in an underestimate of ischemia alterations in terms of extent and severity .SPECT imaging can be used to assess myocardial perfusion and tissue viability using a variety of methods. There is no single procedure that is appropriate for all patients, and investigations must be adjusted for each patient based on the diagnostic information required by the clinician and the patient’s characteristics. Tc-99m and thallium-201 (Tl-201) are the most frequently used radiotracers in SPECT imaging ,102.Images are captured in a variety of ways, including short axis cuts, long vertical and horizontal axes, and transaxial views. Poor myocardial perfusion results in lower radiotracer uptake, whereas adequate perfusion results in brighter images. The comparison of rest and stress images can contribute to identifying regions of viable, reversible perfusion abnormalities from non-reversible perfusion abnormalities. This visualization includes determining whether revascularization is required .The sensitivity and specificity of SPECT perfusion imaging for the identification of coronary artery disease have been addressed in several studies. The reported sensitivity has generally varied from 70–90%, and the reported specificity has generally ranged from 60–90% ,105.PET is a non-invasive procedure that has a wide range of clinical and research applications in the evaluation of the pathophysiology of a variety of disorders, including neurodegenerative disorders, infections, epilepsy, seizures, psychiatric disorders, and brain tumors. It is also useful for studying blood flow. PET is a very sensitive imaging technology that allows three-dimensional mapping of positron-emitting radiopharmaceuticals in mcg doses without generating any substantial physiologic or pharmacologic effects. In contrast to MRI and computed tomography (CT), which are better suited to evaluating a body’s structure, PET is a molecular imaging technology that allows the study of biologic function in conditions of health and disease .After PET examination, despite the existence of sustained TIMI flow grade 3 in the infarct-associated epicardial coronary artery, more than a third of patients were found to have reduced myocardial tissue perfusion .13NH3 being used to monitor myocardial blood flow. The areas with a myocardial blood flow <80% of regularly perfused myocardium (hypoperfusion) and <50% (NR) were automatically identified for each subject [A prospective study was conducted on 45 patients with STEMI who were treated with thrombolysis or PCI,  subject ,109.3 (ammonia) experiments [13NH3, an emission scan was taken. The perfusion study’s summed frame was generated. The myocardial image was resampled and segmented into 16 radial slices. Each polar map was divided into 33 areas, consisting of four rings of eight regions and one apex region. Using a previously established approach, a zone of normal tracer uptake was automatically delineated on the 13NH3 polar map. The reference value (100% 13NH3 uptake) was set at the mean values of that region, and the entire polar map was normalized to this value. Depending on the coronary structure shown on the angiography, the infarct-related region in each patient was manually developed on the polar map by grouping some of the 33 regions. The amount of perfusion defect in the LV was calculated by adding the myocardial wall volumes of the pixels in the affected area, and expressed as a percentage of total LV volume [A whole-body PET was used for the NHeriments . After iV volume .No association was detected between the relative resolution of ST segment deviation and any of the PET myocardial damage indicators. This fact indicates that relative resolution makes it impossible to draw clear conclusions about the magnitude of an infarct in a specific patient. In large patient populations, however, the average relative resolution of ST segment deviation has been shown to have significant predictive potential .The use of PET allows the assessment of the infarct myocardium’s metabolic status and is the gold standard for determining myocardial viability. However, maintenance costs and other local considerations limit the number of institutions that may install and use PET .The most important characteristics of classical and modern methods for diagnosis of NR are summarized in NR has several triggers and is a complex multifactorial phenomenon. Strategies involving rapid and accurate diagnosis allow intracoronary treatment initiation at the time of PCI. This can dramatically change the prognosis of patients diagnosed with reversible NR leading to similar outcomes as for subjects without this condition. The presence of persistent NR is considered a negative prognostic factor on both the short and long term. Many diagnostic tools to identify the NR phenomenon are available, each of them with specific advantages and certain limitations. The most effective approaches among the non-invasive techniques are the assessment of microvascular flow by means of PET or Cadmium-Zinc-Telluride gated SPECT myocardial perfusion imaging. In the same study these two techniques can simultaneously evaluate: motility, thickening, perfusion, myocardial flow, myocardial flow reserve, and synchrony. In current clinical practice, invasive coronary angiography remains the gold standard technique for NR evaluation.


Transthyretin cardiac amyloidosis (ATTR-CA) is today more frequently recognized but the rate of progression of cardiac dysfunction is not well established. The aim of this study is to investigate the nature of cardiac structure and function changes, over time, in a retrospective cohort of ATTR-CA patients.Fifty-one patients with ATTR-CA  were compared with 20 patients with heart failure but no amyloidosis (HFnCA) , all with septal thickness >  = 14 mm. All patients underwent DPD scintigraphy and an echocardiogram (Echo 2) which was compared with a previous echocardiographic examination (Echo 1), performed at least 3 years before.p < 0.001 for both, by a mean increase of 0.4 mm/year and 0.03 mm/year, (p = 0.009 and p = 0.002 compared with HFnCA), respectively. RWT > 0.45 (AUC = 0.77) and RELAPS > 2.0 (AUC 0.86) both predicted positive DPD diagnosis for ATTR-CA.Over the follow-up period, the interventricular septal thickness (IVST) and relative wall thickness (RWT) in ATTR-CA increased from 16 (4) to 18 (5) mm and from 0.51 (0.17) to 0.62 (0.21) respectively, In ATTR-CA patients, the overtime-increase in RWT and IVST was worse than that seen in patients with heart failure but no cardiac amyloidosis. Also, RWT and relative apical sparing predicted diagnosis of ATTR-CA, thus could strengthen the use of follow-up echocardiographic findings as red flag for the diagnosis of ATTR-CA. Transthyretin (TTR) amyloidosis (ATTR) is the most common type of systemic amyloidosis and is classified into a hereditary type (ATTRv), and a wild-type transthyretin (ATTRwt) amyloidosis , 2. One The aims of this study were firstly, to investigate the ATTR-CA disease progression using echocardiography and compare it with that of heart failure patients with increased wall thickness but no CA (HFnCA), based on DPD scintigraphy. Secondly, to evaluate echocardiographic predictors for DPD scintigraphy verified ATTR-CA diagnosis.This is a retrospective study in patients with heart failure and increased septal thickness. Inclusion criteria for further investigations in the patients were (1) septal thickness > 14 mm, (2) absence of types of CA other than ATTRwt and ATTRv, and (3) confirmed final diagnosis of ATTR amyloidosis, using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy examination. Part of this cohort findings was previously published . We inclExcluding AL amyloidosis in all patients was based on blood and urine analysis of serum free light chain (FLC) abnormalities  and the presence of monoclonal bands. Sequencing of the TTR-gene was also undertaken in all patients to diagnose ATTRv amyloidosis. Patients with Perugini score 1 were excluded from the study due to uncertain diagnosis. To evaluate the disease progression rate, we compared the two echocardiograms (Echo 1 and Echo 2) obtained using the same vendor. All patients had had an echocardiogram at the time of the DPD scan (Echo 2) and a previous echo (Echo 1) at least 3 years before.Echocardiographic examination was performed using a Vivid E9 system  equipped with an adult 1.5–4.3 MHz phased array transducer. All Echo 2 studies were performed by the same investigator (PL) blinded to Echo 1 findings. Echo 1 studies were performed by various physiologists at the Clinical Physiology Department, Umea University. Standard views from the parasternal long axis-, short axis- and apical four-chamber views were used, following conventional protocols. Flow velocities were obtained using pulsed and continuous wave Doppler techniques as proposed by recent guidelines , 17. AllRelative ventricular wall thickness (RWT) was calculated according to the American society of echocardiography (ASE) recommendations  diastolic diameter [LVDd]). Trans-mitral blood flow velocities were obtained with the sample volume placed at the tips of the mitral valve leaflets with optimal angulation to LV inflow. From trans-mitral flow velocities, we measured early (E) diastolic and atrial contraction (A) flow velocities. Retrograde systolic trans-tricuspid flow was obtained from either parasternal right ventricular inflow or apical 4-chamber view, for measuring peak retrograde trans-tricuspid pressure drop using continuous wave Doppler, which reflects pulmonary artery systolic pressures. Left atrial volume was measured using the modified Simpson’s single plan calculation [4 chamber view] .Pulsed wAnatomical landmarks were used, and care was taken for echocardiographic image acquisition to ensure adequate LV myocardium tracking, avoiding foreshortening of LV cavity when measuring global LV strain. Longitudinal myocardial deformation was assessed from the two-dimensional echocardiographic acquisitions using speckle tracking technology and was analyzed off-line. From the apical four chamber, two chamber and apical parasternal long axis views the endocardial border detection of the septal, apical and lateral LV walls was made manually, to analyze global LV strain (GLS) measurements. Strain recordings from three cardiac cycles were averaged, to assess GLS which were measured at end-systole with the reference point set at the onset of two consecutive QRS-complexes of the superimposed ECG. RELAPS was also calculated as average apical strain / . Strain analyses were measured using a dedicated workstation . 2D strain assessment was done based on the recommendations of the European Association of Cardiovascular Imaging .All patients underwent DPD scintigraphy examination using an Infinia Hawkeye hybrid single-photon-emission computed-tomography gamma camera (SPECT-CT)  with a low-energy high-resolution collimator. An intravenous injection of ~ 750 MBq DPD was given 3 h prior to the acquisition of whole-body planar image, followed by a non-contrast, low dose CT scan and a SPECT acquisition, 60 projections, iteratively reconstructed to a 128 × 128 matrix  with scatter and CT-based attenuation correction. Reconstruction of SPECT images was performed on the Xeleris workstation . DPD scores were reported by two experienced clinicians using the Perugini’s grading system  with graU tests for non-normally distributed data. Wilcoxon paired test was used for comparing non-parametric data. Data were presented as median and interquartile range 25–75 for non-normally distributed data. Normality was assessed by Shapiro–Wilk’s test. ROC analysis was performed to evaluate the accuracy (area under the curve) and differentiating groups. P values were presented with a 0.05 level of statistical significance Fig. 1Statistical analysis was preformed using SPSS®, version 27 (IBM). Data are presented as mean, standard deviation (SD) if data were normally distributed, maximum and minimum values for continuous variables. Percentages were used to describe categorical variables. Categorical variables were compared using chi-square and McNemar tests, and continuous variables were compared using the Student’s t-tests for normally distributed data or Mann–Whitney The study complied with the declaration of Helsinki and the study protocol was approved by the Regional Ethics Committee of Umeå  and all subjects gave written informed consent to participate in the study.p < 0.001). All HFnCA patients had diagnosis of systemic hypertension as the cause for increased LV wall thickness. At the time of DPD, ATTR-CA patients had significantly higher NT-proBNP (p = 0.045), lower diastolic blood pressure (p = 0.046) and weight (p < 0.001), Table Patient’s characteristics are presented in Table p < 0.001) but not in HFnCA. LV posterior wall and relative wall thickness both increased only in ATTR-CA . In the same group GLS decreased significantly (p < 0.001). 16% of ATTR-CA had AF at Echo 1 which increased significantly to 55% at the time of Echo 2. In comparison, only one patient with HFnCA had AF at Echo 1 and 12% had AF at Echo 2. The prevalence of AF at Echo 2 was significantly higher (p < 0.001) in ATTR-CA than HFnCA. RELAPS did not change over time in either of the two groups, Table 2There was no difference in septal thickness between the two patient groups at the time of Echo 1. At follow up, septal thickness increased significantly in ATTR-CA (p = 0.024), had thinner IVS (p = 0.03), larger LAV (p = 0.02) and lower LV GLS (p = 0.008) compared with ATTRv. At the time of Echo 2, RWT and RELAPS were lower (p = 0.019 and p < 0.001) in ATTRwt. The prevalence of AF was higher in ATTRwt at Echo 1 but lower at Echo 2. However, the prevalence of AF increased in both groups Table At the time of Echo 1, ATTRwt patients were older . There was no difference between groups in the rate of progression of RELAPS, right ventricular-right atrial pressure drop or left atrial volume. The rate of fall of LV GLS was faster in ATTR-CA compared to HFnCA (p = 0.05).Since the time difference between Echo 1 and Echo 2 varied between patients, we investigated the rate of progression in echo measurements, such as RWT, RELAPS, GLS, RV-RA retrograde pressure drop and LA volume. We calculated the rate by dividing the difference in these measurements from Echo 1 to Echo 2 by the time difference between the two studies, in years. In ATTR-CA, septal thickness and RWT both increased by 0.39 mm and 0.023 mm/year, respectively which was significantly faster for both compared with HFnCA (p = 0.012). Comparing ATTR-CA patients with or without hypertension showed no differences in disease progression rate, Table The disease progression in ATTRwt and ATTRv was not different between groups, except for RWT that progressed faster in ATTvt (p = 0.002 and RELAPS; AUC = 0.86, p < 0.001, respectively. A RWT > 0.45 at baseline had a sensitivity of 76% and specificity of 71% in predicting ATTR-CA. Respective values for RELAPS > 2 were 71% sensitivity and 86% specificity in predicting ATTR-CA. Wall thickness did not predict DPD findings.Relative wall thickness and relative apical sparing predicted the diagnosis of ATTR-CA by DPD, RWT; AUC = 0.77, In two groups of heart failure patients with similar LV cavity morphology and wall thickness, our findings show significant differences in the rate of increased wall thickness changes over time, according to objective evidence for the presence of ATTR. Patients with ATTR-CA had faster rate of increased septal and relative wall thickness compared with HFnCA due to systemic hypertension. In the same group of patients with ATTR-CA, LV myocardial strain showed significant fall, more than that seen in HFnCA. Our findings also show a potential impact of the two types of ATTR-CA, with the wild type patients being older, frequently males, with larger left atrium and have faster rate of increased relative wall thickness compared to the non-amyloid. Hypertension in ATTR-CA did not seem to influence progression rate in cardiac function and morphology. Finally, RWT and RELAPS with a similar accuracy predicted the presence of ATTR-CA on the DPD scan.. We and others have reported a number of measures which assist in differentiating the two conditions of benign myocardial hypertrophy and infiltration as a causes for increased wall thickness [It is well known that increased myocardial thickness is a common finding in patients with heart failure and preserved LVEF because of the increased prevalence of long-standing hypertension in these patients . Recent hickness . Firstlyhickness . In thisThe increase in wall thickness in our two heart failure groups of patients is fundamentally different. While the benign increase in wall thickness due to hypertension is caused by cellular hypertrophy and myocyte disarray, that in cardiac amyloidosis is mainly due to extra cellular amyloid deposition. The latter has been reported to be less pronounced in AL amyloidosis  but has Our results show that both RWT and RELAPS could predict DPD-scintigraphy based diagnosis of ATTR-CA, a finding that has significant clinical relevance. It indicates the significant potential and importance of echocardiographic measurements in the diagnosis of ATTR-CA, with high accuracy, thus supporting its clinical role as red flag for ATTR cardiac amyloidosis. However, this potential relationship is limited since 12 of the ATTR-CA patients had septal thickness < 14 mm at baseline. Therefore, the proposed measures need to be re-tested in a larger cohort of patients. The unique application of RWT as an imaging marker for disease should be praised for being simple, universally available and does not need sophisticated expensive techniques. Its accuracy is also not dependent on rhythm patterns, as is the case with other investigations. In addition, a reduction in RWT and LV wall thickness and improved GLS has been found in ATTRv patients treated with RNA interference therapy  which stLimitations: The main limitation of this study is the relatively small sample volume; hence findings should be reproduced in a larger cohort before been considered for clinical guidance. The presence of atrial fibrillation could have influenced the results, especially those of LV function. We did not adjust for treatment, medical or liver transplantation, in either of the two patient groups which could have an influence on the results. However, we considered DPD verified evidence for ATTR cardiac amyloidosis an important differentiating evaluation of the disease progress.In ATTR-CA patients, the overtime increase in septal thickness was more profound than that seen in patients with heart failure but no cardiac amyloidosis. Also, relative wall thickness and relative apical sparing predicted diagnosis of ATTR-CA, thus could be considered as early echocardiographic markers for ATTR-CA. However, this findings need to be revalidated in a larger group of ATTR-CA.


To evaluate the diagnostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) thresholds for acute heart failure and to develop and validate a decision support tool that combines NT-proBNP concentrations with clinical characteristics.Individual patient level data meta-analysis and modelling study.Fourteen studies from 13 countries, including randomised controlled trials and prospective observational studies.Individual patient level data for 10 369 patients with suspected acute heart failure were pooled for the meta-analysis to evaluate NT-proBNP thresholds. A decision support tool ) that combines NT-proBNP with clinical variables to report the probability of acute heart failure for an individual patient was developed and validated.Adjudicated diagnosis of acute heart failure.Overall, 43.9% (4549/10 369) of patients had an adjudicated diagnosis of acute heart failure (73.3% (2286/3119) and 29.0% (1802/6208) in those with and without previous heart failure, respectively). The negative predictive value of the guideline recommended rule-out threshold of 300 pg/mL was 94.6% ; despite use of age specific rule-in thresholds, the positive predictive value varied at 61.0% (55.3% to 66.4%), 73.5% (62.3% to 82.3%), and 80.2% (70.9% to 87.1%), in patients aged <50 years, 50-75 years, and >75 years, respectively. Performance varied in most subgroups, particularly patients with obesity, renal impairment, or previous heart failure. CoDE-HF was well calibrated, with excellent discrimination in patients with and without previous heart failure (area under the receiver operator curve 0.846 (0.830 to 0.862) and 0.925 (0.919 to 0.932) and Brier scores of 0.130 and 0.099, respectively). In patients without previous heart failure, the diagnostic performance was consistent across all subgroups, with 40.3% (2502/6208) identified at low probability  and 28.0% (1737/6208) at high probability  of having acute heart failure.In an international, collaborative evaluation of the diagnostic performance of NT-proBNP, guideline recommended thresholds to diagnose acute heart failure varied substantially in important patient subgroups. The CoDE-HF decision support tool incorporating NT-proBNP as a continuous measure and other clinical variables provides a more consistent, accurate, and individualised approach.PROSPERO CRD42019159407. Nearly 1 million people are living with heart failure in the UK, and the prevalence is projected to rise by approximately 50% over the next 25 years owing to the ageing population.Although many models have been developed to predict prognosis in patients with heart failure, very few have been developed to aid in the diagnosis of acute heart failure.In this collaborative international analysis, we evaluated the diagnostic performance of guideline recommended NT-proBNP thresholds for acute heart failure across patient subgroups. We subsequently developed and validated a decision support tool for patients with suspected acute heart failure that uses statistical modelling to combine NT-proBNP concentrations with clinical characteristics.We did a systematic review to identify studies that evaluated the diagnostic performance of NT-proBNP in patients with suspected acute heart failure. We updated a previous review by Roberts et alWe contacted the corresponding authors of all eligible cohorts to request anonymised individual patient level data on NT-proBNP concentrations, adjudicated diagnosis of acute heart failure, demographics , past medical history , physiological variables during the initial assessment (heart rate and blood pressure), and clinical haematology and biochemistry profiles. We checked accuracy, definitions of variables, and completeness with all corresponding authors before harmonisation. All studies were conducted in accordance with the Declaration of Helsinki and with ethical approval to permit sharing of individual patient level data to conduct this meta-analysis. Two investigators (KKL and MA) independently assessed risk of bias for each study by using the Quality Assessment of Diagnostic Accuracy Studies version 2 (QUADAS-2) tool,We derived meta-estimates with 95% confidence intervals of the sensitivity, specificity, negative predictive value, and positive predictive value of the guideline recommended NT-proBNP rule-out threshold (300 pg/mL)https://decision-support.shinyapps.io/code-hf/) by using statistical modelling to compute a value (0-100) that corresponds to an individual patient’s probability of acute heart failure. Owing to significant differences in comorbidities and the prevalence of acute heart failure, we developed and validated models for patients with and without previous heart failure separately. We used NT-proBNP concentrations as a continuous measure and selected simple objective clinical variables that are known to be associated with acute heart failure, which were found to have the highest relative importance in our model training phase  (supplementary text 2).We developed and validated a decision support tool ; We evaluated four different statistical models in the development of CoDE-HF: generalised linear mixed model, naïve Bayes, random forest, and extreme gradient boosting (XGBoost) (supplementary text 2).We assessed the performance of each model across a range of diagnostic metrics . The Brier score is a measure of both discrimination and calibration and is calculated by taking the mean squared difference between predicted probabilities and the observed outcome.Members of a patient and public panel were involved in the interpretation of results. There are plans to disseminate the results of the research to relevant patient communities.We contacted investigators from 30 eligible studies, of which 19 responded. Fourteen studies  provided individual patient level data on 10 369 patients with suspected acute heart failure  from 13 countries , 96.8% (94.6% to 98.1%), 62.9% (51.3% to 73.3%), and 49.3% (35.4% to 63.4%), respectively , 73.5% (62.3% to 82.3%), and 80.2% (70.9% to 87.1%), respectively . CorrespOverall, we identified seven studies as having a high risk of bias (supplementary table A). In sensitivity analyses restricted to studies in which the adjudication of acute heart failure was blinded to NT-proBNP concentrations and those with a low risk of bias, diagnostic performance of the guideline recommended and age specific NT-proBNP thresholds remained unchanged (supplementary tables E and F).An NT-proBNP threshold of 100 pg/mL achieved our optimal rule-out criteria with a pooled negative predictive value of 97.8% (95.8% to 98.8%) and sensitivity of 99.3% (98.5% to 99.7%) (supplementary table D). However, only 17.9% (1851/10 369) of patients had NT-proBNP concentrations below 100 pg/mL and the negative predictive value remained lower in older patients and those with previous history of heart failure, ischaemic heart disease, and impaired renal function (supplementary figure J). Similarly, a NT-proBNP threshold of 1000 pg/mL achieved our optimal rule-in criteria with a positive predictive value of 74.9% (64.4% to 83.2%) and specificity of 76.1% (65.6% to 84.2%), although performance was also lower within patient subgroups, particularly those without previous heart failure  .The extreme gradient boosting (XGBoost) model and generalised linear mixed model were the best performing models  and 0.931 (0.925 to 0.937), respectively) (supplementary text 2). Although the performance of XGBoost was similar to the generalised linear mixed model, a key advantage of XGBoost is its ability to compute a score despite missing values. This is an important functionality that we wished to build into the CoDE-HF decision support tool to facilitate its implementation in clinical practice, so we selected the XGBoost model as the final model for CoDE-HF.CoDE-HF was well calibrated with excellent discrimination in patients with and without previous heart failure (area under the receiver operator curve 0.846 (0.830 to 0.862) and 0.925 (0.919 to 0.932) and Brier scores of 0.130 and 0.099, respectively) ; fig 7. Patients who were identified as low probability by CoDE-HF had a substantially lower rate of all cause and cardiovascular mortality at 30 days and one year compared with those who were identified as intermediate and high probability  . In patiWe did a meta-analysis of individual patient level data to evaluate the diagnostic performance of NT-proBNP thresholds in more than 10 000 patients with suspected acute heart failure recruited in 14 prospective studies from 13 countries, and we developed and externally validated a decision support tool that uses NT-proBNP as a continuous measure. We report several important findings. Firstly, the guideline recommended threshold to rule out acute heart failure was heterogeneous across important patient subgroups.To our knowledge, this is the largest study evaluating the diagnostic performance of NT-proBNP for acute heart failure to date. All included studies were prospective, and the final diagnosis was adjudicated by a panel of clinicians using all available information. Importantly, the availability of individual patient level data across a large study population allowed a robust evaluation of diagnostic performance across a full range of possible NT-proBNP thresholds within patient subgroups and the development and validation of a novel diagnostic score.Most national and international guidelines recommend the use of an NT-proBNP threshold of 300 pg/mL to rule out acute heart failure,To improve the clinical utility of NT-proBNP, we developed and externally validated a clinical decision support tool, the CoDE-HF score. This score incorporates NT-proBNP as a continuous measure together with simple, objective clinical variables to provide an individualised assessment of the likelihood of the diagnosis of acute heart failure. We showed that the diagnostic performance of the CoDE-HF score was robust across patient subgroups. CoDE-HF was able to rule out and rule in the diagnosis of acute heart failure in a larger proportion of patients compared with using optimised NT-proBNP thresholds alone. Furthermore, in our decision curve analysis, we found that CoDE-HF had a higher net benefit than NT-proBNP alone across the full range of threshold probabilities. We believe that this finding is intuitive given that NT-proBNP is a continuous marker of risk and concentrations are influenced by other patient related factors, such as body mass index, age, and renal function.We anticipate that CoDE-HF, our novel decision support tool, has the potential to improve the triage of patients with suspected acute heart failure presenting to multiple medical specialties and to transform their care by facilitating more accurate diagnosis. Previous studies have showed that prompt and accurate delivery of evidence based treatments for patients with acute heart failure can lead to a substantial reduction in mortality and length of hospital stay, whereas delays are associated with worse outcomes.We acknowledge several limitations. Firstly, we were able to obtain individual patient level data for 14 of 30 studies that met our eligibility criteria, so the introduction of selection bias is a possibility. Nevertheless, the eligible studies that were not included had similar prevalence of acute heart failure, publication dates, and geographical coverage, and the population had similar demographic and clinical characteristics to those that were included. Secondly, in combining information from multiple studies, data were missing for some variables in several studies. To maximise the use of information, we have used a hierarchical multiple imputation method. Thirdly, we did not have consistently recorded data from the electrocardiogram and chest radiograph to enable inclusion of these data in our model. The interpretation of NT-proBNP in patients with suspected acute heart failure should be made in conjunction with these investigations,We have shown that the diagnostic performance of guideline recommended NT-proBNP thresholds for acute heart failure varies across important patient subgroups. We developed and validated the CoDE-HF score, which combines NT-pro-BNP as a continuous measure with clinical variables by using statistical modelling to determine the probability of acute heart failure for individual patients. This decision support tool accurately ruled in and ruled out acute heart failure and performed consistently across all subgroups. Prospective studies are now needed to evaluate the effect of implementing this decision support tool on healthcare resource utilisation and patients’ outcomes.The diagnosis of acute heart failure can be challenging because patients often present with non-specific symptomsMost national and international guidelines recommend N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing to aid in the diagnosis of acute heart failureNT-proBNP testing has not been universally implemented owing to concerns about diagnostic performance in clinically important patient subgroupsThe guideline recommended NT-proBNP thresholds for acute heart failure had relatively poor diagnostic performance in important patient subgroupsA validated decision support tool that uses statistical modelling to combine NT-pro-BNP as a continuous measure with clinical variables has been developedThis tool ruled in and ruled out acute heart failure more accurately than did any approach using NT-proBNP thresholds alone and performed consistently across all subgroups


The significant morbidity and mortality associated with heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) justify the search for novel therapeutic agents. The nitric oxide (NO)–soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in the regulation of cardiovascular function. This pathway is disrupted in HF resulting in decreased protection against myocardial injury. The sGC activator cinaciguat increases cGMP levels by direct, NO-independent activation of sGC, and may be particularly effective in conditions of increased oxidative stress and endothelial dysfunction, and then reduced NO levels, but this comes at the expense of a greater risk of hypotension. Conversely, sGC stimulators (riociguat and vericiguat) enhance sGC sensitivity to endogenous NO, and then exert a more physiological action. The phase 3 VICTORIA trial found that vericiguat is safe and effective in patients with HFrEF and recent HF decompensation. Therefore, adding vericiguat may be considered in individual patients with HFrEF, particularly those at higher risk of HF hospitalization; the efficacy of the sacubitril/valsartan-vericiguat combination in HFrEF is currently unknown. Heart failure (HF) affects over 20 million people worldwide, and its prevalence is increasing because of the population ageing and the better outcome after acute cardiovascular events . Many thThe emerging challenge of HFrEF treatment is to tailor the therapeutic strategy on each individual patient, namely to identify the combination of treatments with the greatest benefit  while minimizing the adverse events (AEs). In this review, we analyze current evidence about vericiguat trying to identify its place in the changing landscape of HFrEF treatment.Nitric oxide (NO) is produced by endothelial NO synthase (eNOS), which is induced by laminar flow and shear stress . NO diff. By acting on a downstream target of the NO-sGC-cGMP pathway, sGC modulators may circumvent NP resistance more effectively than other therapeutic strategies aiming to enhance NP concentration, such as the administration of pharmacological doses of recombinant BNP , associated with worsening renal function and no effect on outcome.In HFrEF, impaired LV systolic function leads to tissue hypoperfusion, which causes inflammation and oxidative stress, leading to decreased NO bioavailability and cGMP deficiency . The cGMThe sGC activator cinaciguat increases cGMP levels by direct, NO-independent activation of sGC, with a high risk of hypotension . Convers2 or those with mild-to-moderate liver disease [Vericiguat is a weakly basic drug with a low water solubility and high intestinal permeability (class II according to the Biopharmaceutics Classification System) . In heal disease . In heal disease , 25. Fur disease , UGT isoIn the setting of HFrEF, vericiguat has been investigated in phase 2 (SOCRATES-REDUCED) and phase 3 trials (VICTORIA) Table . Both th2 and systolic blood pressure < 110 or ≥ 160 mmHg. Patients were randomized to 5 arms . Only 77% of patients completed the 12-week follow-up, and 72% of patients randomized to the highest dose reached the target of vericiguat 10 mg daily. The change in log-transformed N-terminal fraction of pro-BNP (NT-proBNP) over 12 weeks did not differ significantly in the pooled vericiguat group and the placebo arm, while the exploratory comparison between vericiguat 10 mg and placebo achieved statistical significance (p = 0.048). Patients on the highest vericiguat dose displayed also a greater increase in LVEF (p = 0.02). Vericiguat therapy did not seem to affect haemodynamic function and appeared safe, with lower rates of serious AEs than placebo. A similar proportion of AEs was observed in the pooled vericiguat group and the placebo arm [SOCRATES-REDUCED enrolled 456 patients with LV ejection fraction (LVEF) < 45% and a recent episode of HF decompensation, defined by worsening HF symptoms requiring hospitalization or outpatient administration of intravenous diuretics, signs of congestion, and elevated NP levels , excluding those with eGFR < 30 mL/min/1.73 mcebo arm . A post cebo arm .p = 0.02), with a number needed to treat of around 24. These results were driven by a lower incidence of first HF hospitalization , associated with a reduced number of HF hospitalizations . Vericiguat seems less effective in patients in the highest quartile of NT-proBNP levels (> 5314 ng/L), those aged ≥ 75 years, with worse renal function (eGFR 15–30 mL/min/1.73 m2), or LVEF 40–45%, although the trial was underpowered for these subgroup analyses [The VICTORIA trial enrolled patients with LVEF < 45%, a HF decompensation requiring hospitalization over the previous 6 months, and/or intravenous diuretics < 3 months , 28 and In some post hoc analyses, the superior efficacy of vericiguat over placebo was confirmed for NT-proBNP levels at randomization up to 8000 ng/L . FurtherWhile a comparison of HR values for the primary and secondary endpoints might suggest a lower efficacy of vericiguat compared to sacubitril/valsartan (in PARADIGM-HF) or dapagliflozin , the annualized event rate for the primary endpoint was greater for the VICTORIA than for the PARADIGM-HF (4.2 events per 100 patient-years at risk vs. 2.7), and close to the rate observed in DAPA-HF (4.0 events per 100 patient-years). Even the benefit on first HF hospitalization was greater in VICTORIA than that in PARADIGM-HF (3.2 events per 100 patient-years vs. 1.6) and close to DAPA-HF (2.9 events per 100 patient-years) . NonetheHF is characterized by a neurohormonal activation aimed at maintaining an adequate tissue perfusion mainly by improving haemodynamics by an increase in arterial pressure and plasma volume, and promoting cardiac remodelling. Although initially compensatory, these mechanisms are ultimately detrimental, fostering HF progression. The renin–angiotensin–aldosterone (RAAS) and sympathetic nervous systems (SNS), acting through the second messenger cyclic adenylate monophosphate (cAMP) at the cellular level, are key players in this pathophysiological context, and therapies targeting these systems  represent the standard of care for HFrEF .The NO-sGC-cGMP pathway acts as a counterregulatory axis in HF. In particular, NPs counteract the effects of RAAS and SNS by promoting sodium and water excretion and inhibiting cardiac and vascular remodelling by activating cGMP signalling, which, in turn, can reduce cAMP by activating the phosphodiesterase 2 isoform . As a co+/H+ exchanger 1 at cardiomyocyte level) is likely based on preclinical studies [SGLT2i have been recently added to the armamentarium of therapies for stable HFrEF following the striking results in terms of reduced cardiovascular mortality and HF hospitalizations of DAPA-HF and EMPEROR-REDUCED trials , 6. Alth studies . Given t studies , 6. Base studies ; nonethe studies . These r studies . Accordi studies .LV pump failure is a main feature of HFrEF; however, until recently, no orally taken drug directly acting on cardiac inotropism was available for chronic HFrEF, with the sole exception of beta-blockers. Omecamtiv mecarbil is a novel selective cardiac myosin activator that directly increases LV systolic function. The GALACTIC-HF trial randomized 8256 patients with stable LVEF ≤ 35% to either omecamtiv mecarbil or placebo, demonstrating a modest beneficial effect of this drug on the composite endpoint of time to first HF event  or death from cardiovascular causes, without significant differences regarding the separate components of the primary endpoint or the KCCQ score. Notably, about 19% of patients enrolled in this trial were on sacubitril/valsartan and < 3% on a SGLT2i, without significant results at the subgroup analyses [


Thanks to the advances in medical therapy and assist devices, the management of patients hospitalized in cardiac intensive care unit (CICU) is becoming increasingly challenging. In fact, Patients in the cardiac intensive care unit are frequently characterized by dynamic and variable diseases, which may evolve into several clinical phenotypes based on underlying etiology and its complexity. Therefore, the use of noninvasive tools in order to provide a personalized approach to these patients, according to their phenotype, may help to optimize the therapeutic strategies towards the underlying etiology. Echocardiography is the most reliable and feasible bedside method to assess cardiac function repeatedly, assisting clinicians not only in characterizing hemodynamic disorders, but also in helping to guide interventions and monitor response to therapies. Beyond basic echocardiographic parameters, its application has been expanded with the introduction of new tools such as lung ultrasound (LUS), the Venous Excess UltraSound (VexUS) grading system, and the assessment of pulmonary hypertension, which is fundamental to guide oxygen therapy. The aim of this review is to provide an overview on the current knowledge about the pathophysiology and echocardiographic evaluation of perfusion and congestion in patients in CICU, and to provide practical indications for the use of echocardiography across clinical phenotypes and new applications in CICU. Patients in the cardiac intensive care unit (CICU) are frequently characterized by conditions that rapidly change and evolve into several clinical phenotypes connected with the underlying etiology and its complexity; phenotyping patients helps to early guide the appropriate management strategies towards the underlying etiology. In these patients with signs of hemodynamic instability, echocardiography is the most reliable bedside method to assess cardiac function repeatedly, assisting clinicians not only in characterizing hemodynamic disorders, but also in helping to guide interventions and monitor response to therapies . Standard echocardiographic evaluation should rapidly provide sufficient information to confirm/exclude tamponade, mechanical complications of acute myocardial infarction (AMI), left ventricular (LV) outflow tract obstruction (LVOTO), severe valvular lesions and LV and right ventricular (RV) dysfunction ,2,3.The goal of this review is to summarize the current knowledge concerning the definition, pathophysiology and echocardiographic evaluation of perfusion and congestion in patients in the CICU, also based on recent tools such as lung ultrasound (LUS) and the Venous Excess UltraSound (VexUS) grading system. It will also detail another application of echocardiography in the CICU based on the evaluation of the presence of pulmonary hypertension, both as an additional element for the assessment of the patient’s hemodynamics, and to guide the setting and modifications of ventilatory oxygen therapy.Only a minority of patients in the CICU with acute heart failure (HF) present with signs and symptoms of low perfusion correlated to low cardiac output (CO). Cardiac insult causing the severe impairment of cardiac performance may be acute, as a result of an acute coronary syndrome (ACS) (80% of cases of cardiogenic shock) ,5 or mayA state of perfusion that is inadequate to meet the metabolic demands of tissues results in hypoxia and inadequate aerobic metabolism and, ultimately, systemic inflammation, cell injury, cell death, tissue injury and organ failure . Cold swAcute HF with a clinical profile of low CO is usually associated with low systolic blood pressure (BP) (<90 mmHg) and mean arterial pressure <65 mmHg) . Of note5 mmHg . First of all, perfusion can be evaluated through LV Ejection Fraction (EF), but it is well known that this parameter is greatly influenced by LV geometry, heart rate and loading conditions (preload and afterload). As a result of that, its usefulness is limited in critically ill patients . Hence, Furthermore, LV global systolic function could be examined through peak global longitudinal strain (GLS) that describes the relative length change of the LV myocardium between end-diastole and end-systole. This parameter is less used in the context of critical ill patients, but it is a valuable and sensitive tool for follow-up examinations. LV GLS should be made in the three standard apical views and averaged, after optimizing image quality, maximizing the frame rate and minimizing foreshortening  ,12. In pMoreover, being more sensitive to acute changes in cardiac loading conditions than conventional echocardiographic parameters, LV GLS may have another important application in ICU. In particular, the evaluation of LV strain in acute HF has the potential to define treatment responsiveness among different clinical phenotypes .Likewise, the echocardiographic assessment of RV in critically ill patients is important. First, it should include the assessment of the right ventricle outflow tract (RVOT) VTI that gives information about the RV function and pulmonary vascular resistance (PVR), even if the echocardiographic measurement of PVR (through the ratio between tricuspid regurgitant jet velocity (TRV) and RVOT VTI ) is not The assessment of perfusion should also include the possible presence of dynamic LVOTO in which certain anatomical variations facilitate this phenomenon: the small diameter of the LVOT due to basal septal hypertrophy; elongated anterior mitral leaflet; and the presence of systolic anterior motion of the anterior mitral leaflet with leaflet-septum contact in mid-systole. A continuous Doppler is used to measure the degree of obstruction and pulsed Doppler to locate the exact point where the obstruction is occurring. The typical morphological appearance of the Doppler signal is a “dagger-shaped” and late peaking curve . This isThe vast majority of acute heart failure (AHF) episodes are characterized by increasing symptoms and signs of congestion. Congestion has a pivotal role in critically ill patients and it results in increased cardiac filling pressures that determine signs and symptoms of extracellular fluid accumulation . FillingThe raise in preload by congestion leads to increased ventricular wall stress, valvular regurgitation, myocardial stretch, remodeling, ventricular myocyte necrosis and a progressive decline in cardiac function . MoreoveIt is well known the importance of detecting and monitoring congestion before it leads to decompensation, is a clear predictor of poor outcome. However, the assessment of congestion can be difficult, especially when the extrapulmonary signs of congestion are mild, such as in the setting of acute pulmonary congestion due to hypertension. Increased intracardiac filling pressures often silently precede the appearance of congestive symptoms by days or weeks.Echocardiography provides detailed information about cardiac structure and function in acute cardiovascular disease, and remains the gold standard for evaluating blood volume and LV filling pressures .Echocardiographic parameters can be used to estimate right- and left-sided filling pressures, although with less reliability in AHF. The estimation of right atrial (RA) pressures can be performed by assessing the diameter of the IVC and the percentage decrease in the diameter during inspiration. The diameter of the IVC decreases in response to inspiration when the negative intrathoracic pressure leads to an increase in RV filling from the systemic veins. IVC is commonly dilated and may not collapse in patients on ventilators, so it should not be routinely used in such cases to estimate RA pressure  Figure .Left-sided filling pressures assessment is performed by assessing the trans-mitral flow by PWD and then estimating mitral inflow E (early diastolic relaxation) and A  waves. TDI is then used to assess the mitral annulus diastolic velocities (e’ and a’). An increase in early diastolic mitral inflow velocities (E wave) occurs when filling pressure raise. This is indicative of increased filling pressures in the presence of a low e’  size and tricuspid regurgitation (TR) jet are also required for a comprehensive LV diastolic function assessment. In particular, echocardiography is the most used non-invasive tool for estimating pulmonary arterial pressure (PAP). Systolic PAP (sPAP) can be measured by adding the RAP to the TR peak systolic gradient, that derived from the TR peak systolic velocity. Moreover, the measurement of the pulmonary artery acceleration time (PAAT) could indicate an elevation in the PVR, which is demonstrated by shortening of the PAAT  with or without mid-systolic notching; PAAT, in fact, represents pulmonary flow acceleration, which increases as the vascular resistance is augmented, based on the Newton law of motion. Different studies have demonstrated a reasonable accuracy of PAAT in correctly estimating sPAP and mean PAP (mPAP). However, PAAT measurement to derive sPAP is not reliable in critically ill patients, particularly in the coexistence of RV systolic impairment ,32 Figu.Finally, the left atrium influences LV filling and performance through its functions of contractile pump and reservoir. LA enlargement  is a marker of both the severity and chronicity of diastolic dysfunction and the magnitude of LA pressure elevation . The evaA new landscape in cardiac imaging is represented by the application of artificial intelligence (AI) algorithms (particularly machine learning), that could enhance efficiency, precision and timeliness, which are of great relevance in the CICU. AI optimize the quality of images, endocardial tracing, Doppler representations and supports three-dimensional echocardiography, allowing the cardiologist to save time and help standardize reproducibility.Moreover, AI aids to better define static, dynamics, planimetric and volumetric measurements of the valves, flows and regurgitations. Even though it is considered an expanding topic needing further research, AI is near to being fully integrated into clinical practice and its use could be of great utility in the CICU, where time-saving and precise evaluation are fundamental ,35,36,37The use of bedside ultrasound in children may be quite different and should consider different aspects. First of all, data supporting the use of bedside ultrasound for hemodynamic assessment in children are limited, however, the two primary indications are considered the identification of pericardial tamponade and the assessment of hemodynamic status, on one hand studying left ventricular function and on the other hand assessing volume status by respiratory variation of the inferior vena cava. Then, some limitations should be encountered: specific expertise should be preferred, due to the wider range of structural and anatomic abnormalities in congenital heart disease than in adult heart disease, which may increase inter-operator variability in the case of low expertise with children; moreover, children may be less cooperative for the examination requirements compared to adults .The quantification of significant venous congestion could also be performed by the VExUS grading system, considering that large veins (vena cava) as well as abnormal venous waveforms connected with the limit of the systemic venous compliance in the portal vein, hepatic veins and intrarenal veins have been associated with the congestive process, and with adverse consequences of venous hypertension. In states of intravascular volume overload the limits of venous compliance are reached; as a consequence, the normal dampening of the venous pulse due to the compliant nature of the smaller veins is lost, and the pulsations are transmitted back into the smaller veins.The VExUS grading system is based on the evaluation of IVC diameter and venous Doppler waveform of the portal, hepatic and interlobular renal veins. In the presence of a IVC > 2 cm, each of these veins are evaluated and assigned to be representative of either being normal, mild congestion, or severe congestion. Hepatic Doppler is considered severely abnormal when the systolic (S) component is reversed (towards the heart) than the diastolic (D) component. Portal Doppler is considered severely abnormal when a variation in the velocities during cardiac cycle of ≥50% is seen. Intra-renal venous Doppler is considered severely abnormal when it is discontinuous with only a diastolic phase seen during the cardiac cycle.VExUS grade 0 is with no sign of congestion in any organ, VExUS grade 1 is with only mild congestive findings, VExUS grade 2 is with severe findings in only one organ, and VExUS grade 3 is with severe congestive findings in at least two of three organ systems . MoreoveThe VExUS score should be of interest as a guide to the daily decision-making about fluid balance management in critical ill patients, even if further studies should aim to validate this grading system in different clinical settings. Moreover, the fact that each of the proposed markers has some limitations should be considered: hepatic vein Doppler is strongly connected with TR, which may influence its interpretation; pulsatile portal vein flow and IVC dilatation have been reported in healthy athletic volunteers; and intra-renal venous Doppler is more technically complicated to perform ,39.Lung ultrasound (LUS) can be extremely useful in patients in the CICU as it provides, in patients with acute respiratory failure and hypotension/shock, a point-of-care evaluation of pulmonary congestion, lung consolidation, pleural effusion, and pneumothorax .Lung ultrasound can be performed with the investigation of three or four zones for B-lines on each hemithorax. Vertical B-lines provide a graded measure of interstitial or alveolar oedema with high interoperator reproducibility. At least three B-lines in two or more intercostal spaces bilaterally are considered indicative of interstitial or alveolar oedema in the acute care setting .Despite their high accuracy in the identification of pulmonary oedema in patients with suspected AHF, B-lines can also be found in other conditions, such as interstitial lung disease, acute respiratory distress syndrome, pulmonary contusions and pneumonitis ,29,41. NLUS is also useful for follow up and the prognostic stratification of patients and can help the clinician to guide the management of the therapy; in fact, B lines have shown to reduce with diuretic therapy, and their number it is directly proportional to the BNP and the NYHA class . Thus, LPulmonary hypertension (PH) is a common finding in patients admitted to the cardiac intensive care unit and is associated with worse prognosis compared to controls . In critActually, PH is defined as an increase in mean pulmonary arterial pressure (mPAP) > 20 mmHg at rest, measured by right heart catheterization (RHC) . FurtherAlthough different groups of PH vary in terms of etiologies and pathogenesis, there is a common evolution of the disease, resulting in RV dysfunction and ultimately RV failure, which is an important predictor of survival in patients with PH. Thus, the optimal management of critically ill patients requires an understanding of RV function, the appropriate monitoring and identification of RV failure, and a physiologic approach to the optimization of volume status, RV afterload, and cardiac function.RV failure, also referred as right HF, is defined as low CO and/or elevated right-sided filling pressures due to systolic and/or diastolic RV dysfunction. It often begins with a significant increase in RV afterload (pressure and/or volume overload), which leads to RV remodeling. RV consist of a thin wall and low volume/surface area, and shows greater compliance than the muscular thick-walled left ventricle. As results of the increased afterload in PH, RV wall hypertrophies and eventually dilates, developing a spherical shape accompanied by increased RV wall stress and RV dysfunction .Systolic right-sided HF results in LV underfilling and low cardiac output, which impairs tissue perfusion and oxygenation. Moreover, LV filling and function is also impaired due to ventricular interdependence. Indeed, RV dilation causes the interventricular septum to shift towards the LV (“fattening”), which persists through the cardiac cycle, with consequently LV end diastolic volume reduction and LV ejection impairment . The comThe evaluation of RV function by transthoracic echocardiography remains the most valuable and useful tool, especially in critically ill patients, for diagnosis and monitoring patients with PH . DespiteRecently, ventricular strain has been implemented to assess regional and global RV function ,60 and tMoreover, further attempts to find surrogates of RHC measures has been made in the last years, leading to the evaluation of two parameters i.e., echocardiographic Pulmonary to Left Atrial Ratio (ePLAR) and the ratio between tricuspid regurgitation and the velocity time integral assessed on RVOT (TRV/VTI RVOT).ePLAR has been found to be a noninvasive parameter to distinguish pre-capillary and post-capillay PH, and is calculated as maximum tricuspid regurgitation continuous wave Doppler velocity (m/s) divided by the transmitral E-wave:septal mitral annular Doppler Tissue Imaging e’-wave ratio. Its normal values were estimated as 0.30 ± 0.09 m/s. Pre-capillary PH patients were found to have higher values, while post-capillary PH patients had lower values than the reference in a big study comparing the echocardiographic measures with invasive measures obtained by right heart catheterization .On the other hand, TRV/VTI RVOT has been found to be a noninvasive parameter to estimate PVR augmentation. Particularly, it has showed to be a good screening tool to assess PH and PVR> 2 WU compared with invasively assessed PVR; however, it has showed less accuracy for the assessment of high PVR , above aThe echocardiographic assessment of RV function and the estimation of sPAP remains difficult and challenging, especially in patients under mechanical ventilation (MV). In this circumstance, insufflation increases intrathoracic chest pressure resulting in a decreased venous return, reduction in RV preload and increase in RV afterload. This translates into a reduction in RV stroke volume and the development of paradoxical septal bowing, which in turn results in decreased LV SV and CO . PositivIn patients undergoing MV echocardiographic an estimation of sPAP is also tricky. The increase in pulmonary systolic pressure observed during MV results in higher tricuspid and pulmonary regurgitation velocities during mechanical insufflation. Moreover, neither the size nor the variation of the IVC during MV are reliable variables in the estimation of right atrial pressure (RAP) . In theiIt should be noted that studies that examined the outcomes of patients with PH in the ICU reported higher in-hospital mortality and longer hospital stays in those treated with MV . Thus, a


A total of 27/38 (71%) enrolled patients  completed the training protocol and were considered in the analysis. At baseline, no hypertensive patient was noted; all echocardiographic variables were within the normal range. After training, we observed a significant reduction in BP parameters, including systolic BP values and Z-score, diastolic BP values, centiles and Z-score, and mean arterial pressure . Significant variations in echocardiographic interventricular septum (IVSd) thickness (p = 0.011), IVSd Z-score (p = 0.001), left ventricular (LV) end-diastolic diameter (p = 0.045), LV posterior wall thickness Z-score (p = 0.017), and LV global longitudinal strain (p = 0.016) were detected. No differences in LV diastolic function and right ventricular strain were noted. PA plays a decisive role in improving BP control and has benefits on left ventricle systolic function, representing a strategic approach to limit CV risk. Online exercise could be an excellent method of training in children with obesity.Physical activity (PA) is a crucial factor in preventing and treating obesity and related complications. In this one-arm pre–post longitudinal prospective study, we evaluated the effects of a 12-week online supervised training program on cardiac morphology, function and blood pressure (BP) in children with obesity. The training program consisted of three sessions per week, each lasting 60 min. Advanced echocardiographic imaging  was used to detect subclinical changes in heart function. Categorical variables were described as counts and percentages; quantitative variables as the mean and standard deviation (SD) as they were normally distributed (Shapiro–Wilks test). Pre–post comparisons were made with a paired  The increasing incidence of obesity has become a significant public health concern . The WorObesity in childhood affects multiple organ systems in an adverse manner, causing insulin resistance, dyslipidemia, type 2 diabetes mellitus (T2DM), metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), excess stress on the musculoskeletal system ,5,6, pulFurthermore, obesity has a great impact on the cardiovascular system ,11; the Despite how widespread this disease is, interventions for the prevention and management of obesity in children are still not well defined and difficult to assess  PhysicalThe aim of this study was to evaluate the effects of a program of remote PA on echocardiographic and blood pressure (BP) parameters in children with obesity. The use of advanced echocardiographic imaging, such as tissue Doppler and longitudinal strain analysis, has been made to detect subclinical changes in heart function. The hypothesis is that online exercise could improve cardiac function and arterial pressure, regardless of weight loss. PA training in remote modalities may also represent a useful tool to prevent early cardiovascular risk ,23,28.This is a one-arm pre–post longitudinal prospective study performed at the Pediatric Department of the Children’s Hospital Vittore Buzzi of Milan with the collaboration of Laboratory of Adapted Motor Activity (LAMA), University of Pavia, Italy. A total of thirty-eight children with obesity, referred to our pediatric unit for obesity by their primary care pediatric consultant, were consecutively enrolled (March 2021–November 2021) in this study. Obesity was defined as a BMI z-score ≥ 2 according to the World Health Organization [In all the participants, height, weight, puberal stage, BMI, BMI z-score, waist circumference (WC), and waist-to-height ratio (WHtR) were measured as previously described . BrieflyCardiological evaluation with BP and echocardiography was performed before (T0) and within one week after the completion of the physical fitness protocol (T1). All children underwent standard and advanced transthoracic echocardiography (TTE), recorded with Vivid S5 GE Healthcare by a single pediatric cardiologist (M.G.) and validated by a second cardiologist (S.S). Standard echocardiographic measurements were made according to the American Society of Echocardiography Guidelines , includiBP was detected using multiple office blood pressure measurement (MOBP): systolic and diastolic values were the result of the arithmetic mean of ten successive measurements. Percentiles and z-scores  of the cTo evaluate PF in children, we used common field test batteries. Prior to and after the training protocol period, we assessed different domains of PF: cardiovascular fitness through the 6 min walking test performed in accordance with international guidelines ,38, lowe® platform in real time, allowing live interaction among instructors and children. Moreover, three days per week, participants had to exercise individually using a YouTube channel (“LAMA Junior”) implemented with training video routines by the sport specialists. All the training sessions were structured with a 5–10 min warm-up, 20 min of aerobic interval training, 20 min of a strength circuit, and 5–10 min of cool-down or stretching [Children performed the training protocol for 12 weeks with three 60 min online sessions  per week, totaling 36 sessions that were supervised by two expert trainers. According to the literature, a 12-week protocol is sufficient to improve both physical fitness and health outcomes in children with obesity, reducing the risk of exercise program abandonment ,47,48,49retching . All theretching . To underetching .p < 0.05) mean pre–post difference when SD is 1.5-fold greater than mean difference.Categorical variables were described as counts and percentages; quantitative variables as the mean and standard deviation (SD) as they were normally distributed (Shapiro–Wilks test). Pre–post comparisons were made with a paired t-test. All analyses are performed with Stata v17.0 (StataCorp USA). Power consideration: with 27 subjects, it will be possible to achieve a power >90% to find a significant .p = 0.06); no significant differences were noted in BMI z-score (p = 0.38) and WC (p = 0.52). Puberal stage remained stable in all patients, except in two in which there was a progression from prepuberty to middle puberty (p = 0.19).An improvement was recorded between baseline and after the exercise program in WHtR without reaching statistical significance  had high–normal systolic pressure before intervention (Z-score between 2 and 3) and 4/6 (66.7%) improved their Z-score to <2.p= 0.05) and systolic BP Z-score (p = 0.027), diastolic BP values (p= 0.001), diastolic centiles (p <0.063) and diastolic BP Z-score (p <0.001) and mean arterial pressure (MAP) (p= 0.002).Concerning the echocardiographic evaluation, at baseline, all the measured variables were within the range of normality for body surface area and age. We recorded only 6 subjects (22.2%) with a mildly increased left ventricular end-diastolic diameter (LVEDD) with a LVEDD z-score between 2 and 3. Both left ventricular diastolic and systolic function were normal at baseline and remained normal at the follow-up. p = 0.011) and IVSd z-score , for the left ventricular end-diastolic diameter (p = 0.045) and the left ventricular posterior wall thickness z-score . LV mass indexed for height values showed no significant differences between T0 and T1 (p = 0.39).A statistically significant variation was evident for interventricular septum thickness (IVSd) . In 11/27 patients (40.7%), a 10% LVGLS improvement was noted after training compared to baseline (range 10–22%).The advanced evaluation did not show differences in LV diastolic function and right ventricular strain. The left ventricular global longitudinal strain (LVGLS) was normal at baseline but improved significantly after the completion of the PA program (2Childhood obesity is a multisystem disease that leads to several comorbidities, cardiovascular diseases, hypertension, T2DM, NAFLD, hyperlipidemia and other conditions associated with chronic inflammation, which cause disability and shorten the life span [ife span . Even ifife span ,53,54 toife span ,55.This study was performed to evaluate the cardiovascular effects of remote PA in children with overweight and obesity, without providing a dietary regimen and therefore regardless of weight loss. Our study shows satisfactory participation in the project, with 71% of the children who completed the training program. Concerning the effect of exercise on BP, our analysis showed a significant improvement in all systolic, diastolic and MAP values of both absolute and BP z-score. Although there were no patients with hypertension in our population at baseline, 22% of them had high–normal systolic pressure before intervention, and 66.6% of them improved their Z-score. At the echocardiographic evaluation, normal chamber morphology and cardiac function at baseline was noted in all patients, indicating that obesity-related cardiac dysfunction was still not clinically evident in our population. Nevertheless, the echocardiographic assessment also showed a statistically significant reduction in IVSd and PWd thickness when considering concomitant child growth. In contrast, statistically significant increase in the absolute value of the LVEDD did not correspond to a significant Z-score increase, demonstrating that this parameter is likely to be dependent on patient growth. No significant changes occurred in parameters related to diastolic dysfunction and all patients had normal baseline global longitudinal strain, which further improved at T1; 41% of subjects showed a significant improvement in the LVGLS after the training program, considering a 10% change from baseline in LVGLS a significant variation ,56A positive effect in multiple measures of muscular and cardiorespiratory fitness in children with overweight and obesity  is proveIt is well known that obesity can cause hypertension and that obesity and hypertension together can cause increased metabolic demand and cardiac remodeling, leading to high end-diastolic pressure and to diastolic dysfunction . HoweverThe main limitation of this study is the small number of participants; an increased sample size will be useful to validate these results, offering the possibility to also assess the effect of BP on cardiac function. Moreover, the effect of heart rate variability and autonomic activity could be not excluded; heart rate potentially reflects changes in sympathetic activity and may influence both BP values and cardiac function. Additionally, as adiposity indices, we considered only clinical parameters, which are inaccurate measures of body components; using a tool for the examination of body composition may be useful to evaluate the relationship between changes in fat and/or lean mass and echocardiographic assessment.The findings of our study confirmed the importance of PA as a key treatment tool for improving health outcomes and preventing and reversing CV modifications in patients with obesity at any age. Online physical exercise is an interesting activity to be proposed for overweight children and could be implemented in schools or included as part of a medical program for the prevention and treatment of obesity.Our study confirms that physical exercise plays a decisive role in improving BP and has positive effects on left ventricle systolic function, measured with advanced techniques. To prevent the progression of obesity from childhood to adulthood as well as the development of CV risks, it is necessary to teach children to exercise regularly. PA increases physical fitness and modifies children’s cardiometabolic risk even after a short period of training. Online exercise could be an excellent method of training for the pediatric population: it is appreciated by children and adolescents and could be more manageable for families.


Landolfi’s sign, alternating systolic constriction and diastolic dilatation of pupils, is a clinical hallmark of aortic regurgitation. It is thought to stem from exacerbation of physiological circulatory hippus in the vessels of iris due to a wide pulse pressure in a backdrop of severe aortic valvular incompetence. Degenerative and rheumatic heart diseases are exquisitely common in rural India and often these patients turn up late with complications to the primary care physicians. Herein, the authors report a 34-year-old pregnant female who presented with acute heart failure, and on examination, Landolfi’s sign was found. It was immediately followed by Doppler echocardiography to stamp it as a case of severe aortic regurgitation. The patient was stabilized with anti-failure medications and feto-maternal health was closely monitored. The authors want to conclude claiming that bedside clinical training in cardiology will forever remain important, more so, while dealing patients at non-sophisticated primary health-care facilities. Besides, they also argue that basic tool supports like an echocardiography should be made available at those centers. It gives rise to the phenomenon of rapid systolic contraction and diastolic dilatation of the pupils, which is synchronous with the cardiac rhythm. However, medical literature has curtailed relevance of this sign in the current practice due to lack of evidence. Still in the era of modern technology, meticulous physical examination and demonstration of eponymous signs of aortic valve disease aid and abet our memories and remind us of our cultural and professional continuity of knowledge.Landolfi’s sign is one of the popular eponyms used to describe a clinical sign of aortic regurgitation.A 34-year-old primigravida at 30 weeks of gestation, from rural India belonging to lower socio-economic strata was referred from a block primary health center to the obstetric emergency of our institute with progressively worsening dyspnea (New York Heart Association class 3), orthopnea, and extreme fatigability. It was associated with intermittent palpitations and two episodes of pre-syncope. On physical examination, she had features of acute heart failure . A grade grade 3/6, soft, high-pitched, early diastolic, blowing, decrescendo murmur was heard best at the third intercostal space on the left (Erb’s point) at the end of expiration with the patient sitting up and leaning forward. Pulse pressure was wide with bounding femoral and carotid arterial pulses. Hill’s sign was positive. Careful examination of her eyes revealed alternating dilatation  and cons Recent evidence suggests that hippus is generated from complex interplay between parasympathetic and sympathetic nervous system activities at the pupil. The altered hemodynamic state in presence of elevated stroke volume, systolic hypertension, and low diastolic pressure give rise to wider pulse pressure resulting in exacerbation of hippus, which in this index case is considered as Landolfi’s sign. It is a rarely reported finding in the Western developed world and even in Asian subcontinent nowadays.Exact mechanism of hippus is yet to be elucidated. Still in several rural areas of India, facilities for even a simple two-dimensional echocardiography are only available at apex centers . Hence, in these areas, rheumatic and non-rheumatic heart diseases are solely diagnosed on clinical basis by experienced primary care doctors. With the advent of evidence-based medicine, the training and expertise in clinical cardiology is gradually but certainly losing its place. Therefore, it is often seen that cases of valvular heart diseases are not being diagnosed until very late and overtly symptomatic at the primary health facilities.Modern medicine is in the era of interventional cardiology and multi-modality cardiac imaging (including nuclear cardiology).This case emphasizes on the fact that an observation as simple, as a pupillary exam examination, can guide the first-to-contact clinician to a life-threatening diagnosis. Our case demonstrating Landolfi’s sign is dedicated to honor the rigorous clinical training in bedside cardiology in pre- and post-echocardiography era. Besides, it also highlights the importance of availability of the basic cardiac imaging tools at primary health-care facilities.Video