The prognostic role of left ventricular (LV) papillary muscle abnormalities in patients with preserved LV systolic ejection fraction (LVEF) is unknown. We sought to evaluate the prognosis role of LV papillary muscle abnormalities by CMR in patients with ventricular arrhythmias, preserved LVEF with no cardiac disease.A total of 391 patients with > 500/24 h premature ventricular complexes and/or with non-sustained ventricular tachycardia (NSVT), preserved LVEF, and no cardiac disease were enrolled. Different features of LV papillary muscles were considered: supernumerary muscles, papillary thickness, the attachment, late gadolinium enhancement (LGE). Dark-Paps was defined as end-systolic signal hypointensity of both papillary muscles in early post-contrast cine CMR images. Mitral valve prolapse, mitral annular disjunction (MAD), and myocardial LGE were considered.p < 0.0001). Dark-Paps was significantly associated with hard cardiac events in all the multivariate models. Dark-Paps improved prognostic estimation when added to NSVT (p = 0.0006), to LGE (p = 0.005) and to a model including NSVT+LGE (p = 0.014). Dark-Paps allowed a significant net reclassification when added to NSVT , to LGE , and to NSVT + LGE .Dark-Paps was found in 79 (20%) patients and was more frequent in females. It was associated with higher prevalence of mitral valve prolapse and MAD. During a median follow-up of 2534 days, 22 hard cardiac events occurred. At Kaplan-Meier curve analysis, patients with Dark-Paps were at higher risk of events than those without  is a novel prognostic marker in patients with ventricular arrhythmias and preserved ejection fraction.• Dark-Paps had an additive prognostic role over late gadolinium enhancement and non-sustained ventricular tachycardia.The online version contains supplementary material available at 10.1007/s00330-023-09400-x. Papillary muscles have an important role in left ventricular function participating to mitral valve continence during systole , 2.Papillary muscle abnormalities may be associated with different cardiac conditions as congenital heart disease, cardiomyopathies, and ischemic heart disease (papillary ischemia or necrosis) as well as cardiac neoplasm, but they may also be found in otherwise normal heart. –5. PapilPapillary muscles abnormalities may also be associated with mitral valve anomalies elongation of leaflets, prolapse, and maybe also mitral-annular disjunction (MAD). The prognostic role of MAD was assessed in the last few years, and a causative association between MAD and myocardial fibrosis of lateral myocardial wall and the relative greater risk of ventricular arrhythmias was recently described –16. CardThe aim of the present study was to evaluate the prevalence and the clinical and prognostic impact of papillary muscle abnormalities in patients with frequent premature ventricular complexes (PVC) or with non-sustained ventricular tachycardia (NSVT), with preserved LV systolic function and without previous diagnosis of cardiac disease. Also, the association of papillary muscle abnormalities with mitral valve abnormalities as prolapse and MAD was assessed.In this multicenter study, an initial population of 1461 consecutive patients who underwent CMR from March 2006 to August 2015 with ventricular arrhythmias (> 500 premature ventricular complexes/24 h or NSVT at 24h ECG Holter monitoring) were evaluated in two participating centers. Study protocol was approved by the the institutional internal review board. Inclusion criteria were reported in supplemental data. Patients with frequent PVCs or ventricular bigeminism during examination were treated with an oral antiarrhythmic agent for 3 days before CMR examination in order to optimize ECG trigger and to obtain optimal image acquisition. The final population included 391 patients  images was acquired in short-axis views from atrioventricular valve plane to the apex with the following parameters: 8-mm slice thickness, no gap, flip angle of 60°, 30 cardiac phases, NEX 1, FOV 35–40 cm, a matrix of 224 × 224, a 45° flip angle, TR/TE ≈ 2, and a bandwidth of 125 KHz.A set of long-axis view including 4-, 2-, and 3-chamber views and para-axial views  were also acquired to evaluate papillary muscle and mitral valve anatomy.Late gadolinium enhancement (LGE) images were acquired 10 min after administration of a 0.5 molar Gd-based contrast agent with a dosage of 0.2 mmol/kg in the same short-axis and para-axial views. An inversion recovery T1-weighted GRE was used with the following parameters: field-of-view 35 mm, slice thickness 8 mm, no gap between each slice, repetition time 4.6 ms, echo time 1.3, flip angle 20°, matrix 224 × 224, reconstruction matrix 256 × 256, and one excitation. The appropriate inversion time was set using a TI-scout pulse sequence.The CMR images were independently analyzed by four expert investigators using a dedicated software .The presence of supernumerary papillary muscle was evaluated in long- and short-axis views in the presence of an accessory muscle having ≥ 50% main diameter compared with the main papillary muscles and presenting with a separate attachment in the LV walls.The radial angles of the 2 main papillary muscles were measured, in a medio-ventricular short-axis view, as the angle with the ventricular centroid as vertex, one side passing from right ventricular insertion point at the anterior septum and the other side passing in the center of, respectively, the AL and PM papillary muscle.The end-systolic maximal diameter of papillary muscles was manually measured.The signal intensity (SI) of the 2 main papillary muscles and in the interventricular septum was measured in the end-systolic and in the end-diastolic cine frame of a medio-ventricular short-axis view. For each papillary muscle, the end-systolic hypointensity was defined when its measured SI was lower than the SI of the septum . Dark-PaThe type attachment of papillary muscle was visually evaluated and classified as (a) finger-like attachment, presenting as a focal point attachment with few or no trabeculation, or (b) tethered attachment, presenting with a large base of attachment and several trabecular bridges as a ‘mangrove root’ , 9.The presence of ectopic papillary muscle attachment was evaluated longitudinally for attachment of papillary muscle in the utmost basal or distal sections of LV or radially for attachment directly from the anterior/anteroseptal or from inferior/inferoseptal wall.The presence of papillary muscle fibrosis was evaluated in LGE images.The morphology and function of mitral valve was also evaluated including the presence of valvular prolapse, mitral annular disjunction (MAD), and regurgitation. Mitral valve prolapse was defined as superior displacement ≥ 2 mm of any part of the mitral leaflet beyond the mitral annulus, according to the American Society of Echocardiography guideline , 24. MADThe characteristics of papillary muscle were assessed in the early post-contrast cine short-axis views. Briefly, the following parameters of the 2 main papillary muscles, namely anterolateral (AL) and posteromedial (PM) muscles, were evaluated Fig. :The presThe presence and distribution of myocardial fibrosis in both the left and right ventricular myocardium was visually evaluated in LGE images.Clinical follow-up was performed in all patients for a median of 2534 days (25th–75th 983–3345 days) after the CMR examination. A clinical questionnaire was compiled during periodic ambulatory visits to our institute or via telephone contact. The clinical questionnaire included the definition of the hard cardiac events: cardiac death, resuscitated cardiac arrest, and appropriate implantable cardioverter defibrillator (ICD) shock, sustained ventricular tachycardia (lasting ≥ 30 s at ≥ 100 beats/min). A complete interrogation of the ICD was performed by the referring physician to confirm the appropriateness of the shock. ICD shocks were designated as appropriate if triggered by lethal arrhythmias: ventricular tachycardia above the programmed cutoff of the ICD  or ventricular fibrillation. The New York Heart Association functional class, data about cardiac hospitalization, and pharmacologic therapy were also collected.t test or 1-way analysis of variance or the Kruskal-Wallis test as appropriate. The chi-square test or the Fisher exact test were used, when appropriate, for categorical variables. Analysis of Kaplan-Meier curves was used to evaluate survival free from hard cardiac events among groups. Univariate and stepwise multivariate Cox proportional hazard regression analysis were used to evaluate predictors of hard cardiac events. Variables selected a priori for clinical relevance were first explored with a univariate Cox regression and then different multivariable models were performed. The Harrell-C statistic and McFadden R2 were calculated for the different models. The incremental value in predicting hard cardiac events by stepwise inclusion was assessed according to the chi-square test by using the Omnibus Tests of Model Coefficients. Reclassification of risk of patients was determined by using net reclassification improvement (NRI) analysis for hard cardiac events. Time-dependent AUC for predicting hard cardiac events was performed using the time-ROC package of R softwareValues are presented as mean ± SD or as median and 25th–75th for variables with normal and non-normal distribution, respectively. Comparison among groups for continuous variables was made with the Student’s The final population included 391 patients  with a mean age of 39 ± 9 years. Characteristics of the patients and healthy control is shown in Table Supernumerary papillary muscles were found in 56 (15%) of patients, prolapse of the anterior mitral leaflet in 31 (8%), of the posterior in 18 (5%). MAD was found in 25 (6%) of patients and in no healthy controls . Papillary muscle LGE was identified in 6 (2%) patients. Among healthy controls, no subjects had Dark-Paps despite a minority had systolic hypointensity of a single papillary muscle (6% of AL and 4% of PM muscle). Controls had the same prevalence of supernumerary muscle (16%) than patients.In cine post-contrast short-axis views, Dark-Paps was found in 79 (20%) patients.p = 0.03), than those without. Patients with Dark-Paps had significantly more frequently mitral prolapse of one or both leaflets. MAD was more frequently seen in patients with Dark-Paps than those without . Dark-Paps was associated with a greater prevalence of tethered, “mangrove-like” attachment of papillary muscles . Moreover, Dark-Paps was associated to a wall thinning in the inferolateral middle wall and to a hyperkinetic inferolateral basal wall. Examples of CMR images of Dark-Paps are shown in Fig. Characteristics of patients with Dark-Paps is shown in Table p < 0.0001) and syncope (p = 0.004). Among CMR parameters, patients with hard cardiac event had more frequently LV LGE (p = 0.004), more frequently Dark-Paps (p < 0.0001), supernumerary papillary muscles (p = 0.02), and MAD (p = 0.001).During a median follow-up of 2534 days, 22 hard cardiac events occurred . Characteristics of patients with and without hard cardiac events are shown in Table p < 0.0001) and LGE (p < 0.0001) . Supernumerary papillary muscle and MAD were also associated to a worse survival from events. However, as evident in Fig. As evident in Kaplan-Meier curve analysis of Fig. 01) Fig.  were assAt univariate Cox regression analysis, NSVT, Syncope, LV LGE, supernumerary papillary muscle, MAD, and Dark-Paps were associated with the occurrence of hard cardiac events Table .Table 4Up value at univariate. Dark-Paps was significant associated with events in every model.Considering the number of events, 4 different models of multivariate Cox regression analysis were performed Table . Every mp = 0.0006), to LGE (p = 0.005), and to the model including NSVT+LGE (p = 0.014). As shown in the same figure, Dark-Paps allowed a significant net reclassification when add to NSVT , to LGE , and to NSVT + LGE . Time-dependent AUC for predicting events is shown in supplemental figure As shown in Fig. On the best of our knowledge, this was the first study evaluating the prognostic role of papillary muscle abnormalities in patients with ventricular arrhythmias (frequent PVC and/or NSVT) and preserved LV EF and without a definite diagnosis of cardiac disease. We evaluated different aspects of papillary muscles and mitral valve abnormalities, as MAD and mitral valve prolapse. Results of this study may be summarized as follows: (1) in patients with ventricular arrhythmias, Dark-Paps is found in 20% of cases, whereas it was absent in healthy controls; (2) Dark-Paps was an independent predictor of events in all the multivariate models and demonstrated an additive prognostic role over NSVT and myocardial LGE, permitting a significant reclassification of risk.Papillary muscle abnormalities may play a role in the genesis of ventricular arrhythmias. Indeed, the present study suggests that Dark-Paps might be a new prognostic factor in patients with ventricular arrhythmias and preserved LV EF. Dark-Paps is seen in early post-contrast cine images as well-defined, homogeneous, signal hypointensity of both papillary muscles during the end-systolic phase of cardiac cycle. The explanation of Dark-Paps is not clear, but it is probably caused by a transitory perfusion defect of muscles during the peak of ventricular contraction. Most of papillary muscles do not attach directly to the LV free wall but through the “trabeculae carneae” consisting in a network of muscular strands, acting as tree roots. These trabecaulae may be large, well-defined, and attached in a small focal point of LV wall, giving the aspect of a “finger-like” attachment or, alternatively, they may be thin, multiple, with an ill-defined large attachment, resembling the roots of a mangrove. In our study, 80% of patients with Dark-Paps showed a “mangrove-like” attachment of papillary muscle. This type of attachment could be associated with a rarefaction of blood vessel causing such end-systolic perfusion defect of Dark-Paps.The mechanical stretch of both papillary muscle and of the inferolateral LV wall caused by MAD and/or by mitral prolapse may participate to this systolic hypoperfusion –31. We cSyncope and NSVT were the only clinical variables associated with hard cardiac event in our population. This result was expected since these parameters were prognostic markers also in cardiac conditions as arrhythmogenic cardiomyopathy, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Moreover, this study confirmed previous evidences, suggesting the prognostic role of LGE in patients with ventricular arrhythmias. However, Dark-Paps demonstrated an additive prognostic role, when added to NSVT, to LGE, and to NSVT + LGE with a significant improvement of predicted risk of events. Based on these results, Dark-Paps may be considered a new marker of structural heart disease associated with a significant increase of risk of malignant arrhythmias in patients with NSVT as well in those with MAD, or with supernumerary papillary muscles. Furthermore, the combination of Dark-Paps and non-ischemic LGE might suggest a more advanced stage of structural heart disease.The mechanism underlying the arrhythmogenesis associated with Dark-Paps is unknown; however, papillary muscles are vulnerable sites for arrhythmic events. Animal studies demonstrated that papillary muscle may be the site of origin of ventricular arrhythmias that may be treated with radiofrequency ablation , 34. VanSantoro and coworkers demonstrated that papillary muscles from both ventricles represent an anatomic structure potentially involved in the onset of VF, even in apparently normal structural heart . We founSome study limitations have to be mentioned. First, we performed all the CMR using 1.5-T machines and with a high dose of 0.5 molar Gd-based contrast agent (0.2 mmol/kg) and acquired cine-SSFP immediately after injection. Different magnetic field or dosage of Gd-based c.a. could influence the detection of Dark-Paps.Second, first-pass perfusion imaging could provide further information on myocardial perfusion of lateral wall and even of papillary muscles. However, perfusion imaging is acquired in diastole, with lower spatial resolution than cine-SSFP and usually in only 3 short-axis views. Since Dark-Paps is seen in end-systolic phase, it could have been missed in perfusion images.Third, T1 and T2 mapping may be used to evaluate papillary muscle tissue abnormalities. However, the spatial resolution of mapping is lower than cine-SSFP and considering the dimension of papillary muscles, the risk of partial volume effect may be relevant with these techniques.Among papillary muscles parameters, Dark-Paps emerged as a novel marker for prediction of hard cardiac events in patients with preserved LV EF and ventricular arrhythmias. Dark-Paps has an incremental prognostic role over NSVT and LGE. Dark-Paps is associated with MAD and mitral valve prolapse and may be used to improve risk stratification of long-term arrhythmic event.ESM 1(DOCX 926 kb)


Background: The delta variant of SARS-CoV-2 has been associated with increased mortality and multi-organ failure, affecting various systems in the body. Cardiovascular manifestations including arrhythmias, heart failure, myocarditis, myocardial damage, and thromboembolism are commonly observed in patients infected with the delta variant.Materials and methods: This study enrolled 106 individuals who tested positive for the delta strain of SARS-CoV-2 using real-time RT-PCR between May 25, 2020, and October 15, 2021. All patients underwent 2-D echocardiography, and based on the severity of their infection, were divided into two groups: serious and non-serious.Results: Univariate correlation analysis showed significant positive correlations between right ventricular (RV) diameter and hs-TnI and D-dimer levels. Conversely, left ventricular ejection fraction (LVEF) was negatively correlated with hs-TnI, C-reactive protein (CRP), and D-dimer levels. Additionally, RV fractional area change (RV-FAC) showed a negative correlation with D-dimer and hs-TnI levels but not with CRP levels.Discussion: RV dysfunction has been identified as an important predictor of mortality in various patient populations, including those infected with the delta variant of SARS-CoV-2. A significant proportion of severe delta variant cases require mechanical ventilation, which can have hemodynamic effects on the ventricular performance. Mechanical ventilation can increase pulmonary arterial pressure and worsen right heart dysfunction, especially when lung-protective ventilation strategies are not optimized.Conclusions: Our study highlights that patients with severe delta variants, particularly those with cardiac injury, may exhibit biventricular systolic dysfunction. Echocardiographic parameters such as LVEF, RV diameter, and RV-FAC were found to be associated with laboratory markers of poor prognosis, including elevated hs-TnI, CRP, and D-dimer levels. 2-D echocardiography can be a valuable tool in identifying early signs of ventricular dysfunction, aiding in the management of this patient population. By November 22, 2021, it was detected in over 179 countries, indicating its widespread global circulation. In June 2021, the World Health Organization (WHO) identified the delta variant as the dominant strain of SARS-CoV-2 globally2. The delta variant has been associated with increased mortality and multi-organ failure, affecting various systems, such as the cardiac, respiratory, renal, hepatic, neurological, and intestinal systems3. Cardiovascular manifestations, including different types of arrhythmias, left heart failure, myocarditis, myocardial damage, and arterial and venous thromboembolisms, are commonly observed in patients affected by the delta variant of SARS-CoV-2. Myocardial necrosis and ischemia can lead to impaired ventricular function, further increasing the risk of mortality in these patients4.The delta variant, also known as the B.1.617.2 variant, is a strain of the SARS-CoV-2 virus responsible for the second wave of COVID-19 infections. It was initially identified in India on October 5, 2020, and officially named the delta variant on May 31, 2021A valuable noninvasive test for evaluating hemodynamic status and cardiac function is 2-D echocardiography, which has become particularly relevant in SARS-CoV-2 delta variant patients with multi-organ involvement and hemodynamic instability. However, the routine use of two-dimensional echocardiography in all patients with the SARS-CoV-2 delta variant is not recommended due to the risk of infection, and comprehensive studies on two-dimensional echocardiography variables in patients with SARS-CoV-2 delta variants are currently lacking. Therefore, the aim of this study was to examine two-dimensional echocardiography variables and their potential relationship with disease severity in patients with the SARS-CoV-2 delta variant.A total of 106 individuals who tested positive for the SARS-CoV-2 delta strain using real-time RT-PCR were enrolled in the study between May 25, 2020, and October 15, 2021. Two-dimensional echocardiography was performed for all patients. Patients were divided into two groups based on the severity of their infection: serious and non-serious. •<18 years of age. •History of cardiac disease . •History of chronic obstructive pulmonary disease, atrial fibrillation, or •end-stage hepatic or renal failure.Data collection was conducted retrospectively, and comprehensive details regarding patient demographics, laboratory investigations, and clinical features were obtained from clinical data. High-resolution computed tomography (HRCT) images of the lungs were acquired using a communication system and picture archiving. Furthermore, laboratory outcomes upon admission, including complete blood count, comprehensive biochemistry, including C-reactive protein (CRP), High-Sensitivity Troponin I (hs-TnI), serum electrolytes, liver and kidney function tests, and D-dimer, were meticulously documented.The 2-D echocardiography examinations were carried out in our department using an Echo transducer  to estimate apical and parasternal images, including M-mode, 2D, and Doppler echocardiography, by a patient lying in the left lateral decubitus position. Following the methods recommended by the American Society of Echocardiography (ASE), echocardiographic pictures were taken using the four standard views, namely apical (2- and 4-chamber), as well as parasternal (short- and long-axis). •LVEDD (Left Ventricular End-Diastolic Diameter): Normal range varies based on age and body size, but typically around 35–45 mm. •LVESD (Left Ventricular End-Systolic Diameter): Normal range varies based on age and body size, but is typically around 25–35 mm. •LVEF (Left Ventricular Ejection Fraction): Normal range is typically >55–60%. •Left atrial diameter during end-systole: Normal range varies, but typically <40 mm. •Right ventricular dilatation : A reading of more than 42 at the base may indicate right ventricular dilatation. •RV mid-dimension of more than 35 indicates right ventricular dilatation. •Right atrial enlargement: Long axis RA dimension >40 mm may indicate right atrial enlargement. •TAPSE (Tricuspid Annulus Plane Systolic Excursion): Normal range is typically >16–18 mm. •RV-FAC : Normal range is typically >38–45%. •TDI-Derived Tricuspid Lateral Annular Systolic Velocity(S’): Abnormal cutoff <9.5 cm/s.The severe SARS-CoV-2 delta strain group was defined based on the presence of any of the following criteria. 1.Respiratory distress, categorized by a respiratory rate of ≥ 30 breaths per minute; 2.resting SpO2 (oxygen saturation) ≤ 93%; 3.PaO2/FiO2 ratio  ≤ 300 mmHg; or 4.presence of serious complications such as respiratory failure requiring septic shock, mechanical ventilation (MV), and/or MODS (multiple organ dysfunction syndrome) necessitating ICU admission.Elevated hs-TnI levels higher than the 99th percentile upper reference limit were used as the criteria for defining cardiac injury.t-test. Spearman’s correlation analysis was conducted to assess the relationships among variables, considering the normality of the data. Multiple linear regression analyses were performed using a stepwise technique to identify independent variables that significantly affected the dependent variable. Multicollinearity among the independent variables was assessed using the Variance Inflation Factor (VIF), with a VIF value exceeding 3.0, which was considered indicative of collinearity. The confidence level for this study was set at 95%. Statistical significance was determined using a 2-sided test with a p-value <0.05.Statistical analysis was performed using SPSS version 21.0 for Windows . The Kolmogorov–Smirnov test was used to assess the null hypothesis of a normal distribution for each dataset. Continuous data are reported as the mean ± standard deviation. Percentages were used to express statistical data. The Chi-square test was used to analyze variations in categorical variables between groups. Unpaired samples were compared using various tests such as the Mann–Whitney U test or Student’s Univariate correlation analysis  examined5–6. In the serious group, there was evidence of diastolic dysfunction, which is known to occur before systolic dysfunction, in the progression of myocardial injury. This was reflected by the lower values of E wave velocity, LVEF, RV-FAC, and E/A ratio. These findings regarding diastolic dysfunction have implications for morbidity, mortality, and poor patient outcomes. These studies have emphasized that approximately one-third to half of sepsis patients develop reduced LVEF. In the early stages of sepsis, two-dimensional echocardiography shows hyperdynamic cardiac function, characterized by increased cardiac output and LVEF due to systemic inflammatory responses. However, in the late stages, severe hypoxia and inflammation can lead to extensive myocardial depression.The SARS-CoV-2 delta strain is known to cause multi-organ dysfunction, and the presence of cardiac involvement is associated with poorer outcomes. Although two-dimensional echocardiography is a valuable tool for evaluating cardiac function and hemodynamic status in these patients, it is not frequently used because of the risk of disease transmission. Nonetheless, two-dimensional echocardiography can provide important noninvasive data on disease severity. Furthermore, it can be utilized to rule out obstructive issues such as pericardial effusion resulting in cardiac tamponade and pulmonary thromboembolism, as well as hypotension due to hypovolemic shock (indicated by collapsed IVC and low cardiac output). Recent studies have highlighted the significance of two-dimensional echocardiography in patients with sepsis requiring mechanical ventilation7–9. In serious patient groups with deteriorating clinical conditions and elevated markers of myocardial injury (such as high-sensitivity cardiac troponin I), along with an increased RV mid-dimension, which is a significant parameter for patients on mechanical ventilation and those with COVID infections, poorer RV function was observed compared to patients without myocardial injury or those in the non-serious group.Injury to the myocardium has been associated with a worse prognosis in patients with the SARS-CoV-2 delta strain. Findings such as regional wall motion abnormalities or global hypokinesia of the left ventricle, suggested to be caused by inflammation and hypoxic myocardial injury, have been observed, which can lead to respiratory distress. Contemporary studies emphasize the importance of a reduction in RV longitudinal strain (<23%), which can be associated with a poor prognosis, even in patients with normal LVEF10–12. In contrast to other studies that reported normal or increased LVEF with dilated and reduced RV function, our findings showed reduced LVEF and RV-FAC, as well as increased LV and RV dimensions, and a higher frequency of LV diastolic dysfunction in serious patients, including those who required mechanical ventilation. However, within the serious group, echocardiographic indices were similar regardless of the mode of ventilation used, although RV function and LV systolic function were still poorer than those in the non-serious group.This study differs from previous studies in that we observed low LVEF and left ventricle (LV) dilatation, along with a decrease in RV-FAC, in serious patients with myocardial injury13–15. The utilization of noninvasive ventilation  was significantly higher in the serious group (96%) compared to the non-serious group (13%). This approach was based on our previous experiences, as we attempt noninvasive ventilation in every patient before resorting to mechanical ventilation.RV dysfunction has been identified as a significant predictor of mortality in various patient populations, including those infected with the SARS-CoV-2 delta strainA considerable proportion of serious SARS-CoV-2 delta strain cases require mechanical ventilation, and it is well-established that mechanical ventilation can have significant hemodynamic effects on ventricular performance. Mechanical ventilation can elevate pulmonary artery pressure and worsen right heart dysfunction, especially when lung-protective ventilation strategies are not optimally implemented. Therefore, it is recommended that the initiation of mechanical ventilation be delayed for as long as possible in every patient to minimize the potential adverse effects of mechanical ventilation on ventricular function.In our study, we observed that patients with severe SARS-CoV-2 delta strain, particularly those with cardiac injury, may exhibit biventricular systolic dysfunction. Echocardiographic variables such as LVEF, RV mid-dimension, and RV-FAC were found to be related to laboratory markers of poor prognosis, including elevated hs-TnI, CRP, and D-dimer levels. 2-D echocardiography can be valuable in identifying early indications of ventricular dysfunction, which can aid in guiding therapy in this patient population. Additionally, 2-dimensional echocardiography can be valuable in identifying global or regional wall motion abnormalities of the LV in particular patients and in exhibiting acute RV dysfunction in the presence of acute respiratory distress syndrome (ARDS), particularly in the presence of hemodynamic instability.Like any study, our research had several limitations. One significant limitation was the absence of a control group, which may have affected the study design. Another drawback of our research was that the information was acquired from a single center, and the sample size was comparatively small; therefore, the generalizability of the findings may be limited. Additionally, measurements of important hemodynamic parameters  for both the left & right ventricles were not available, which could have provided more comprehensive insights into ventricular function. Moreover, the lack of pre-disease and follow-up two-dimensional echocardiography data for patients related to echocardiography parameters was also a limitation of the study, further reducing the ability to draw robust conclusions. Future studies with larger sample sizes, multicenter designs, and comprehensive hemodynamic measurements are warranted to further elucidate the cardiac manifestations of the SARS-CoV-2 delta strain.


Sustained hypertension causes structural, functional, and neurohumoral abnormalities in the heart, a disease commonly termed hypertensive heart disease (HHD). Modern concepts of HHD, including processes of remodeling leading to the development of various LVH patterns, HF patterns accompanied by micro- and macrovasculopathies, and heart rhythm and conduction disturbances, are missing in the available definitions, despite copious studies being devoted to the roles of myocardial and vascular fibrosis, and neurohumoral and sympathetic regulation, in HHD development and progression. No comprehensive and generally accepted universal definition and classification of HHD is available to date, implementing diagnostic criteria that incorporate all the possible changes and adaptions to the heart. The aim of this review series is to summarize the relevant literature and data, leading to a proposal of a definition and classification of HHD. This first article reviews the processes of initial myocardial remodeling, and myocardial and vascular fibrosis, occurring in HHD. We discuss important pathophysiological and microstructural changes, the different patterns of fibrosis, and the biomarkers and imaging used to detect fibrosis in HHD. Furthermore, we review the possible methods of targeting myocardial fibrosis in HHD, and highlight areas for further research. Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Hypertension (HTN), despite considerable progress being made in recent decades, remains a major public health problem and the most frequent modifiable risk factor associated with considerable cardiovascular morbidity and mortality. The number of people aged 30–79 years with hypertension has doubled from 1990 to 2019, despite stable global age-standardized prevalence , [left ventricular hypertrophy], [adverse cardiac remodeling], [cardiac remodeling], [hypertension], [hypertensive heart failure], [heart failure], [myocardial fibrosis], [hypertensive cardiopathy], [cardiac biomarkers], [circulating biomarkers], [atrial fibrillation], [arrhythmia].We excluded studies on non-adult populations, case reports, commentaries, and abstracts. The bibliographies in the identified publications and review articles were also reviewed.Studies were eligible for inclusion if they fulfilled the following criteria: full articles published in English in peer-reviewed journals and published from 1 January 2000 to 1 January 2022.All authors independently evaluated the quality of the articles, searched the studies for pooled analyses based on correspondence to the study criteria, and constructed the final list of references.Myocardial remodeling (MR) in HHD includes changes in the size, shape, and structure of the heart cavities, as well as in the biochemical, electrophysiological, and functional properties of the myocardium. It develops under the influence of a complex of various hemodynamic and non-hemodynamic factors. Experimental evidence suggests that chronically elevated blood pressure negatively impacts the normal geometry and function of both the ventricles and atria—primarily the left ventricle (LV) and left atrium (LA), which simultaneously increase in size as the initial adaptation to a deteriorating function .Consequently, there is a variety of interrelated alterations between cardiomyocytes, the interstitial space, and the coronary microvasculature develop . These cPublished studies have suggested that both microvascular resistance and reactivity are impaired in hypertension, and this may further contribute to the development of both systolic and diastolic heart failure . In addiOf note, the process of remodeling does not start at a certain blood pressure threshold in individuals with hypertension, as defined by the different guidelines, but should rather be regarded as a continuum. It is known that even prehypertensive patients are at risk for remodeling . The PAMAdditionally, these results were supported by a meta-analysis performed by Cesare Cuspidi et al. (2018) examining echocardiographic variables derived from pooled data of pre-HTN, which also clearly showed that pre-HTN may be associated with abnormalities in LV structure and function . The autThus, on a structural level, HHD is not just a matter of LVH, but the result of complex myocardial, cellular, and tissue arrangements, leading to changes in the shape, size, and function of the LV and other cardiac chambers.Myocardial fibrosis (MF) is considered one of the key features of hypertensive MR. Myocardial stiffness, which is thought to be a fundamental characteristic of hypertensive maladaption, is associated with fibrosis, altered contractile and relaxation properties, and changes in cardiac cellularity  .MF is classified into two principal types: interstitial  and replacement (or reparative) fibrosis ,45. RepaThe fibrotic remodeling of the heart not only affects the parenchyma, but also the extracellular matrix (ECM), which normally represents a three-dimensional elastic network of collagen fibers and non-structural proteins including cardiomyocytes, vessels, cardiac fibroblasts, and immune cells, playing an essential role in maintaining cellular and vascular integrity, cell signaling, and the regulation of cell–cell interactions . This thIt was also determined that type I and type III fibrillar collagens are major components of the cardiac ECM. Type I collagen represents approximately 85% of the total collagen proteins and builds thick, highly cross-linked fibers that are important for strength, whereas type III collagen (approximately 11%) provides elasticity to the ECM by forming flexible, thin fibers ,44. The A large body of evidence from animal models and human patients suggests that LV pressure overload induces interstitial and perivascular fibrosis . In dog Vascular fibrosis itself is characterized by increased intima-media thickening and vascular stiffness in small and large arteries ,52. In lWith regard to the right ventricle, a few studies confirm the relationship of RV fibrosis with end-diastolic wall stress . Using REndomyocardial biopsy is the gold standard method for diagnosing MIF, but it is invasive, not sufficiently widely available, and offers uncertain benefits in clinical practice. Therefore, attempts have been made to establish circulating biomarkers as non-invasive alternatives to detect early changes in routine clinical practice. It is postulated that inflammatory cytokines, chemokines, and reactive oxygen species may be more important in reparative fibrosis, while mechanical stress, the RAAS, and fibrogenic growth factors appear to be involved in both reparative and reactive fibrosis . HoweverThe best of the studied circulating biomarkers associated with prognosis are B-type natriuretic peptide (BNP) and Troponin, which do not reflect MF, but pressure overload/wall tension and cardiomyocyte damage, respectively. To date, the most convincing association with histologically proven MIF has been demonstrated for the serum carboxy-terminal propeptide of procollagen type I (PICP), serum amino-terminal propeptide of procollagen type III (PIIINP), and serum collagen type I telopeptide (CITP) to serum matrix metalloproteinase-1 (MMP-1) - CITP:MMP-1 ratio ,45. RavaAll these findings suggest that monitoring plasma biomarkers of myocardial ECM remodeling might provide important prognostic information with respect to ongoing adverse LV remodeling in patients with HHD in the future, but this has to be proven prospectively.Regarding the RV, changes in the development of MF and the activity of circulating biomarkers under pressure overload conditions, such as matrix metalloproteinases (MMPs), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), galectin-3 , transforming growth factor-β1 (TGF-β1), and endothelin-1 (ET-1), have been repeatedly studied and emphasized in various types of pulmonary hypertension ,68,69. NConsidering the complexity and possible risks associated with using endomyocardial biopsy to diagnose diffuse MF in HHD in routine clinical practice, there is a need for non-invasive techniques, such as advanced non-invasive imaging methods, for MF evaluation. To quantify MF, cardiac magnetic resonance imaging (CMR), including late gadolinium enhancement (LGE), is used, but diffuse MF cannot be detected by LGE, which is a serious limitation of this technique . In thisThere is currently experimental evidence that certain antihypertensive drug therapies  receptor blockers, mineralocorticoid receptor inhibitors, etc.) reduce the collagen content and LV stiffness in hypertensive patients regardless of their blood pressure-lowering effect ,33,51,74Besides the lipid-lowering, anti-inflammatory, and cardioprotective effects, statins have been shown to be effective in attenuating cardiac fibrosis both in mouse models of HHD (rosuvastatin) and in patients with systolic HF and normal cholesterol (atorvastatin) ,80,81. AAt present, no drug primarily targeting anti-fibrotic mechanisms has been approved for the treatment of MF in cardiovascular disease, but different substances are under evaluation. The first results from the phase II clinical trial PIROUETTE (The Efficacy and Safety of Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) suggest that pirfenidone may be safe and effective in patients with HFpEF ,84. AddiThe above-mentioned data suggest that the diffuse fibrosis seen in hypertension may be reversible. However, it is also noteworthy to mention that the degradation of ECM in a hypertrophic heart might not be benign. There is a hypothesis that the transition from compensated LVH to heart failure in HHD is associated with the degradation of ECM: diastolic heart failure (with accumulated perimysium) and systolic heart failure  ,44. GracIn summary, reactive fibrosis might function as an initial adaptive mechanism, and it is important to find out at which stage and at what quantity it becomes maladaptive. Additionally, it is important to determine if there is a point of no return for reverse remodeling. Therefore, there is a clinical need to gain a deeper pathophysiological understanding and, in particular, to further evaluate and validate the prognostic impact of circulating biomarkers and advanced imaging techniques, such that they can be used to guide the initiation of possible antifibrotic treatments, and to monitor the responses to such therapy in HHD in future trials.


Myocardial glycosphingolipid accumulation in patients with Fabry disease (FD) causes biochemical and structural changes. This study aimed to investigate sympathetic innervation in FD using hybrid cardiac positron emission tomography (PET)/magnetic resonance imaging (MRI).11C]meta-hydroxyephedrine ([11C]mHED). Fourteen patients with either no evidence of cardiac involvement (n = 5), evidence of left ventricular hypertrophy (LVH) (n = 3), or evidence of LVH and fibrosis via late gadolinium enhancement (LGE) (n = 6) were analyzed. Compared to patients without LVH, patients with LVH or LVH and LGE had lower median T1 relaxation times (ms) at 1.5 T  and 3T (1290 vs. 1172 vs. 1184 p = .014). Myocardial denervation ([11C]mHED retention < 7%·min) was prevalent only in patients with fibrosis, where a total of 16 denervated segments was found in two patients. The respective area of denervation exceeded the area of LGE in both patients (24% vs. 36% and 4% vs. 32%). However, sympathetic innervation defects ([11C]mHED retention ≤ 9%·min) occurred in all study groups. Furthermore, a reduced sympathetic innervation correlated with an increased left ventricular mass  and a reduced global longitudinal strain (GLS) .Patients with different stages of Fabry disease were prospectively enrolled to undergo routine CMR at 1.5T, followed by 3T hybrid cardiac PET/MRI with [Hybrid cardiac PET/MR with [11C]mHED revealed sympathetic innervation defects, accompanied by impaired GLS, in early stages of Fabry disease. However, denervation is only present in patients with advanced stages of FD showing fibrosis on CMR.The online version contains supplementary material available at 10.1007/s12350-023-03205-7. GLA gene, typically leads to structural changes within the cells and tissues of affected organs, including the heart, the kidneys, and the nervous system. These changes are the consequence of glycosphingolipid accumulation, mainly of globotriaosylceramide (Gb3), and subsequent processes.1Fabry disease (FD), a lysosomal storage disorder characterized by a lack of the enzyme alpha-galactosidase A due to different variants of the 2 Replacement fibrosis of the myocardium constitutes the irreversible organ damage and leads to various clinical complications, including arrhythmia and heart failure.3 The clinical signs of FD-associated cardiomyopathy are detectable by electrocardiography (ECG), echocardiography, and cardiac magnetic resonance (CMR) and can be found in up to 60% of male and 50% of female patients.4In patients with classic FD and late-onset cardiac phenotypes, hypertrophy of cardiomyocytes, as well as necrosis and apoptosis, can be found in histological examinations.12 Cardiac PET/MRI, in particular, may offer further perspectives on the detection of cardiac changes during the course of the disease, combining the simultaneous information of both methods.Modern imaging techniques, such as CMR, including T1 and T2 mapping and late gadolinium enhancement (LGE), facilitate tissue characterization of the myocardium. However, essential aspects of the links between structural and functional changes may be missed. Myocardial scintigraphy, using single-photon emission-computed tomography (SPECT) and positron emission tomography (PET), has already delivered valuable information about coronary microvascular dysfunction, acute and chronic inflammation, and sympathetic cardiac innervation in various diseases, including FD.123I]-metaiodobenzylguanidine (MIBG) SPECT, and have found evidence that denervated areas might affect left ventricular function in patients with or without LGE.13 Furthermore, evidence has previously been found that sympathetic neurons appear more vulnerable than myocardial cells.14 However, the direct association of reduced sympathetic innervation with myocardial fibrosis in FD is still unclear. Recently, [11C]meta-hydroxyephedrine ([11C]mHED) hybrid cardiac PET/MRI was proposed as a potential tool to precisely examine the cardiac sympathetic innervation in Fabry disease.15As the progressive glycosphingolipid accumulation in FD can ultimately lead to myocardial fibrosis and its subsequent link to cardiac sympathetic denervation, recent studies have evaluated the extent of such accumulation and consequences using [11C]mHED in FD cardiomyopathy and to provide further insights into the presence of myocardial areas with impaired sympathetic innervation or denervated areas and potentially linked abnormalities of routine CMR in patients with different stages of FD.This pilot study, therefore, aimed to demonstrate the feasibility of hybrid cardiac PET/MRI with mHED was administered intravenously with start of the PET acquisition in list mode for a total of 40 minutes. List mode data were then reconstructed to static images  and dynamic images . The simultaneously recorded ECG was used for synchronizing PET and CMR data acquisition with the cardiac cycle. As a contrast agent for LGE and post contrast T1 mapping 0.15 mL·kg bodyweight gadobutrol  was injected.Additional to hybrid cardiac PET/MRI, 1.5T CMR examinations were performed as part of the yearly clinical routine follow-up on a Siemens Avanto Fit MRI scanner  with a standardized multiparametric protocol. Details are described within the Supplemental Materials.18 Global longitudinal strain (GLS) was calculated by feature tracking in 2-, 3-, and 4-chamber SSFP cine sequences. Ejection fraction (EF) was calculated using the biplane Simpson's method.CMR image analysis was done via a dedicated CMR postprocessing software  by one observer, who was blinded to clinical and PET data. Left ventricular size and function were derived from the 3T cine-balanced steady-state free precession short-axis images at the time of end-diastole and end-systole. The full width at half maximum technique with semi-automatic contouring was performed for the quantification of LGE. The extent of LGE was calculated as percent volume of the total myocardial mass. Segments with any evidence of LGE, after exclusion of artifacts during visual image analysis, were defined as LGE positive, otherwise as LGE negative. ECV was calculated with pre- and post contrast T1 maps from the 3T CMR images using the standard formula and the patient's current hematocrit.19PET images were post-processed by a different observer than for CMR using a dedicated quantification software . The observer was blinded to clinical and CMR data. After defining the long axis, a volumetric sampling algorithm created a polar map of the tracer distribution throughout the left ventricle.11C]-mHED retention index (%·min) in the left ventricle was quantified from dynamic images and calculated by dividing tissue activity between the minutes 30 and 40 through the integral of blood counts from minute 0 to minute 40.20 Attenuation-corrected images were iteratively reconstructed  in a 256 × 256 matrix. A 17-segment model was used for regional analysis, where the mean retention index was calculated for each segment. Below a retention index of 7%·min, the myocardium was defined as denervated in accordance with previous studies.22 Although no normal ranges for only mildly impaired sympathetic innervation were published so far, previous studies provided data for healthy control groups who presented with a retention index above 9%·min.24 Hence, the sympathetic innervation of segments with a retention index of ≤ 9%·min was considered to be impaired.The [11C]mHED retention. The apical segment was excluded due to a high rate of artifacts.The analysis of each myocardial segment within the AHA 17-segment model was done for LGE, T1/T2 mapping, ECV, and mHED retention of > 9%·min.While none of the LVH-LGE- or LVH+LGE- patients had denervated areas, two patients of the LVH+LGE+ group, presented with an individual denervated area of 36% and 32%. The percentual denervated area of the myocardium also correlated with the percentual amount of LGE .[Supplementary file1 (DOCX 19 kb)Supplementary file2 (PPTX 5138 kb)Supplementary file3 (MP3 5601 kb)Below is the link to the electronic supplementary material.


In this work we performed an imaged-based computational study of the systolic fluid dynamics in presence of mitral valve regurgitation (MVR). In particular, we compared healthy and different regurgitant scenarios with the aim of quantifying different hemodynamic quantities.We performed computational fluid dynamic (CFD) simulations in the left ventricle, left atrium and aortic root, with a resistive immersed method, a turbulence model, and with imposed systolic wall motion reconstructed from Cine-MRI images, which allowed us to segment also the mitral valve. For the regurgitant scenarios we considered an increase of the heart rate and a dilation of the left ventricle.regurgitant jets through the mitral orifice impinging against the atrial walls and scratching against the mitral valve leading to high values of wall shear stresses (WSSs) with respect to the healthy case.Our results highlighted that MVR gave rise to CFD with prescribed wall motion and immersed mitral valve revealed to be an effective tool to quantitatively describe hemodynamics in case of MVR and to compare different regurgitant scenarios. Our findings highlighted in particular the presence of transition to turbulence in the atrium and allowed us to quantify some important cardiac indices such as cardiac output and WSS. Mitral valve regurgitation (MVR) is a congenital or acquired pathological condition of the mitral valve leading to an incomplete closure of the leaflets during the systolic phase, causing a retrograde blood flow from the left ventricle to the left atrium. The major complications are atrial fibrillation or flutter, pulmonary arterial hypertension and heart failure . EpidemiThe quantitative assessment of blood dynamics quantities, such as pressure, velocity and stresses, in presence of MVR during the systolic phase is crucial for the understanding of the phenomena and to elaborate the diagnosis. For example, the regurgitant volume (RV) and the regurgitant fraction (RF) can help physicians in assessing the severity of the pathological condition  and poteComputational methods in realistic cardiac geometries represent a non invasive way to provide blood dynamics information  and helpComputational studies investigating the mitral valve and its interaction with the blood flow have been proposed since the early 2000s, and can be divided into two categories: (i) fluid–structure interaction (FSI) models and (ii) computational fluid dynamics (CFD) models with imposed wall motion.Regarding the FSI approach, some authors investigated the mitral valve dynamics in physiological conditions , 48, 77,In order to reduce the high computational costs of FSI simulations, CFD models with imposed ventricular and leaflets motion provided by dynamic imaging have also been considered. Such models require a great effort in elaborating the dynamic images and in merging them with CFD. However, they noticeably simplify the problem from the modeling point of view.The majority of such works are based on images provided by ultrasound (US) techniques (like 3D echocardiography). 3D Echo has the advantage of providing high temporal resolution, particularly useful when resolving the rapid movements of the mitral valve leaflets . For exaAnother dynamic imaging technique used for ventricular CFD is Cine-MRI. However, such technique has been used to reconstruct only the motion of the ventricle whereas different models of the mitral valve have been considered. For example, we cite Ref.  where thRegarding the study of the MVR by CFD with imposed motion, we cite Refs. , 16, wheThis work aims at providing an original study of the systolic blood dynamics in the left ventricle in physiological and MVR conditions. For this purpose, we introduced some contributions in the context of computational models for ventricular fluid-dynamics. First, we adapted to the systolic phase  a method based on radial sampling Cine-MRI acquisitions developed in Ref.  for the healthy (H): we inserted a structurally normal mitral valve (taken from dedicated MRI images) and we considered a heart rate equal to 75 bpm/minregurgitant with increased heart rate (R1): we inserted a regurgitant mitral valve with a posterior leaflet prolapse of the P2 segment (reconstructed from dedicated MRI images) and we increased the basal heart rate to 90 bpm/min ;regurgitant with dilatation (R2): we inserted the same regurgitant mitral valve of R1, with heart rate equal to 75 bpm/min, and we dilated all the geometry .The regurgitant scenarios represent different stages of the pathological evolution of the heart function in case of MVR due to prolapse, leading to a decrease of the cardiac output (CO). To compensate, in an early stage the heart rate spontaneously increases (R1) [medium-long term, the early compensatory changes are gradually replaced by a remodeling process with dilation of the left ventricle and restoring of the basal heart rate (R2). The resultant increase of the stroke volume (SV) tends to compensate for the low CO [In this work we provided a comparison of blood flow dynamics in scenarios with healthy and regurgitant mitral valves during the systolic phase.ses (R1) . Howevere low CO .Cardiac Cine-MRI data were provided by the Department of Radiology of Borgo Trento Hospital, Verona, Italy. Ethical Review Board approval and informed consent were obtained from all patients.Left ventricle: (i) volumetric short-axis series made of 15 slices with thickness and distancing of 8 mm along the left ventricle main axis, with a spatial resolution of 1 mm; (ii) a set of single-slices, two-dimensional long-axis acquisitions on the so-called two-chamber and four-chamber planes, with space resolution of 1 mm and slice thickness of 8 mm. Both series had a time resolution equal to 30 frames/cardiac cycle. This protocol was carried out for a subject who did not present any alteration of the left ventricle wall and movement;Mitral valves: two-dimensional long-axis series of 18 evenly rotated (one every In what follows we describe how such images were elaborated and reconstructed.The acquisitions were performed with the Achieva 1.5T (TX)-DS  technology with the following characteristics:In this section we described the strategy followed to reconstruct the geometry and the displacement field of the left ventricular endocardium.ad hoc series for the reconstruction of the left ventricular anatomy. However, one of the main disadvantages often characterizing such images in the daily clinical practice is the low resolution among slices (in our case about 8 mm). As a consequence it is difficult to capture some important findings of the heart contraction, as the longitudinal shortening of the ventricle. To account for this, in this work we applied the short–long axis merging (SLAM) algorithm, proposed in Refs. [creation of a new artificial image with the same dimensions of the short-axis view and with a uniform space resolution (1 mm in our case) in all three Cartesian directions;for each voxel V of this new artificial image, identify, for each slice of the original Cine-MRI image, the nearest voxel, and compute the distance compute the weighted average of the values of the voxels identified at point 2, where the weights depend on These steps lead to an enhanced time-dependent series of volumetric images with a uniform space resolution of 1 mm in all directions, including the cross-slice one.The starting point were the volumetric short-axis images, which are in Refs. , 31, whiwww.mitk.org) [Starting from these enhanced images, we segmented and reconstructed the shape of the endocardium and epicardium at six instants from the end diastolic (ED) to the end systolic (ES) configuration, by adopting the semi-manual segmentation algorithm proposed in Ref.  and implitk.org) , 22. Thiwww.vmtk.org) [After, we performed a Boolean difference between the epicardium and the endocardium, in order to extract the region of the endocardium from the apex to the level of the valvular ring by using the Vascular Modeling Toolkit (VMTK) (mtk.org)  and suitmtk.org) . We poinmtk.org) , 88, 78.http://elastix.isi.uu.nl), consisting in the minimization of the difference between two images under the assumption that they represent the same region, i.e. the same bounding box [These steps were repeated for all the six frames, obtaining surface meshes made of triangles, representing the configurations of the endocardium during its contraction phase. Then, we registered the displacement needed to pass from a configuration to another one by exploiting the non-affine B-splines algorithm implemented in the Elastix open source library . In particular, we merged such templates to the ES configuration of the reconstructed ventricular endocardium. For the healthy case H, we started our simulation at the aortic valve opening instant Since the ventricular Cine-MRI images at disposal were not sufficient to allow a 3D reconstruction of the left atrium, aorta and aortic valve, that are only partially visible in long-axis images, we considered a template geometry of the internal atrial surface and the aortic valve from the t cases) , 17. Forvmtksurfaceharmonicconnector), to project a displacement field on a surface (vmtksurfaceprojection), and to solve a harmonic extension problem (vmtksurfaceharmonicextension) [Moreover, we generated an aortic flow extension of the left ventricle outflow tract to account for the aorta  . This alThen, to provide a displacement field also to the atrium and the aortic root, we harmonically extended the ventricular endocardial displacement to the corresponding surfaces  and for each of the 18 acquired longitudinal planes we traced the leaflets profile in the ED configuration by using a spline curve sampled in 32 points . After, we imported this matrix in MATLAB (www.mathworks.com) to perform a smoothing process in order to reduce possible inaccuracies due to image noise and to the manual segmentation of the leaflets. To do this, we created a new matrix where blocks of 36 consecutive rows represent the (36) points of a ring , with the first ring corresponding to the annulus and the last one to the free margin. Then, the points of each ring were fitted by using a B-Spline , see step E in Fig. https://www.meshmixer.com), see step F in Fig. We repeated this operation for all the 18 planes to obtain the final 3D point cloud representing the mitral valve profile  based on the deal.II core [https://iheart.polimi.it/).To solve numerically the Eqs.  and 2),,2), we cnt}lifex  (https:/.II core  and deveTetGen (vmtkmeshgenerator) and for the mesh refinement (vmtkmeshrefinement) [Hexahedral meshes were generated by using suitable algorithms developed in VMTK, in particular, for the mesh generation based on inement) , 61. The 2% see “”.Numerical simulations were run on the cluster iHEART  available at MOX, Dipartimento di Matematica, Politecnico di Milano.We start our analysis by reporting the results in terms of geometry reconstruction in order to check the validity of the registration procedure, see “Then, we discuss the computational opening of the aortic valve. As stressed in “Figure To obtain a description of the spatial distribution of the pressure, in Fig. Regarding the closure of the aortic valve, from Fig. mentclass2pt{minimIn Fig. In Fig. From these curves we calculated some cardiac indices reported in Table To obtain a description of the the velocity patterns in the whole domain, in Fig. regurgitant jet in the atrium for R1 and R2. At In particular, we considered three representative time instants: mentclass2pt{minimIn Fig. From these results, we found elevated values of see Fig. : at the mentclass2pt{minimIn Fig. We noticed a hotspot of shear forces localized at the mitral orifice, where high velocities occurred  [In this work we performed an image-based computational study to analyze the hemodynamics in presence of a healthy (H) and regurgitant valve with either increased heart rate (R1) or dilated left ventricle (R2). These two phases represent two different mechanisms the heart employs to compensate the decreasing of the CO due to MVR. This process is known as  forces) .First, analysing the ventricular-aortic pressure drop which represents and quantifies the force generated by the ventricle to win the aortic resistances, we found that in R1 and R2 the ventricle was not able to provide the same pressure drop between ventricle and aorta of the H case ;We quantified the chaotic velocity pattern in the atrium in the regurgitant cases highlighting the presence of two distinct jets; moreover, we assessed the WSS magnitude on the mitral valve and atrial wall, focusing on the increase of viscous forces due to regurgitation.Some limitations characterized this study: Starting from a ventricular geometry segmented from MRI, we filled the missing geometric data by considering a template for the left atrium and the aortic valve and a flow extension for the aorta. We notice however that such information are not in general visible from standard short-axis MRI acquisitions. For this reason, we are currently investigating the integration of short axis images with other MRI acquisition series that include also the left atrium and the aorta. Another geometric limitation consists in the smoothed ventricular endocardial reconstruction which did not include the papillary muscles, whose effect should be investigated in order to assess their influence in the quantities of interest of this study.We expanded harmonically the ventricular displacement to the wall of the left atrium and aorta. With this choice we neglected the dilation of the left atrium and aorta during the ventricular systole. This point is currently under scrutiny, to understand how to include plausible dilation motions of aorta and left atrium, following e.g. the strategy proposed in Ref. .We simulated only systole, including the isovolumic contraction for R1 and R2, since MVR is a pathology involving mostly this phase. Further investigations to extend our study to the diastolic phase will be mandatory in order to assess the effects of MVR during this phase and to remove the influence of the null initial condition more heartbeats should be performed. Notice that, we had nine systolic frames at our disposal, but in fact we worked only with six of them, and discarded three instants, since they were affected by a huge amount of noise that yielded a reconstruction that was incompatible with the other six, with a consequent irregularity of the displacement field and distortion of the mesh during its movement. Notice that these three frames were intermediate ones, thus we guaranteed to work with the patient specific SV.We are aware that, in the clinical setting, the degree of MVR, for the same type of valvular disease, is extremely variable, depending upon several variable factors, such as heart rate, ventricular contractility, pre-load and after-load. Our current study was limited to the description of hemodynamics considering only one degree of MVR and two possible scenarios (increased heart rate and increased ventricular dimensions), maintaining all other parameters unchanged in all groups. The effects of different degrees of MVR on the hemodynamic quantities could be of clinical interest and investigated in future works, both conducting parametric studies accounting for a synthetic reduction/dilation of the mitral orifice, or analyzing several patients with different regurgitation severity.In this work, we created three different virtual scenarios starting from a reference case. This is a well accepted strategy when one wants to compare the effect of a single change  on some outputs (see e.g. Ref.  for the The main outcomes and contributions of the present study could be summarized as follows:


Heart failure is a clinical syndrome with significant heterogeneity in presentation and severity. Serial risk-stratification and prognostication can guide management decisions, particularly in advanced heart failure, when progression toward advanced therapies or end-of-life care is warranted. Each currently utilized prognostic marker carries its own set of challenges in acquisition, reproducibility, accuracy, and significance. Left ventricular ejection fraction is foundational for heart failure syndrome classification after clinical diagnosis and remains the primary parameter for inclusion in most clinical trials; however, it does not consistently correlate with symptoms and functional capacity, which are also independently prognostic in this patient population. Utilizing the left ventricular ejection fraction as the sole basis of prognostication provides an incomplete characterization of this condition and is prone to misguide medical decision-making when used in isolation. In this review article, we survey and exposit the important role of metabolic exercise testing across the heart failure spectrum, as a complementary diagnostic and prognostic modality. Metabolic exercise testing, also known as cardiopulmonary exercise testing, provides a comprehensive evaluation of the multisystem  response to exercise performance. These differential responses can help identify the predominant contributors to exercise intolerance and exercise symptoms. Additionally, the aerobic exercise capacity  is directly correlated with overall life expectancy and prognosis in many disease states. Specifically in heart failure patients, metabolic exercise testing provides an accurate, objective, and reproducible assessment of the overall circulatory sufficiency and circulatory reserve during physical stress, being able to isolate the concurrent chronotropic and stroke volume responses for a reliable depiction of the circulatory flow rate in real time. Heart Failure (HF) is a clinical syndrome that is caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion; it affects more than 6.7 million adults in the United States alone . The calIn 2022, the ACC/AHA/HFSA endorsed a revised HF classification, dividing patients into four main groups: heart failure with reduced left ventricular ejection fraction (LVEF) ≤ 40% (HFrEF); heart failure with mildly reduced LVEF 41–49% (HFmrEF); heart failure with preserved LVEF ≥ 50% (HFpEF); and heart failure with improved LVEF (HFimpEF), meaning a baseline LVEF of <40% and a subsequent 10-point LVEF increase from baseline and also being >40% /[(peak VO2 − rest VO2)/(predicted peak VO2 − rest VO2)] . The assSeveral risk score models have been used to prognosticate patients for chronic HFrEF, acute decompensated HFrEF, and HFpEF and are listed in Natriuretic peptides (NPs) are released by cardiac myocytes to maintain circulatory homeostasis. NPs are secreted in response to myocardial tension and increased intravascular volume . N-termiDue to the challenges in assessing HF severity with the parameters previously mentioned, there is a need for a more precise definition of hemodynamic involvement and refined prognostic assessment of HF . MetabolMET allows for an integrated physiological assessment of the pulmonary, cardiovascular, muscular, and cellular oxidative systems . The tesCurrent consensus statements and guidelines provide clinical indications for the use of MET, including the assessment of unexplained dyspnea and exercise intolerance, timing of intervention for valvular or congenital heart disease, clinical-trial initiation, and grading severity and prognosticating established advanced cardiac or pulmonary disease ,83,84.The American Thoracic Society/American College of Chest Physicians guidelines on cardiopulmonary exercise testing  describes full procedural and operational standards . As part2 production; also know as VE/VCO2 slope), VO2 at the ventilatory-derived anaerobic threshold (VO2@AT), oxygen uptake efficiency slope , end tidal pressure of CO2 (PEtCO2), and presence of oscillatory ventilation (EOV), among others /(SBPrest × HRrest) and was first described by Vainshelboim et al. Initial studies identified the association between a lower HGI and a greater risk of all-cause mortality ,140. Fur2), adjusting the pVO2 to lean body mass may be considered; a lean-body-mass-adjusted pVO2 < 19 mL/kg/min can serve as a suitable threshold for cardiac transplantation eligibility [Data from Mancini et al. proposed a pVO2 < 14 mL/kg/min as the cutoff for cardiac transplantation eligibility in patients who are intolerant to beta-blockers, and a threshold of <10 mL/kg/min for those HFrEF patients on chronic betablocker therapy . Currentgibility . Althouggibility ,97. Convgibility ,144,145.MET parameters post-transplantation demonstrate improvement compared to pre-transplant values; however, they may continue to remain abnormal when compared with age-matched healthy individuals, likely due to circulatory deconditioning and impaired cardiac denervation, limiting acute exercise response ,147. SevSeveral MET parameters have been described to predict outcomes after implantation of durable mechanical circulatory support devices (LVADs). Peak VO2 and OUES were associated with 1-, 3-, and 5-year mortality after LVAD implantation. Also, the VE/VCO2 minimum was associated with 3- and 5-year mortality, while the VE/VCO2 slope was also strongly correlated with 5-year mortality . These pThe effect of LVAD implantation on VO2 is uncertain, as studies have demonstrated inconsistent results ,154,155.The invasive MET (iMET) incorporates the use of radial and pulmonary catheters for simultaneous hemodynamic monitoring. With the hemodynamic data provided by iMET, it is possible to dissect the oxygen delivery from the oxygen extraction component from the aerobic capacity , evaluating in isolation the cardiovascular and mitochondrial functions of the skeletal muscle, sequentially. It is essential for the diagnosis of mitochondrial myopathies and helpful in the evaluation and diagnosis of other conditions of undifferentiated dyspnea, such as exercise-induced pulmonary arterial hypertension (PAH), exercise-induced HFpEF, preload-dependent limitations to cardiac output, chronic thromboembolic disease (CTED), and chronic thromboembolic pulmonary hypertension (CTEPH), among others ,166,167.MET has been used as an endpoint for clinical trials because it allows for the objective measurement of functional capacity at both maximal and submaximal exertion. However, MET incurs a greater overall cost than a submaximal functional or health status assessment and requires expertise in implementation and interpretation. The Heart Failure Collaboratory, and the Academic Research Consortium consensus document indicates that the minimal clinically important difference for maximal VO2 on MET has not been validated. Meaningful difference in peak VO2 has been reported as a 6% change or 1 mL/kg/min but is based on repeat test variability and lack of clinical relevance . OverallHeart failure is a clinical condition with great heterogeneity in presentation, severity, and prognosis. Utilizing LVEF alone to characterize HF will lead to an incomplete assessment of HF severity. MET provides a comprehensive assessment of the integrative multiorgan physiological response to exercise, highlighting its place in the clinician’s evaluation of heart-failure patients. MET data should be incorporated into the characterization of the HF disease state, prognostication, and the decision about the best treatment course for patients.


Emergency and critical care physicians frequently encounter patients presenting with dyspnea and normal left ventricular systolic function who may benefit from early diastolic evaluation to determine acute patient management. The current American Society of Echocardiography Guidelines approach to diastolic evaluation is often impractical for point of care ultrasound (POCUS) evaluation, and few studies have evaluated the potential use of a simplified approach. This article reviews the literature on the use of a simplified diastolic evaluation to assist in determining acute patient management. Symptomatic heart failure continues to have a significant associated morbidity and mortalityIn 2016, the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACI) published guidelines for the evaluation of diastolic dysfunction using echocardiography In this article, we review the literature for evaluation of diastolic dysfunction using a simplified echocardiographic approach.We reviewed the literature to look for simplified approaches to evaluating diastolic dysfunction using echocardiography. We identified articles through a systematic search of the Medline (PubMed) and EMBase databases for relevant articles published after September 1, 2016. Our search terms were 'diastolic heart failure'/exp OR 'diastolic function'/exp) AND ('transthoracic echocardiography'/exp OR 'point of care ultrasound'/exp) for EMBase and  AND ("Echocardiography"[Mesh] OR "Ultrasonography"[Mesh])) for PubMed.We identified 1345 studies satisfying the search terms . We excluded 21 duplicate studies and 1314 irrelevant studies. We excluded studies using transesophageal echocardiography, 3D echo-cardiography or volumetric strain echocardiography measurements. We also excluded studies which included patients with decreased left ventricular ejection fraction, pediatrics, congenital or valvular heart disease. Lastly, we excluded review articles, posters, and abstracts. We found five articles responsive to our initial question. In addition, we found seven articles which discussed echocardiographic identifiers of mortality rather than diagnostic signs of diastolic dysfunction. The authors felt this was important to the overall topic and should be included in this report. The characteristics of the included studies are summarized in Table 1 and Table 2. Most of the studies used retrospective data. Seven studies enrolled inpatients and three enrolled outpatient clinic patients. The sonographers for these studies were usually not identified in the reports, but we assumed they were certified cardiology echocardiographers with interpretation by a cardiologist if not otherwise stated. Most of the studies did not reference the 2016 ASE guidelines or compare the data directly to these guidelines.Recognizing echocardiographic evidence of diastolic dysfunction can be very helpful when attempting to differentiate the underlying etiology of patients presenting with dyspnea and it has also been found useful as a clinical predictor for patients with sepsis without the need for invasive measurements In 2016, the ASE and the EACI published an updated guideline for the evaluation of diastolic dysfunction. The goal of the update was to create a more simplified set of guidelines, as it was noted that the prior guidelines, published in 2009, were considered too complex and led to difficulty for providers in diagnosing diastolic dysfunction For patients found to have a normal LVEF, the guidelines recommend the evaluation of four parameters: E/E’ ratio, septal e’ or lateral e’ velocity, tricuspid regurgitation (TR) velocity and left atrial (LA) volume index. The first three values are to be obtained through the apical 4 chamber (A4C) view with pulse wave Doppler of the mitral valve flow, tissue Doppler imaging of the mitral valve septum or lateral plane, and continuous wave Doppler of the tricuspid valve. The last calculation, volumetric analysis of the left atrium, requires a volume assessment in the traditional A4C and then an additional orthogonal view from the A4C view. For diastolic dysfunction to be diagnosed, three or four of these measurements must be abnormal. If only one or none of these values is noted to be abnormal, diastolic dysfunction is excluded. If two of these values are noted to be abnormal, then the result is “indeterminate.” Unlike the 2009 guidelines, the 2016 guidelines do not specify further gradation of diastolic dysfunction in patients with normal EF.The 2016 ASE guidelines, despite simplifying the 2009 guidelines, still present challenges for a timely evaluation at bedside in the ED setting. One of the biggest challenges is that providers in the emergency department are trained in POCUS. POCUS is a limited survey seeking to answer a simple yes or no question. However, the diagnosis of diastolic dysfunction often requires more complicated parameters and measurements than what POCUS can provide involving both echogenic and clinical evaluation.A review by Greenstein highlights the difficulties in the critical care setting, many of which also apply in the ED setting In our review there was substantial heterogeneity across studies in the evaluation of diastolic dysfunction and the markers of mortality. Most of the studies looked at mitral valve Doppler velocities Two studies directly compared a simplified method with a comprehensive method of evaluating for diastolic dysfunction While a simplified diastolic analysis can provide further diagnostic information, the technique has some drawbacks. If not properly obtained, these measurements would likely have more limited accuracy The accuracy and utility of a simplified evaluation method for diastolic dysfunction likely needs further investigation and validation studies. There are a few proposals for a simplified diastolic dysfunction evaluation, but robust research in this area, including prospective trials, is lacking. Much existing research in this area is based on retrospective review of comprehensive echocardiographic examinations with parameters that are increased in patients who have been diagnosed with diastolic dysfunction. Furthermore, a few of the articles in our review proposed a simplified diagnostic approach, yet still required complex calculations for the evaluation of diastolic dysfunction.Simplified diastolic evaluation methods do not preclude the need for a comprehensive echocardiogram or provide a definitive diagnosis, but it helps physicians target their care in a timely fashion when comprehensive echocardiography is neither feasible nor readily available.The authors have no conflicts of interest to disclose.


Editorial on the Research TopicNovel and emerging therapies in heart failureHeart failure (HF) has been named “the growing epidemic” , 2. OverThis research topic was initiated by Triposkiadis et al. and published in 2022 in Frontiers in Cardiovascular Medicine. Our aim was to invite articles highlighting current research in novel or emerging therapeutic approaches -pharmacological and invasive- in both the acute and chronic setting of the disease, as well as potential interaction and/or barriers with concomitant cardiovascular or non-cardiovascular diseases. In this special issue, we present 7 original research articles, 3 systematic review articles and 1 opinion article that address such issues and investigate why, despite the emergence of novel therapeutic approaches that promise life prolongation and hospital length reduction, this patient population often has a poor prognosis and often requires rehospitalization. Below is a summary of these articles.Quan Qiu et al. the efficacy of CSWT on coronary artery disease (CAD) patients was evaluated. A total of 8 randomized controlled trials (RCTs) and 2 prospective cohort studies involving 643 patients (n = 336 CSWT and n = 307 control) were included in the study. CSWT was shown to moderately improve myocardial perfusion and cardiac function among patients with CAD, a finding that may provide the clinicians with a meaningful and valuable option for revascularisation, for instance in selected HF patients with ischemic cardiomyopathy.An increased number of HF patients suffer from chronic angina, which seriously impairs their quality of life . CardiacZunjiang Li et al. conducted a systematic review and meta-analysis that aimed to assess the adjunctive efficacy and safety of Puerarin injection (PI) in acute HF patients. Eight studies were included with a total of 614 patients with acute HF that demonstrated that adjunctive treatment with PI was superior to, and as safe as, conventional medicine alone. Specifically, PI increased the total effective rate and improved left ventricular ejection fraction (LVEF) as compared with conventional therapy without raising safety concerns, as there was no significant difference in adverse events between the two groups.Puerarin  is the major bioactive ingredient of the root of Radix Puerariae and has been widely applied for the adjunctive management of CAD; its main drug delivery method is intravenous injection . ZunjianDanning Yang et al. performed a meta-analysis to illustrate the therapeutic impact of sodium-glucose cotransporter-2 (SGLT2) inhibitors in HFpEF patients. Treating HFpEF patients with SGLT-2 inhibitors was associated with a 22% reduction in the composite outcome of cardiovascular death or hospitalization for HF and had a similar improvement in health-related quality of life; interestingly, no statistical difference was observed in 6MWT distance. In an opinion article, Luis Tolento Cortes and Lisa Hong highlight the flaws of all recent RCTs regarding the use of ACEIs/ARBs/ARNIs, beta-blockers, aldosterone antagonists and SGLT2 inhibitors in patients with HFpEF. In a subsequent original research article, María Valero-Muñoz et al. identified the cardiac-specific features of protein and phosphoprotein changes in a murine model of HFpEF using mass spectrometry. Proteomics analysis of the left ventricular (LV) tissue showed that almost 900 proteins were expressed differentially between HFpEF and sham mice including changes in sarcomeric proteins, mitochondrial-related proteins, and NAD-dependent protein deacetylase sirtuin-3 (SIRT3). In summary, this study demonstrates marked changes in proteins related to mitochondrial metabolism and the cardiac contractile apparatus in HFpEF; the authors propose that SIRT3 may play a role in perpetuating these changes and, therefore, may be a target for drug development in HFpEF.The pharmacological management of heart failure with preserved ejection fraction (HFpEF) continues to be an area of uncertainty due to multiple studies failing to show a clear benefit associated with therapies that have otherwise proven useful in the management of other HF subtypes. Therefore, both the 2021 ESC and the 2022 AHA/ACC/HFSA updated HF guidelines state that “in the absence of recommendations regarding disease-modifying therapies, treatment should be aimed at reducing symptoms of congestion with diuretics” , 7. BaseYishu Wang et al. examined the effects of early phase 1 cardiac rehabilitation (CR) on cardiac function in patients with coronary heart disease (CHD) and acute HF using impedance cardiography (ICG). A total of 98 patients were recruited and randomized into two groups. The control group received standard pharmacotherapy and the CR group received standard pharmacotherapy combined phase 1 CR. NT-proBNP and hemodynamic parameters measured by ICG were estimated at baseline and at the end of the treatment period. Phase 1 CR resulted in a more pronounced reduction in NT-proBNP levels. Similarly, most hemodynamic parameters improved in the CR group, but not in the control group. These findings suggest that phase 1 CR in combination with the standard pharmacotherapy could improve hemodynamic characteristics by elevating cardiac output, ameliorating preload, improving systolic and diastolic function, and relieving afterload. Therefore, suitable stabilized patients with CHD and acute HF should undergo phase 1 CR.Lien-Cheng Hsiao et al. aimed to assess the safety and efficacy of combined intracoronary (IC) and intravenous (IV) transplantation of umbilical cord-derived mesenchymal stem cells (UMSC01) for heart repair in patient with a ST-elevation myocardial infarction (STEMI) with impaired LVEF (30%–49%) following successful reperfusion by percutaneous coronary intervention. In the 6 subjects who completed the study, there were no treatment-related serious adverse events or major adverse cardiovascular events during infusion or follow-up. NT-proBNP levels and wall motion scores decreased, whereas the LVEF increased significantly at the 12-month follow-up compared to the baseline values. This pilot study showed that combined IC and IV transplantation in this patient population appears to be safe, feasible, and potentially beneficial in improving heart function. Phase 2 studies will be needed to further investigate the effectiveness of dual-route transplantation of UMSC01 in STEMI patients.In a phase 1, open-label, single-arm, first-in-human study, Bin He et al. the pathogenesis, immune-related pathways and important biomarkers involved in the progression of cardiomyopathy due to various etiologies were investigated. The authors reported that the hub genes  can be used as markers to distinguish patients with cardiomyopathy. Furthermore, the authors demonstrated that the innate immune response, either dysregulation/imbalance of innate immune cells or activation of adaptive immune responses, were involved in the progression of HF.In another interesting original research study by via an early increase in erythropoietin (EPO) production, which leads to a rise in hematocrit  were examined. RDW increased with time in patients who received dapagliflozin and this increase was mainly attributed to the induction of hemopoiesis from dapagliflozin. Interestingly, increased baseline, but not post-SGLT2 inhibitor therapy, RDW values were independently associated with poor outcomes in patients with HF and DM.Red blood cell distribution width (RDW) is a simple hematological parameter that reflects the heterogeneity of the red blood cell size (anisocytosis); higher levels of RDW have been associated with poor outcome in patients with HF , 9. Recematocrit . HoweverYing Gu et al. the feasibility and efficacy of LBBP in HF patients with a LVEF <50% and left bundle branch block (LBBB) was investigated; the study suggested that LBBP using a low and stable pacing threshold was feasible with a high successful implantation rate and was effective in correcting LBBB and improving LV structure and function.Left bundle branch pacing (LBBP) is emerging as an effective alternative to achieve cardiac resynchronization therapy (CRT) and improve heart function . In a reZhang Fang et al. aimed to evaluate the proper energy intake patterns and daily calorie intake in adult patients with HF in the United States of America. Among almost 1,000 participants, moderate malnutrition was more frequently related with mortality. Low-carbohydrate pattern (LCP) and median-carbohydrate pattern (MCP) diets had a lower risk of death as compared to a high-carbohydrate pattern (HCP) diet. There was no association between different amounts of calorie intake and all-cause mortality. Therefore, the relationship between energy intake and all-cause mortality may be influenced by energy intake patterns in HF patients.Finally, Novel and Emerging Therapies in Heart Failure will provide a meaningful contribution to the literature, will shed light to the understanding of HF, and will open new treatment pathways for the benefit of our patients.Research in HF is an exciting and continuous endeavour. The hope is that this special edition on