Myocardial infarction (MI), the blockage of arterial blood supply of the heart, is among the most common causes of death worldwide. Even when patients receive immediate treatment by re-opening blocked arteries, they often develop chronic heart failure (CHF) in the aftermath of MI events. Yet, the factors that contribute to the development of MI-associated CHF are poorly understood. In our recent study (Nat Commun 13:6394), we link intramyocardial hemorrhage, an injury which can occur during reperfusion of areas affected by MI, to an increased risk of CHF. Mechanistically, our data suggest that an iron-induced adverse cascade of events after hemorrhagic MI drives fatty degeneration of infarcted tissue, which ultimately contributes to negative cardiac remodeling. In this Microreview, we discuss the implications of our findings regarding the molecular mechanism, more targeted treatment options as well as perspectives in the clinical care of CHF after hemorrhagic MI. Acute myocardial infarction (AMI), from sudden obstruction of a coronary artery, afflicts approximately 1M people in the US yearly. Prompt restoration of blood flow through the epicardial arteries (reperfusion) has been a major advance, which has reduced immediate death from AMI. However, in the post-AMI period, adverse LV remodeling can result in chronic heart failure (CHF), or malignant ventricular arrhythmias can precipitate sudden cardiac arrest, both of which can increase morbidity and mortality.The incidence of post-MI CHF has increased in recent decades. In the US, ∼2.1M patients are affected, and >250,000 new cases are reported every year. According to the Centers for Disease Control, >300,000 deaths/yr. are due to CHF. The terminal recourse of these patients is heart transplantation, which is limited by donor hearts, eligibility, and cost.Fig. 1 shows a schematic of various MI types based on the “wave front hypothesis”. Notably, >60% of AMIs have late (persistent) microvascular obstruction (MVO) resulting in “no-reflow” (zone C), despite re-establishing flow in the culprit artery. MI size is an established independent predictor of major adverse cardiac events . With advances in imaging, particularly cardiac magnetic resonance imaging (CMR), late MVO has also emerged as a key risk factor for MACE. Hemorrhage is present in ∼75% of MIs with late MVO, conferring >50% increased risk for MACE over MIs with late MVO but no hemorrhage. Thus, hemorrhagic MIs (hMIs) present the greatest risk for MACE among all MI patients.Not all myocardial infarctions (MI) are the same. Currently available post-MI medications are not specific to patients with late MVO or hemorrhage and have not been beneficial to these patients over other MI types. Several mechanical/post-conditioning treatment options to reduce late MVO during reperfusion have been investigated but their benefit has not been consistent. Several pharmacological interventions at the time of reperfusion have also been investigated but none has been able to significantly reduce MACE. Moreover, late MVO limits the influx of inflammatory cells into the MI and thereby delays infarct healing in the sub-acute phase. But how this contributes to continuous infarct remodeling throughout the chronic period, especially after late MVO resolves, is unknown. Recent studies have shown that (i) hMIs lead to persistent iron deposition within MI, (ii) new macrophages are recruited to the site of iron, and (iii) iron within MI is an independent risk factor for adverse remodeling in the chronic period in animals and patients – providing a strong correlation among hMI, iron deposition, inflammation, and adverse remodeling. These findings support the notion that hemorrhage may be a key driver of myocardial damage in reperfused MIs; however, whether hemorrhage is causally linked to adverse remodeling was unknown until the recent publication which is incorporated herein by reference.We hypothesized that the iron from hemorrhagic MI drives fatty transformation of infarcted tissue from continuous iron-induced macrophage activation, lipid oxidation, foam cell formation, ceroid production, foam cell apoptosis and iron recycling, which progressively drives loss of cardiac function.Iron metabolism is tightly controlled and balanced by complex signaling networks. Macrophage, a key immune cell, plays critical role in iron homeostasis, and its regulatory mechanisms are increasingly recognized in cardiovascular disease. Dysregulation of intracellular iron metabolism in macrophages can lead to marked phenotypic and functional changes. These changes include the promotion of pro-inflammatory state, acceleration of lipid accumulation and differentiation into foam cell formation.Fig. 2).Our recent work shows that excessive iron from intramyocardial hemorrhage is a deleterious contributor to the development and progression of adverse outcomes following hMI. Excessive iron within the MI zone results in the oxidation of the lipids in the infarct zone and promotes the recruitment of unpolarized macrophages into the vicinity. The oxidized lipids and iron are taken up by the macrophages, which increase their polarization into a pro-inflammatory state through enhanced stimulation of cytokine release. The iron within macrophages become cytotoxic when the extent of iron reaches pathological level, polarizing the macrophages to a proinflammatory state. During the development and progression of this process, the pro-inflammatory macrophages are transformed into foam cells when the intracellular lipid content of macrophages exceeds their capacity to maintain lipid homeostasis. Excessive lipid influx via scavenger receptors occurs within the areas of hMI. These foam cells exhibit impaired immune function and contribute to the pathogenesis of lipomatous metaplasia by continually inducing inflammation, tissue damage and remodeling in the heart. These foam cells produce ceroids, destabilize lysosomes and eventually drive foam cell apoptosis. The remnants from foam-cell apoptosis (particularly the lipids and iron) are recycled back to enter a pathway which perpetuates inflammation, formation of foam cells and enlargement of the fat depot , -6 (IL-6), -8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), CC- and CXC- chemokines, or tumor necrosis factor-α (TNF-α) have had beneficial effects on cardiac function. However, neutral and detrimental results have also been reported for some anti-cytokine therapies of IL-1, IL-6, IL-8, and MCP-1. Human clinical studies are currently limited to IL-1 β inhibition, IL-1 receptor antagonists (IL-1RA), IL-6 receptor antagonists (IL-6RA) or TNF-α inhibition, but most prospective studies unfortunately have reported disappointing and inconsistent results. Moreover, a recent study has demonstrated that infiltration of intramyocardial fat within the scarred infraction zone can be a source of infarct-related ventricular arrhythmias (VT) in the chronic stage of MI. Previous studies have also shown that hMI patients may be at greater risk of developing malignant ventricular arrhythmias, which is a critical contributor to sudden cardiac arrest and sudden cardiac death in chronic MI patients. However, whether the initiation of VTs in hMI patients is a consequence of hemorrhage-related iron driving lipomatous metaplasia remains an open question.Oxidative stress has been identified to be a key mechanism of reperfusion injury. This led to anti-oxidant therapies to curb the damaging effects of oxidative stress in AMI, but the results have been mixed. Recent Trial to Assess Chelation Therapy (TACT) in post MI patients showed that 6 months of EDTA therapy starting 6-weeks post MI did not substantially decrease MACE. It is to be noted however that EDTA is (a) not specific for ferric iron and (b) cannot cross cell membranes. Further, hemorrhage-derived iron is intracellular and trivalent, and that TACT did not stratify patients for hMI.Prior studies evaluating iron-chelation therapy (ICT) in the post MI setting were limited to 1-2 days post MI with less than favorable outcomes. Notably, these studies did not (i) target hMI; (ii) adequately dose the subject; (iii) consider the size of the iron chelators; or (iv) confirm/quantify the clearance of iron from MI territories. ICTs are routinely used clinically to treat iron overload cardiomyopathies . Outside of systemic iron overload, ICTs are rapidly gaining importance for their capabilities to reduce infarct expansion in ischemic strokes, neurodegenerative decline, and relief from cerebral malaria. However, outside of our study and another study in a swine model, iron chelators have not targeted hMIs to prevent heart failure. Our findings reveal that hMI zone has an elevated and stable level of iron level across a 6-month period. Notably, we found that there is a significant positive correlation between iron accumulation in hMI and fat deposition throughout the chronic phase of MI, suggesting that iron concentration within the MI zone is a primary determinant contributing to the extent of fat deposition within the infarct territory. Our work also supports the notion that an alternative therapeutic approach, one that is based on reduction of iron within the hMI zone can be beneficial.3). Importantly, our findings redefine the conventional wisdom regarding pathogenesis of hemorrhagic MI, implicating excessive iron and the associated introduction of foam cell into the chronic phase of infarction as new and important players in the pathogenesis towards post-MI heart failure. We envision that this new knowledge will be an impetus for further studies on DFP as well as the development of novel, patient-specific therapeutic strategies that target iron and fat depot to better address adverse consequences associated with hMI.Our studies demonstrate that deferiprone (DFP), an FDA-approved iron chelator, when administered days after reperfusion, reduces iron towards baseline and lipomatous metaplasia within hemorrhagic MI territories, and mitigates adverse cardiac remodeling. Deferiprone is an intracellular and extracellular ferric iron chelator, which has a proven clinical track record for removing iron from cardiomyocytes for mitigating iron overload cardiotoxicity in thalassemia patients. Our preclinical trial showed that oral administration of DFP in the setting of reperfused hMI can also significantly reduce the hemorrhage-derived iron and halt the vicious cycle of iron-mediated cardiotoxicity. In our study, the oral administration of DFP for 8 weeks post MI showed favorable reduction in iron and fat content measured in kinematic fashion by cardiovascular magnetic resonance . In relation to the untreated group, DFP promoted positive LV remodeling as characterized by structural and functional parameters. Most notably DFP treatment improved LVEF by 36% as compared to untreated hMI subjects. Thus, an iron chelator such as DFP has the potential to limit or even regress the progression of adverse effects associated with hMI  for the treatment of hemorrhagic MI. The current study and larger-scale clinical trials are expected to provide evidence on prevention of adverse structural LV remodeling culminating in chronic heart failure secondary to hemorrhagic MIs.


Acute decompensation often represents the onset of symptoms associated with severe degenerative aortic stenosis (AS) and usually complicates the clinical course of the disease with a dismal impact on survival and quality of life. Several factors may derange the faint balance between left ventricular preload and afterload and precipitate the occurrence of symptoms and signs of acute heart failure (HF). A standardized approach for the management of this condition is currently lacking. Medical therapy finds very limited application in this setting, as drugs usually indicated for the control of acute HF might worsen hemodynamics in the presence of AS. Urgent aortic valve replacement is usually performed by transcatheter than surgical approach whereas, over the last decades, percutaneous balloon valvuloplasty gained renewed space as bridge to definitive therapy. This review focuses on the pathophysiological aspects of acute advanced AS and summarizes current evidence on its management. Degenerative aortic stenosis (AS) is the most frequent heart valve disease in industrialized countries with an increasing prevalence due to population aging . Over thThis review summarizes the main pathophysiologic concepts of acute advanced AS and provides an updated overview of the current available tools to manage this condition. For this purpose, we included evidence from randomized clinical trials, meta-analysis, and prospective or retrospective cohort studies, identified by a systematic search in PubMed, Medline, and Embase from each database inception to June 2022. Case reports and letters were excluded, as well as non-English literature.A standardized definition of acute advanced AS is currently lacking. Thus, ascertaining the actual prevalence of this condition is primarily challenged by the heterogeneity of clinical presentations reported across the studies. In addition, variability is also related to the type of analyzed cohorts that may include candidates to surgical aortic valve replacement (SAVR), percutaneous balloon aortic valvuloplasty (BAV) or TAVR. In most of cases, acute decompensation coincides with the need for unplanned hospitalization and/or urgent intervention and has been reported in up to 20% of patients with severe AS . Acute eMoreover, the spectrum of clinical presentation may also include patients with pre-shock or cardiogenic shock –15. ClinA low-flow, low-gradient severe AS may be observed in up to 10% of patients with severe AS. A low flow state may occur with reduced LVEF  or with preserved LVEF , and it is often associated with a low transvalvular gradient given that the gradient is highly flow dependent. The low-flow condition is predominantly a result of pronounced LV concentric remodeling with advanced diastolic dysfunction, impaired LV filling, and reduced longitudinal systolic function. Patients with severe LV dysfunction and low cardiac output usually present relatively low transvalvular gradients leading to an underestimation of AS severity. This scenario poses some challenges in the assessment of severity and management of valvular disease, especially in the acute setting. When applicable, multimodality imaging based on dobutamine stress echocardiography allows risk stratification and clinical decision-making in patients with low-flow AS. Also, valve calcium quantification by CT may be helpful for the management of these patients, especially in those with no LV flow reserve in whom dobutamine stress echocardiography is inconclusive.Symptoms onset in patients with AS largely depends on the structural and functional changes of the left ventricle (LV) as response to long-standing pressure overload. Concentric hypertrophy allows for the preservation of a normal cardiac output despite an increased wall stress; however, at longer term, increased myocyte volume and exaggerated extracellular matrix with development of both diffuse interstitial and focal replacement fibrosis, are responsible for progressive left and right ventricular dysfunction . During Treatment of advanced AS is challenging and burdened by high rates of early and late mortality . Time frDrug use in the setting of severe AS is hampered by the presence of a fixed afterload and the need for maintaining a constant preload. Administration of loop diuretics is the mainstay of therapy in the setting of acute HF. Their effect consists of improving fluid retention and mitigating pulmonary congestion; however, in patients with severe AS, this action is blunted by the relatively fixed outflow obstruction. Moreover, they cause an intravascular volume depletion that reduces preload and cardiac output causing arterial hypotension and peripheral hypoperfusion.Among other measures targeting fluid retention, tolvaptan, an oral selective V2 receptor antagonist, promoting free water excretion in the urine without affecting hemodynamics and renal function, proved safety and effectiveness in small pilot studies including subjects with acute advanced AS . VasodilNitroglycerin is generally contraindicated in patients with severe AS because of the associated risk of marked hypotension. This effect did not emerge from a retrospective comparison of patients with or without AS presenting with acute pulmonary edema and treated with sublingual or intravenous nitroglycerin . OverallVasopressors and inotropes improve tissue perfusion and are usually indicate in the setting of cardiogenic shock. However, in the context of AS, the conveyed risk of major arrythmias as well as the eventual worsening of myocardial ischemia because of increased myocardial oxygen consumption, should be taken into specific account. There is limited experience with the use of levosimendan, a calcium sensitizing agent with inotropic and vasodilator action that does not affect oxygen requirements. Its use was associated with improved hemodynamics and cardiac function among patients with acute HF and severe AS with reduced EF .Percutaneous BAV was first described by Cribier in 1986 as an alternative to SAVR in elderly and/or high-risk patients with symptomatic AS . Later, Unstable patients have been excluded from clinical studies investigating the role of TAVR. Nevertheless, since its introduction in the clinical practice, this procedure is being widely performed in urgent/emergency settings. To comprehensively evaluate evidence coming from studies published in this field, they can be grouped in 3 main categories: studies comparing urgent/emergent with elective TAVR; studies evaluating TAVR outcomes in patients presenting with acute HF or acute advanced AS; studies assessing TAVR in the context of cardiogenic shock. The main clinical and procedural characteristics of analyzed patients are reported in Table Studies focusing on clinical presentation rather than urgency of the procedure also provided inconsistent results. Acceptable rates of in-hospital and 1-year death were reported among 76 patients with acute advanced AS undergoing transfemoral TAVR . In a muIn the absence of standardized protocols, the therapeutic strategy for patients presenting with acute advanced AS is now chosen based on local facilities and expertise with some centers pursuing hemodynamic stabilization by identification and control of precipitating factors and others opting for percutaneous BAV or urgent valve replacement. Nevertheless, based on available evidence, the following algorithm could be recommended Fig. .Fig. 1MaInitial evaluation should take into account respiratory status and drugs type and administration route at home, besides clinical history and risk factors. Prompt identification of new-onset rhythm disorders by standard 12-lead electrocardiogram is pivotal to target eventual triggers of decompensation. Echocardiography (even by point of care ultrasound), routine laboratory values, and eventual X-ray readily inform about LV function, filling pressures, pulmonary congestion, anemia, acute renal failure, and electrolytic imbalances, infections. The main goals at this stage are avoiding tachycardia, optimizing preload, and maintaining an adequate blood pressure. Resuscitation maneuvers, antiarrhythmic drugs, and ventilatory support might be needed. Intubation should be avoided, if possible, as it can aggravate hypotension. Diuretics can be used in case of volume overload (B-lines or signs of congestion), keeping in mind the need to avoid hypotension because of the close dependence of these patients from preload. Based on clinical and hemodynamic status at presentation as well as on the response to initial stabilization maneuvers, the definitive intervention can be classified either as emergent  or urgent . Treatment modality should be ideally discussed within the local heart team.Concomitant coronary artery disease should also be considered before any therapeutic action on the valve, as it may impact procedural risk and patient prognosis . In the In this setting, usually, acceptable control of symptoms and hemodynamic stabilization can be achieved by medical therapy. In addition, percutaneous BAV is a reasonable option as bridge to valve replacement. It allows for a rapid relief of pressure overload that can have a dramatic impact on symptoms and hemodynamics and allows for a more accurate evaluation of the proper modality for valve replacement. BAV can be performed as palliative measure when general conditions prohibit any further intervention. Valve replacement by TAVR or SAVR should be then performed in the same hospitalization to minimize the risk of recurrences of severe symptoms.Emergency is usually dictated by refractory or unmanageable HF with hemodynamic instability. A tailored approach is needed as the decision to intervene is also based on life expectancy, age, and comorbidities. Overall, in the acute scenario, TAVR should be preferred over SAVR because of its less invasiveness. In these cases, preprocedural assessment of valve anatomy for the prosthesis choice can be based on transesophageal echocardiography in place of CT-scan; prosthesis size selection can also be performed by BAV. Along the same line, suitability of femoral access can be assessed by ultrasound. Procedure should be carried out according to standard local protocol and all measures to minimize further hemodynamic instability or complications should be adopted. Specifically, in this setting, particular attention should be paid to avoid or shorten rapid pacing, to optimize valve positioning, minimize the risk of residual paravalvular leak and to ensure adequate hemostasis of vascular access. Careful monitoring of vital parameters and renal function in intensive care unit is recommended for at least 24–48 h thereafter.In patients presenting with cardiogenic shock, extreme caution is needed when selecting the appropriate drugs. Fluid management is very challenging as patients may present with pulmonary congestion but are closely dependent from preload to maintain cardiac output and could not tolerate the volume depletion induced by diuretics. Extreme cases may require crystalloid infusion with continuous monitoring of volume status, particularly, to face the hypotension that can derive from intubation. Among vasopressors, phenylephrine  increases diastolic blood pressure and maintains adequate coronary perfusion pressure; it can also cause reflex bradycardia with favorable impact on diastolic filling. Norepinephrine is a valid alternative. Epinephrine, on the contrary, should not be considered owing to its marked chronotropic effect that increases myocardial oxygen consumption. Low-dose inotropes are also useful, particularly in patients with low flow low gradient AS. Overall, catecholamines and inotropes should be given at the lowest dose and for limited duration.Despite limited evidence supporting their use, escalation to devices for mechanical circulatory support (MCS) can be considered in cases of refractory shock. The purpose of MCS, such as intra-aortic balloon pump (IABP), Impella system , TandemHeart device  and Extra-Corporeal Membrane Oxygenation (ECMO), is to reduce LV work and myocardial oxygen demand while maintaining systemic and coronary perfusion, supporting a rapid hemodynamic stabilization. Several technical aspects must be considered when choosing a MCS device such as indications, access site, concomitant valvular disease, and operator experience . SpecifiThe majority of rehospitalizations for cardiovascular causes within the first year after TAVR occur because of HF , 53. PreMultiple factors can precipitate acute decompensation in patients with severe AS. They represent an extremely high-risk population, with poor prognosis in the absence of a definitive treatment. The use of medical therapy is narrowed by an unfavorable risk to benefit ratio of drugs that can worsen hemodynamics of severe AS. Urgent SAVR is rarely performed because of the prohibitive operative risk. Among transcatheter-based therapies, BAV can palliate symptoms but should be considered as a temporary measure owing to the high rates of failure occurring at early and mid-term while TAVR is consolidating its role as effective and safe stand-alone option in this setting. Technical improvements are expected to further expand the use of TAVR in acute advanced AS. However, continuous efforts should converge on the identification of actions that can minimize the occurrence of critical clinical situations requiring urgent intervention. In this perspective, anticipating the treatment of AS prior to symptoms onset and at earlier stages of cardiac damage seems the way ahead.


We then characterized LV phenotypes using upset plots, ventricular interactions using network analysis, and longitudinal analysis in a representative cohort of 45 patients. We also measured LV metrics in mice subjected to pulmonary arterial banding (PAB) using a 7 T magnetic resonance imaging at baseline, Week 1, and Week 7 post‐PAB (N = 9). Patients with PAH had significantly reduced absolute LVLS , higher sTS  and lower LVLS/sTS  compared to controls. Reduced LVLS/sTS was observed in 89.5% of patients, while diastolic dysfunction, impaired LVLS (<16%), and LV atrophy were observed in 73.7%, 52.6%, and 15.8%, respectively. In the longitudinal cohort, changes in LVLS/sTS were closely associated with changes in N‐terminal pro B‐type natriuretic peptide  as well as survival. Mice subjected to PAB showed significant RV systolic dysfunction and decreased LVLS/sTS compared to sham animals. We conclude that in PAH, LVLV/sTS is a simple ratio that can reflect ventricular systolic interactions.Ventricular interdependence plays an important role in pulmonary arterial hypertension (PAH). It can decrease left ventricular (LV) longitudinal strain (LVLS) and lead to a leftward displacement (“transverse shortening”) of the interventricular septum (sTS). For this study, we hypothesized the ratio of LVLS/sTS would be a sensitive marker of systolic ventricular interactions in PAH. In a cross‐sectional cohort of patients with PAH ( Pulmonary arterial hypertension (PAH) affects the pulmonary vasculature and often leads to right heart failure and premature death.With the development of ventricular strain imaging, there is a growing interest to assess subclinical ventricular dysfunction in PAH.Because LV longitudinal motion is impaired while transverse septal motion is accentuated in PAH, we hypothesized that the ratio of LVLS to septal transverse “shortening” or displacement (sTS) could be a sensitive marker of mechanical changes in PAH Figure . The firThis study was approved by the Stanford University Institutional Review Board  and all patients gave written informed consent. Patient cohorts from Stanford Adult Pulmonary Hypertension Program and Vera Moulton Wall Center for Pulmonary Vascular Disease DataBaseL0) was measured in end‐diastole and final length (L1) in end‐systole. LVLS was calculated as 100 × (L0− L1)/L0  to measure regional LS and TS. CPA generates time‐series curves of regional LS and transverse displacement, as well as LV volume as detailed in the Supporting Information: Methods. Although CPA also generated LVLS curves and peak LVLS was available, the semiautomated feature tracking was considered suboptimal in seven cases in controls and nine cases in patients with PAH due to suboptimal tracking. In cases where tracking was considered of good quality for analysis, we found a consistent correlation between manually traced Lagrangian strain and LVLS measured with semiautomated feature tracking  underwent surgery of PAB around a 25‐G needle as previously described.All animal experiments were performed in accordance with the Guide for Care and Use of Laboratory Animals  and approved by the Administrative Panel on Laboratory Animal Care at Stanford University (Protocol #27626). C57BL6/J mice (JAX 000664) were purchased from the Jackson Laboratory. Male C57ML6/J mice . LVEF and right ventricular ejection fraction (RVEF) were measured using the modified Simpson's method. LVLS and TS were measured as described above.Cardiac MRI in mice was performed with a 7 T magnetic resonance system (Bruker) in a supine position under continuous isoflurane anesthesia (1%–2%). The dose of isoflurane was adjusted to target the respiratory rate of 50–60 breaths/min. All measurements were done using Horos software . For the comparison of unpaired two groups, unpaired two‐tailed Student's Pairwise relationships between variables were summarized using heatmaps and network correlation graphs. The correlations were calculated with the corr method of pandas (version 1.4.3).2, and a cardiac index of 2.01  mL/m2.The baseline characteristics are summarized in Table p < 0.0001), sTS , and reduced absolute LVLS  and MAPSE   Figure . Accordi) Figure . All of ) Figure . Figure p < 0.0001), whereas mid‐septal TS was significantly higher . Mid‐lateral TS between PAH and control cases were not significantly different , whereas no delay was observed in mid‐septal LS , followed by diastolic dysfunction (73.7%), impaired LVLS (52.6%), and LV atrophy (15.8%) as shown in Figure r = 0.53, p < 0.001), between RVLS and MAPSE  or LVLS , and between PVRI and RVLS . In contrast, among LV parameters, the correlation between sTS and LVLS  or MAPSE , as well as between LVEF and LVLS  or MAPSE  were weaker  or PCWP . In addition, pericardial effusion, a known predictor of mortality in PAH, was also found to be inversely related to stroke volume index .The LV abnormalities in PAH were not independent of RV function and hemodynamics. The correlation maps in Figure p = 0.036; Supporting Information: Table We selected three groups of representative samples who had NT‐proBNP and echocardiography within a 1–2‐week period in stable clinical conditions. The baseline NT‐proBNP levels were significantly higher in the improved group compared to the worsened group (p = 0.0009), LVLS (p = 0.0004), and LVLS/sTS (p < 0.0001), whereas the worsened group showed a decrease in all parameters , LVLS (p = 0.80), and LVLS/sTS (p = 0.33) on paired analysis.When categorizing the patients according to the longitudinal NT‐proBNP group, the improved group showed a significant improvement in TAPSE , LVLS , and LVLS/sTS    was moderately associated with changes of TAPSE (p = 0.004) as well as a higher longitudinal increase in TAPSE  and LVLS/sTS .At 5 years, the combined outcome (death or transplantation) occurred in 19 patients (42%). A higher increase in NT‐proBNP over time was related to a higher risk for an outcome . RVEF and TAPSE were significantly decreased at 1‐week post‐PAB and remained impaired until week 7 Figure . LVEF diIn our study, we showed that the ratio of LVLS/sTS provides novel insights into systolic ventricular interdependence in PAH. The LVLS/sTS ratio emerged as a sensitive marker of LV dysfunction in PAH, reflecting both delayed septal displacement and interdependence in the annular excursion. Our longitudinal analysis further demonstrated the extent of ventricular interdependence in PAH as changes in LVLS/sTS were closely related to changes in TAPSE and NT‐proBNP. Finally, we demonstrated that similar findings of LV mechanics could be recapitulated in a mouse model of RV pressure overload.E/A ratioVentricular interdependence plays a central role in PAH. In 1967, Tayler et al.In our study, we introduce a novel index of mechanical shortening that captures both annular interdependence and late systolic septal displacement. Several mechanistic studies have in fact documented the prolonged contraction of the RV that occurs with pressure overload leading to a late systolic shift.E/e′  and all patients gave written informed consent.Supporting information.Click here for additional data file.


The current standard of care for pediatric patients with unrepairable congenital valvular disease is a heart valve implant. However, current heart valve implants are unable to accommodate the somatic growth of the recipient, preventing long-term clinical success in these patients. Therefore, there is an urgent need for a growing heart valve implant for children. This article reviews recent studies investigating tissue-engineered heart valves and partial heart transplantation as potential growing heart valve implants in large animal and clinical translational research. In vitro and in situ designs of tissue engineered heart valves are discussed, as well as the barriers to clinical translation. Congenital heart disease (CHD) is one of the most commonly diagnosed congenital diseases in newborns . In the The most significant drawback to current valve replacement options is the inability of the implant to accommodate the somatic growth of the recipient. The currently available replacement strategies have a fixed functional diameter and ultimately result in acquired patient-prosthesis mismatch . This reTherefore, there is an urgent need for a heart valve implant that grows with the recipient, along with other essential characteristics, including non-thrombogenic, nonobstructive, and able to undergo remodeling to repair injury and maintain function ,15. MostAll currently available heart valve implants have limitations preventing long-term clinical success in pediatric patients. Mechanical heart valves are durable in vivo, but their thrombogenicity requires lifelong anticoagulation . The risThe current heart valve implants available for neonates are exclusively homografts because mechanical and bioprosthetic valves are not small enough for the patient population. To make the homografts widely available for use, frozen cryopreserved homografts are banked and stored below −135 °C in vapor-phase nitrogen . Small aOrthotopic heart transplants provide another treatment option for children with valvular disease. Although immune suppression is required, heart transplants accommodate the somatic growth of the recipient ,48. The The treatment of heart valve dysfunction in neonates and infants remains an unsolved problem. There is an urgent clinical need for growing heart valves for pediatric patients; however, all attempts at creating a growing heart valve implant have failed in clinical translation. Tissue engineering has been at the forefront of research for creating the ideal heart valve replacement. The basic concept is to create a functionally viable tissue that resembles the native valve and is capable of growth, remodeling, and repair. This requires a 3D scaffold, cells to seed the scaffold, and appropriate biomolecules or bioreactors to allow the proliferation of these cells onto the scaffold . This haCells populating heart valves play an important role in maintaining long-term durability by remodeling the extracellular matrix to repair damage caused by the repetitive stress and movement of the leaflets. Cell sources for TEHV can be xenogenic, allogenic, or autologous. The optimal cell source for clinically translational TEHV is autologous rather than the immunogenic xenograft and allograft . Early sFurther research has been conducted testing autologous stem cells as a viable alternative cell population for tissue engineering. Non-hematopoietic bone marrow-derived cells, mesenchymal cells, amniotic fluid cells, umbilical cord cells, and induced pluripotent stem cells (iPSCs) have been considered for study ,55. HoweAnother important consideration when designing TEHVs is the scaffold. Scaffolds provide a 3D support platform for cell adhesion, growth, and tissue formation . They caDecellularized scaffolds made from decellularized xenogenic or allogenic valve tissue are repopulated by autologous cells in vivo. These scaffolds provide maintained tissue morphology, mechanics, and leaflet size as well as non-immunogenicity . HoweverMany studies have attempted to create heart valves via in vitro heart tissue engineering. This method involves harvesting autologous cells from the patient, seeding 3D scaffolds in vitro, allowing tissue growth in vitro, and the implantation of the tissue into the patient a. The usFor example, large animal studies were conducted using harvested autologous vascular cells seeded onto a bio-polyester scaffold. After 17 weeks in vivo, the valves exhibited normal native valve function. However, the valves showed incomplete endothelial cell seeding, and there was inconclusive evidence of the overall cell growth of the valve . AnotherAnother heavily studied method of cell seeding is the concept of in situ engineering b,c. ThisThe use of decellularized, in vitro scaffolds for in situ TEHV b provideThe second in situ approach involves the use of bioresorbable polymeric scaffolds. These provide more affordable and readily available options for clinical use . Pre-cliTo date, the majority of TEHV tested in pediatric patients have consisted of in situ TEHV designs. A successfully growing TEHV was implanted in two pediatric human patients (ages 11 and 13 years) in 2002. The valves consisted of a decellularized human pulmonary valve allograft reseeded with autologous endothelial progenitor cells. After surgical implantation, the implanted valves demonstrated mild pulmonary regurgitation. However, 3.5 years later, echocardiography of the TEHVs revealed decreased regurgitation and no evidence of valve degeneration. Additionally, the valve annulus diameter increased, indicating somatic growth along with the children .Decellularized xenografts implanted in the pulmonary position have failed rapidly in pediatric patients ,29,30. IThere is limited clinical data involving pediatric patients and the implantation of decellularized allografts in the aortic position. The first clinical study involving pediatric patients under 10 years old was published in 2016 by Tudorache et al . An averA clinical trial completed in 2021 provided the first human trial of a bioresorbable pulmonary valve conduit in pediatric patients. The Xeltis pulmonary valve conduit is an electrospun polymeric heart valve composed mainly of bioresorbable supramolecular 2-ureido-4[1H]-pyrimidone. Twelve pediatric patients underwent transplantation and were followed for up to 24 months. The results of this study demonstrated no evidence of stenosis or valve degeneration with clinical improvement in all patients. However, these patients developed moderate to severe pulmonary regurgitation over time. Additionally, follow-up was not long enough to prove somatic growth of the valve with the recipient. Researchers are now testing a new design to address the challenge of regurgitation , but to A new approach to provide a solution for growing pediatric heart valve replacements is partial heart transplantation (PHT). This approach involves transplanting only the root of the heart valve from a donor heart . The traInitial studies published on cold ischemia time of heart valve transplants revealed cellular viability within 48 h of cold storage versus conventional heart transplant with limited cold storage time of up to 6 h. This offers an increased procurement radius for partial heart transplants . AdditioResearchers have published a clinical trial protocol for a prospective single-arm pilot trial to determine the feasibility and safety of PHT as well as analysis of valve annulus growth and evidence of valve regurgitation or stenosis. This trial will be performed on infants and children less than 2 years old in need of semilunar heart valve transplant .In conclusion, a major gap in the treatment of pediatric patients with congenital valvular disease is a heart valve replacement that undergoes somatic growth with the recipient, is non-thrombogenic, nonimmunogenic, and maintains normal valvular function. Tissue-engineered heart valves have been studied extensively in order to provide a solution to this need; however, no tissue-engineered heart valves have succeeded in clinical translation. In vitro tissue-engineered valves have deteriorated in preclinical studies due to valve insufficiency ,17,18,19


Right ventricular function strongly predicts cardiac death and adverse cardiac events in patients with cardiac diseases. However, the accurate right ventricular assessment by two-dimensional echocardiography is limited due to its complex anatomy, shape, and load dependence. Advances in cardiac imaging and three-dimensional echocardiography provided more reliable information on right ventricular volumes and function without geometrical assumptions. Furthermore, the pathophysiology of right ventricular dysfunction and tricuspid regurgitation is frequently connected. Three-dimensional echocardiography allows a more in-depth structural and functional evaluation of the tricuspid valve. Understanding the anatomy and pathophysiology of the right side of the heart may help in diagnosing and managing the disease by using reliable imaging tools. The present review describes the challenging echocardiographic assessment of the right ventricle and tricuspid valve apparatus in clinical practice with a focus on three-dimensional echocardiography. Right ventricular (RV) dysfunction is associated with the worse outcome of several cardiac diseases including heart failure, cardiomyopathies, right ventricular myocardial infarction, congenital heart diseases, pulmonary arterial hypertension, and valvular heart diseases ,7,8,9,10Understanding the anatomy and pathophysiology of the right side of the heart by using competent imaging tools may help in diagnosing and managing the disease ,19. KnowThis review aimed to provide a short overview of the right ventricular and tricuspid valve anatomy, pathophysiology, and 2D/3D echocardiography assessment to demonstrate in detail the added value of 3D echocardiography using the latest published data besides the state-of-the-art literature.The anatomical structure of the right ventricle is complex ,20,21. TThe right ventricle and tricuspid valve are tightly related because the tricuspid annulus is functionally a part of the right ventricle . The anaRight ventricular dysfunction is the consequence of RV pressure overload, volume overload, or impaired myocardial contractility . The RV Acute right heart failure is mainly a result of acute pressure overload  or acute impairment of myocardial contractility  ,29,30. APulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) increase slowly in chronic pressure overload, and consequently the stimulated myocytes lead to adaptive hypertrophy to preserve cardiac output . PulmonaChronic RV volume overload develops mainly in TR, pulmonary regurgitation, and left-to right congenital shunts such as atrial septal defects (ASD) ,40,41. TThe etiology of intrinsic RV myocardial disease involves myocardial ischemia, myocarditis, cardiotoxicity, arrhythmogenic RV cardiomyopathy (ARVC), hypertrophic cardiomyopathy, amyloidosis, and sarcoidosis . IsolateThe routine imaging method of the right ventricle in daily clinical practice is 2D echocardiography. However, due to the complex geometry of RV, many of the 2D parameters are inaccurate, with inherent limitations . Consequ2) [2, measured by 2D echocardiography [The anterior localization of the tricuspid annulus in the mediastinum makes its visualization acceptable by transthoracic echocardiography. The tricuspid annulus consists of fibrous tissue, which is sensitive to preload, afterload, and right ventricular and atrial dilatation ,27. The 2) . The sha2) . The tri2) ,75,76. Tiography ,75,76. Hiography . Furtheriography . Notablyiography . The comiography . Nonetheiography .The complex geometry of the right ventricle with the inflow and outflow segments in different planes made 2D echocardiography inaccurate by relying on geometrical assumption. Advances in 3D echocardiography imaging made RV and tricuspid valve assessment more detailed and comprehensive, which has been validated against CMR ,80,81,822) for men and 37 mm (23 mm/m2) for women by 3D echocardiography [2) for men and 43 mm (26 mm/m2) for women [2 to 75 mm2 [Measurement of tricuspid annulus diameter by 2D echocardiography from apical four-chamber view represents only the mediolateral size, which does not usually reflect the tricuspid annulus size with its complex geometry accurately ,93. In mor women . Earliero 75 mm2 ,95,96. To 75 mm2 . The diso 75 mm2 ,98. The o 75 mm2 . Utsunomo 75 mm2  found ino 75 mm2 ,46,47.The prognostic value of 3D echocardiography-derived RVEF was proved to be superior to conventional RV echocardiographic parameters for predicting mortality ,86. NagaIt is known that patients with PH have enlarged RV volumes, decreased RV EF, and strain values ,101,102.Pulmonary hypertension and right ventricular dysfunction often lead to functional tricuspid regurgitation and consequent volume overload ,108. AdvTwo-dimensional echocardiography-derived vena contracta diameter, PISA-derived EROA, and 3D-echocardiography-derived vena contracta area can be used to quantify the recently proposed severe, massive, and torrential grades of TR, respectively ,110,111.Accurate assessment of RV function is important in patients with acute myocardial infarction. Kidawa and coworkers  demonstrAnthracyclines have been reported as potential dose-dependent, irreversible cardiotoxic drugs to treat cancer, leading to chemotherapy-related cardiac dysfunction (CTRCD) ,127. ZhaThree-dimensional echocardiography opens future directions in right ventricular assessment, including RV shape analysis, RV segmental analysis, RV strain, and myocardial work analysis. The three-dimensional global RV function is determined by longitudinal, radial, and anteroposterior motion components; however, the relative contributions of these motion components are usually not quantified . PreviouSimilar to the left ventricular segmental analysis, a more detailed segmental RV mechanical pattern analysis might enable the detection of subtle segmental dysfunction and improve our diagnostic knowledge of RV pathology . Ishizu Despite the prognostic value of RV longitudinal strain, it is a more afterload-dependent parameter compared to LV global longitudinal strain ,137. RigThe prognostic implications of RV function and TR severity emphasize the need for accurate assessment. Three-dimensional echocardiography is essential for the precise evaluation of RV and TV anatomy and function . Despite


Although hemodynamic alterations in end-stage liver disease (ESLD) and its association with porto-pulmonary hypertension have been well-established, the long-term effects of ESLD on RV systolic function in patients without porto-pulmonary hypertension remain disregarded. Here we aimed to assess the long-term effect of ESLD on RV function and its relationship with the use of NSBBs and clinical, laboratory and imaging parameters in end-stage liver disease. The use of NSBBs is still controversial due to concerns about reduced cardiac contractility and the possibility of increased mortality. Thirty-four liver transplant recipients were included. Demographic characteristics, laboratory and baseline echocardiography measures were obtained. Patients were recalled for transthoracic echocardiographic evaluation after transplantation. Right ventricle dysfunction was identified by having at least one value below the reference levels of RV S’, or TAPSE. Isolated subclinical RV dysfunction was observed at 20.6% of the sample population. The present study demonstrates hemodynamic circulation in cirrhosis and increased preload and afterload might have long-term effects on RV function, even the lack of porto-pulmonary hypertension. These findings underline the significance of cardiac function follow-up in cirrhotic patients after transplantation. In this study, patients treated with propranolol seemed to have better RV function and less gastrointestinal bleeding. We speculated that preoperative propranolol treatment might help preserve RV function by providing RAS suppression, improving endothelial function and hyperdynamic circulation seen in ESLD. This potential protective relationship between the use of propranolol and RV function might improve mortality or graft-failure during OLT and after liver transplantation in patients with cirrhosis. End-stage liver disease (ESLD) affects the pulmonary and cardiac structure and function through several mechanisms. Although the exact mechanism is not clear yet, several hypotheses including hyperdynamic circulation, excess production and impaired clearance of vasoactive substances, portosystemic shunt and genetic predisposition are considered to have a role in this multisystemic effect ,2,3. HypNon-selective beta blockers (NSBBs) are recommended for the primary and secondary prevention of variceal bleeding in patients with cirrhosis ,11,12,13Two-dimensional (2D) transthoracic echocardiography is a routine examination for the assessment of porto-pulmonary hypertension , RV/LV sThe analysis was performed on consecutive adult ESLD patients (age > 18 years) who underwent their first liver transplantation at Medipol University from June 2014 to September 2019. At our institution, echocardiography is a standard of care for all OLT candidates. Orthotopic liver transplantation candidates who had significant left heart disease, severe chronic pulmonary disease, any identified previous episode of pulmonary embolism, hepatocellular carcinoma as the etiology for transplant, <6 months between transplant and echocardiographic follow-up or the absence of critical retrospective data were excluded. Demographic and baseline clinical features at the time of surgery were noted. Preoperative laboratory work-up, estimated systolic pulmonary arterial pressure (sPAP) value at preoperative cardiology consultation and post-transplantation early hepatic and portal venous duplex ultrasound findings were recorded. Patients were recalled for follow-up echocardiographic examination.The study was approved by the Institutional Ethics Review Committee of Medipol University (299/20 and 16 April 2020).Echocardiography was performed using a commercially available echocardiography system ) and the obtained images were digitally stored in cine-loop format. The EchoPAC system was used for offline analysis . The standard biplane Simpson method was used to calculate the left ventricular ejection fraction (LVEF) . Pulsed-p ≤ 0.05 was interpreted as statistically significant. Statistical analyses were carried out by using SPSS .The data were presented as mean ± standard deviation and median (range) for continuous variables and percentage for categorical variables. Shapiro–Wilk test was used to determine whether a continuous variable followed normal distribution or not. To discriminate the patients with and without right ventricular dysfunction, Student’s t and Mann–Whitney U tests were utilized for comparing the variables showing normal and non-normal distribution, respectively. The frequencies of categorical variables were distinguished by the chi-square test. Two-sided A total of 56 liver transplant recipients who had the complete baseline dataset were assessed for recruitment. Seven patients were excluded due to confounding medical conditions as described above . Of the remaining 49 recipients, 15 individuals were lost to follow-up.n = 7) of the sample population. Patients were then grouped according to the presence of isolated RV dysfunction Ultimately, 34 patients (mean age 54.1 ± 8.7) constituted the sample population. Follow-up echocardiography was performed after a mean duration of 18 ± 6 months following OLT. At the follow-up visit, right ventricular dysfunction (RVD) was identified as the measurement of TAPSE and/or peak Doppler annular velocity (RVSm) below the reference values  suggested in the relevant position paper . IsolateThe choice of non-selective beta blocker was propranolol, as nadolol is non-available in Turkey. Patients who used selective beta-blocking agents due to coronary artery disease and hypertension and did not use propranolol seemed to have higher rates of isolated RV dysfunction (RVD) .Preoperative laboratory test variables between the two groups including estimated glomerular filtration rate (eGFR), albumin, INR, ALT, GGT, hemoglobin, platelet count, CRP and pro-BNP were similar . In addiA comparison of echocardiographic parameters in the two groups is shown in In this study, we demonstrated that ESLD has long-term effects on RV function. To the best of our knowledge, this is the first study describing the term “Isolated subclinical right ventricular dysfunction” after orthotopic liver Tx. It is noted that increased preload and afterload in ESLD have an impact on RV function even in the absence of porto-pulmonary hypertension. This study underlines the importance of the long-term follow-up of cardiac functions in patients with cirrhosis. In addition, we also noted that preoperative treatment with propranolol might help preserve RV function. There might be a potential protective relationship between the use of propranolol and RV function in patients with cirrhosis. This finding can be explained by the beneficial effects of PPL in endothelial function, RAS suppression and hyperdynamic circulation that might promote RV function during long-term follow-up in patients with ESLD. Moreover, the patients treated with non-selective beta-blockers had less gastrointestinal bleeding than those who did not use propranolol. This finding agrees with the previous studies, as propranolol is considered effective in the primary and secondary prevention of variceal bleeding.The clinical importance of subclinical RV dysfunction and its association with adverse clinical outcomes has been investigated in different clinical scenarios ,29,30,31Other studies have evaluated RV function in ESLD patients while awaiting and during transplants ,33,34. ANon-selective beta blocker agents, mostly propranolol (PPL), are used for the primary and secondary prophylaxis of acute and chronic gastrointestinal (GI) bleeding caused by esophageal varices in patients with cirrhosis. Carvedilol, nebivolol and nadolol are alternative agents ,37. PropBesides the beneficial effects of propranolol in reducing hepatic vein pressure gradient (HVPG), it has been reported in some studies that propranolol might alleviate inflammatory response, reduce bacterial translocation, improve endothelial function, reduce the angiotensin levels in the portal vein and peripheral vasculature ,42,43,44On the contrary, a study investigated increased mortality with NSBBs in patients with refractory ascites and cirrhosis . This siSome limitations should be acknowledged, such as the single-center nature of the study, the selection biases of a retrospective study and sample size. Moreover, only 2D echocardiographic parameters were assessed for the evaluation of RV function. Strain imaging and novel 3-dimensional echocardiography are preferred to support the present study’s findings.To the best of our knowledge, this is the first study describing the term “Isolated subclinical right ventricular dysfunction” after orthotopic liver Tx. We hypothesized that the impact of propranolol on RAS suppression, hemodynamic circulation and endothelial function might help preserve RV function during long-term follow-up via a more prominent reduction in hepatic venous gradient at the preoperative stage. This potential protective relationship between the use of propranolol and RV function in patients with cirrhosis might improve mortality or graft-failure after liver transplantation. However, future studies with more robust designs are necessary to verify this association and the hypothesis should be supported by evidence obtained via biochemical work-up.


Risk stratification of patients with ischemic heart disease (IHD) still depends mainly on the left ventricular ejection fraction (LVEF). LV inward displacement (InD) is a novel parameter of LV systolic function, derived from feature tracking cardiac magnetic resonance (CMR) imaging. We aimed to investigate the prognostic impact of InD in patients with IHD and prior myocardial infarction. A total of 111 patients  with a history of myocardial infarction who underwent CMR were included. LV InD was quantified by measuring the displacement of endocardially tracked points towards the centreline of the LV during systole with feature tracking CMR. The endpoint was a composite of all-cause mortality, heart failure hospitalization and arrhythmic events. During a median follow-up of 142 (IQR 107–159) months, 31 (27.9%) combined events occurred. Kaplan-Meier analysis demonstrated that patients with LV InD below the study population median value (23.0%) had a significantly lower event-free survival (P < 0.001). LV InD remained independently associated with outcomes  on multivariate Cox regression analysis. InD also provided incremental prognostic value to LVEF, LV global radial strain and CMR scar burden. LV InD, measured with feature tracking CMR, was independently associated with outcomes in patients with IHD and prior myocardial infarction. LV InD also provided incremental prognostic value, in addition to LVEF and LV global radial strain. LV InD holds promise as a pragmatic imaging biomarker for post-infarct risk stratification. Despite a decrease in age-standardized mortality rates for cardiovascular death over recent decades, ischemic heart disease (IHD) remains a leading cause of death worldwide , 2. LeftPatients with previous myocardial infarction who underwent clinically indicated late gadolinium contrast-enhanced (LGE)-CMR between 2004 and 2017 were evaluated retrospectively. Individuals who underwent LGE-CMR within 30 days of myocardial infarction or previous surgical LV reconstruction were excluded from the analysis. Baseline demographic and clinical data were collected from the electronic medical record system of the cardiology department . Cardiovascular medications were optimized according to contemporary guidelines and titrated at the discretion of the treating physician . CardiacCMR was performed on a 1.5-T Gyroscan ACS-NT/Intera MR system or on a 3.0-T Ingenia MR system  using retrospective gating. Cine steady-state free precession (SSFP) CMR images were acquired in the long  and short axes of the LV. LGE-CMR images were acquired 15 min after bolus injection of gadolinium diethylenetriamine pentaacetic acid  (0.15 mmol/kg) with an inversion recovery, three-dimensional, turbo-field echo sequence with parallel imaging. The heart was imaged in one or two breath-holds with short-axis slices at various levels, depending on the size of the heart , 20.CMR data analysis was performed offline using Medis Suite software . LV endocardial and epicardial contours were drawn automatically using the AutoQ function on both short-axis and long-axis cine images. Subsequently, LV contours were automatically propagated in all frames throughout the entire cardiac cycle. Papillary muscles were considered part of the LV cavity, and epicardial adipose tissue was excluded from the region of interest. In case of inadequate automated tracing, the endocardial border was manually adjusted. LV end-diastolic volume, LV end-systolic volume, and LVEF were calculated from short axis reconstructions . LVGRS was calculated from short axis views and LVGLS was calculated from the long-axis views  with commercially-available software  utilizing FT-CMR. LV InD was quantified by measuring the displacement of  tracked endocardial points towards the centerline of the LV during systole from long-axis images . The centerline was located along the LV long axis with a position that varied between one-half and two-thirds of the base-apex distance and was determined automatically by the software  was assessed on the basis of signal intensity (SI) . The myoThe study endpoint was a composite of all-cause mortality, heart failure hospitalization and arrhythmic events. Data on mortality and heart failure hospitalization were obtained from the departmental cardiology information system  which is linked to the governmental death registry database. Arrhythmic events were defined as documented ventricular fibrillation, sustained ventricular tachycardia lasting > 30 s, appropriate ICD therapy or resuscitation after cardiac arrest. The occurrence of ICD therapy was assessed by device interrogation.t-test for continuous variables with a normal distribution, or the Mann-Whitney U-test for non-normally distributed continuous variables, whereas categorical variables were compared using the Pearson chi-square test or Fisher’s exact test, as appropriate. Kaplan-Meier survival analysis was used to estimate the event-free survival rate for the composite endpoint. Bivariate and multivariate Cox regression analyses were performed to evaluate the association between baseline variables and the composite endpoint. Significant variables on bivariate analysis  were included in the multivariate regression analysis. To avoid multicollinearity, variables with a variance inflation factor exceeding 10 were excluded from the multivariate analysis. To investigate the incremental prognostic value of LV InD over various clinical and imaging parameters, including age, sex, LVEF, scar burden, LVGRS and LVGLS, the change in the likelihood ratio (LR) chi-square value for nested models was calculated. Fourteen random patients were selected for the evaluation of intra- and inter-observer variability of LV InD, using intraclass correlation coefficients for absolute agreement of average measures. Moreover, intra- and interobserver agreement for LV InD was evaluated by Bland-Altmann analysis. Two-sided P-values < 0.05 were considered significant. The statistical analyses were performed using SPSS version 25  and R .Continuous data were presented as mean ± standard deviation when normally distributed or median and interquartile range (IQR) when not normally distributed. Categorical variables were expressed as frequencies and percentages. The study population was dichotomized according to the median value of LV InD. LV InD groups were compared using the independent samples Student A total of 111 patients  with a history of myocardial infarction, who underwent LGE-CMR imaging, were included based on inclusion and exclusion criteria. The median time from the index acute MI to CMR was 81 [IQR: 53–168] days. The typical indications for CMR were to assess myocardial viability . Other indications were for the assessment of ventricular function , diagnosis of other etiologies of LV dysfunction , or assessment of myocardial ischemia by stress CMR . The majority of patients were classified as ST-segment elevation myocardial infarction (STEMI), while the remainder had non-STEMI . For the measurement of LV InD, 9 (10%) of patients required manual contour adjustment. Amongst cardiovascular risk factors, diabetes mellitus and chronic kidney disease were seen more commonly in patients with LV InD < 23.0. The use of aspirin, angiotensin-converting enzyme inhibitors (or angiotensin receptor blockers), beta-blockers and statins exceeded 95% in all groups (Table The mean LVEF was 50.4 ± 13.4% and 47 (41%) patients had an LVEF < 50%. The LV end-diastolic and end-systolic volumes were significantly larger in the group with LV InD < 23.0, while the LVEF, LVGLS and LVGRS were more impaired in this group. On LGE-CMR, LV scar tissue was present in 97 (89%) patients . The median LV scar volume was 15.4% [IQR5.2-22.7%], and the burden of post-infarction scar was significantly greater in patients with LV InD < 23.0. LV scar burden was also greater in patients with transmural scar than in those with subendocardial scar . LV InD  and LVGLS  were lower in patients with transmural scar than in those with subendocardial scar only.Over a median follow-up of 142 (IQR 107–159) months, 31 (27.9%) events occurred . Arrhythmic events included 1 episode of ventricular fibrillation, 2 sustained ventricular tachycardias, 2 resuscitations after cardiac arrest, and 9 appropriate ICD therapies. Patients with more impaired LV InD (< 23.0) experienced a significantly lower event-free survival (P < 0.001) , LV scar burden (P = 0.009) and LVGRS (P = 0.012). LV InD did not add significant incremental predictive value to a model which included LVGLS (P = 0.079)Fig. .The intra-observer agreement for LV InD was good, with a mean difference of 1.6 ± 4.0% between repeated measures  zone between normal myocardium and scar tissue creates the substrate for an electrophysiologic re-entry circuit to be established , 28. WhiLV deformation parameters, such as LVGLS or LVGRS, while being sensitive to detect global systolic LV function, are more limited in their ability to identify regional LV systolic impairment. In addition, these strain parameters reflect LV deformation in one direction only, while in reality, LV contraction comprises circumferential, radial, and longitudinal changes. Systolic LV wall motion can be described by the inward motion of the endocardium towards the centerline of the ventricle, which potentially overcomes the limitations of existing strain parameters, i.e.: (1) it can reflect multidirection  LV wall motion and (2) it may be more sensitive for the identification of regional systolic function . While sPost-infarct risk stratification and the decision to implant an ICD in patients with IHD is currently mainly based on the LVEF. However, the use of LVEF to predict sudden cardiac death in these patients, is neither sensitive nor specific, and a clinical need exists for a refinement in risk stratification . LV InD This study is subject to the limitations of its retrospective, single-centre, observational design. Since only patients who underwent clinically-indicated CMR were included, selection bias cannot be excluded, and the limited number of patients precludes subgroup analysis, e.g. in patients with reduced versus preserved LVEF. In addition, no distinction could be drawn between all-cause and cardiac mortality. Another limitation could be that LV InD is only available from a single vendor.In conclusion, LV InD, measured with FT-CMR, was independently associated with outcomes in patients with prior myocardial infarction when correcting for cardiovascular risk factors. LV InD also provided incremental prognostic value over LVEF and LVGRS. Accordingly, LV InD holds promise as a pragmatic imaging biomarker for post-infarct risk stratification.


BackgroundThis study aimed, first, to angiographically investigate and analyze prostatic artery (PA) origin in a Greek male population with benign prostatic hyperplasia (BPH) treated with prostatic artery embolization (PAE) and, second, to correlate prostatic arterial anatomy with technical and clinical aspects of PAE.MethodologyThis was a retrospective study of BPH patients who underwent PAE in a single tertiary center in Greece from June 2019 to July 2022. For the first part of the study, PA was imaged with computed tomography angiography (CTA) before PAE and with digital subtraction angiography (DSA) during PAE in all patients. A widely accepted system for the classification of PA origin was applied. Type I, a common origin of PA and superior vesical artery (SVA) from the anterior division of internal iliac artery (IIA). Type II, PA originating from the anterior division of IIA, separate from, and inferior to SVA. Type III, the origin of PA from the obturator artery. Type IV, the origin of PA from the internal pudendal artery. Type V, rarer origins of PA. For the second part of the study, a subgroup of patients from the first part  was selected. In this subgroup, differences in PA origin were correlated with technical aspects , dose area product (DAP)) and clinical outcomes of PAE.ResultsAfter the exclusion of four patients, 159 patients were included in the first part of the study. From a total of 355 PAs, 110 (31%) were compatible with type I, 58 (16.3%) type II, 45 (12.7%) type III, 110 (31%) type IV, and 32 (9%) type V. PA origin from an accessory internal pudendal artery was the most common among the rare origins of type V. Regarding the second part of the study (a subgroup of 101 patients selected to facilitate comparisons between the different types of PA origin), type I was associated with significantly more incidences of failed or difficult catheterization of the PA compared to all other types combined . Types III, IV, and V showed a relatively low degree of technical difficulty. Patients with type I PA origin of at least one pelvic side (subgroup (I), n = 48) had significantly longer FT and DAP compared to the rest (subgroup (O), n = 53). Clinical success rates of PAE were slightly lower for the subgroup (I), although the difference was not statistically significant . No major complications were observed.ConclusionsThis is the first study of PA origin in Greece. It was demonstrated that types I and IV of PA origin were the most common and had the same prevalence. Type I showed significantly higher technical difficulty compared to the others, but had no significant impact on the clinical outcomes of PAE. During the last 10 years, imaging of prostatic artery (PA) anatomy has been attracting researchers’ interest as a result of the increasing application and promising outcomes of prostatic artery embolization (PAE) for the treatment of symptomatic benign prostatic hyperplasia (BPH) . In 2015Furthermore, the correlation of different types of PA origin with certain technical or clinical aspects of PAE could facilitate preparation for PAE, treatment planning, and patient counseling. If, for example, pre-interventional imaging reveals a ‘’difficult’’ type of PA origin, on-site availability of more dedicated devices  should be ensured, and the patient should also be informed of the possibility of a lengthy or unsuccessful procedure.Taking into account the paucity of relevant data from the Balkan region (and particularly from the country of the authors), a study was conducted to study the prevalence of the various types of PA origin in a Greek population treated with PAE for BPH, as well as to investigate if the type of PA origin has any impact on technical aspects and clinical outcomes of PAE.A retrospective, single-center study of a Greek male population treated with PAE was conducted. Inclusion criteria were similar to those of previous work  and inclFor the first part of the study, angiographic imaging of PA origin was based on two imaging modalities. The first was computed tomographic angiography. This was performed before PAE, with a 64-row scanner  using the following scanning parameters: 120 kV, automatic milliamperage, matrix of 512 x 512 pixels, collimation of 64 x 0.625 mm, slice thickness of 1.25 mm, and pitch of 0.984:1. Iodinated contrast  was injected with mechanical injector in a forearm vein at a rate of 4.5-5 mL/second. For bolus triggering, a region of interest was placed just above aortic bifurcation, and scanning started when a threshold of 250 HU was reached. Vasodilatation before CTA was achieved using a sublingual spray of glyceryl trinitrate (2 x 400 µg).The course of the PAs was first studied on thin (0.625 mm) axial CT slices and PAs were tracked from the prostate capsule back to their origin from the parent artery. Subsequently, maximum intensity projection (MIP) images were produced on coronal, sagittal, and various oblique sagittal planes. MIPs that most clearly showed PA origins were selected for the angiographic analysis and for correlation with DSA images.The second imaging modality was digital subtraction angiography (DSA). This was performed during PAE with a flat-panel angiographic unit . After catheterization of the IIAs with a 5 French (Fr.) angiographic catheter, DSA was performed with manual injection of 10-20 mL of iodinated contrast (300 mg iodine/mL) at a rate of 1 frame/second with the appropriate (‘’Body CARE 1’’) angiographic protocol. The X-ray tube angulation was adjusted according to the obliquity of the aforementioned MIP images that most clearly showed PA origin. Most commonly, DSA was performed in ipsilateral oblique (30-40°) projection with occasional additional slight (5°) caudocranial angulation. Additional DSA runs at other projections were acquired if deemed necessary.DSA and CTA/MIP images were reviewed and correlated by two radiologists (each with seven years of experience in PAE) and the number and type of PA origin(s) were defined on each pelvic side. Cases of discordance between DSA and CTA/MIP images that were encountered during this review process were resolved by consensus between the two reviewers, otherwise, they were excluded. Also excluded were cases in which no PA could be identified on the pelvic side by one or both of the imaging modalities. DSA runs after super-selective cannulation of PA with a microcatheter were also reviewed; however, they were not considered mandatory for the characterization of PA origin. Cone-beam computed tomography (CBCT) was also optional and only occasionally performed in the context of this study.For the second part of the study, a subgroup of patients was selected who had undergone PAE with the same technique and devices Table  and wereDescriptive statistics were calculated for quantitative and qualitative data. The normality of data distribution was assessed using the Shapiro-Wilk test. Independent-sample t-test was used for the comparison of means between subgroups. The chi-square test was used for the comparison of proportions . The Kaplan-Meier method was used to calculate clinical success rates of PAE over time and the log-rank test to compare differences in clinical success rates between subgroups. Statistical significance was defined as a p-value <0.05.Details regarding the patients who were included in the two parts of the study, as well as regarding the excluded patients, are provided in Figure A total of 159 patients were included in the first part of the study. Baseline demographic and clinical data are presented in Table In 123/159 (77.3%) patients, one PA was identified in each pelvic side. In 3/159 (1.9%) patients one PA was identified in one pelvic side, but no PA could be visualized contralaterally. In 28/159 (17.6%) patients, a double PA was found on one pelvic side, with a single PA on the other side. In 3/159 (1.9%) patients, bilateral duplication of PA was observed and in 2/159 (1.3%) patients a triple PA was found on one pelvic side with a single PA contralaterally. Overall, more than one PA per pelvic side was observed in 20.8% of the patients (11.3% of the studied pelvic sides).From a total of 355 identified PAs, type I was represented by 110 (31%) arteries, type II by 58 (16.3%), type III by 45 12,7%), type IV by 110 (31%), and type V by 32 arteries (9%) . Less frequent subtypes of PA origin were  was observed in 51 (32%) patients, with 21, 4, 5, 20, and 1 patient(s) for bilateral types I, II, III, IV, and V, respectively.From the studied population of the first part, a subgroup of 101 patients  were included in the second part of the study. Representation of the various types of PA origin in this subgroup was as follows: type I, 64/202 PAs; type II, 32/202 PAs; type 3, 27/202 PAs; type IV, 62/202 PAs; type V, 17/202 PAs. Type I was associated with significantly more incidences of difficult and failed super-selective catheterization compared to all other types together   and was more frequently associated with type I being the underlying cause of 24/27 (88.8%) incidences of failed or difficult type I catheterizations. Causes of failure or difficulty of catheterization per type of PA origin are provided in Table .cm2 (p < 0.001), respectively. Of note, differences in age, prostate volume, and body mass index between subgroups (I) and (O) were not statistically significant .To investigate differences in radiation exposure between different types of PA origin, patients of the second part of the study were further divided into two subgroups: Subgroup (I) with type I PA origin of at least one pelvic side , and subgroup (O), comprising the rest of the patients, with the other types of origin (n = 53). PAE of subgroup (I) was associated with significantly higher radiation exposure compared to subgroup (O), with FT of 47.7 vs. 41.1 minutes (p = 0.007) and DAP of 21,060 vs. 14,392 μGyClinical success rates at 3, 6, 12, and 18 months post-PAE were 81.3%, 78.7%, 75.8%, and 75.8%, respectively, for subgroup (I) and 94.3%, 83.8%, 83.8%, and 83.8%, respectively, for subgroup (O). Differences between the two subgroups were not statistically significant (p = 0.137). No major complications were observed in the entire study population.In the first part of this study, the type of PA origin was systematically investigated with CTA and DSA for the first time in a Greek population with BPH. Several studies from other countries have utilized the same system for the categorization of PA origin, and, not surprisingly, there is variance between the results of the present and previous studies -6,8-11, More than one PA per pelvic side was also more frequently diagnosed in the present study  compared to others 2.5-14.9%) ,8-10. In4.9% ,8-1The results of the second part of the study revealed significant differences in the degree of technical difficulty associated with access to different PA origins. Type I proved the most technically challenging, with significantly more incidences of failed and difficult catheterization compared to all the other types together. Type I was also associated with increased radiation dose, most likely as a result of the prolonged FT and of the numerous DSA runs, required for clear visualization and catheterization of the common SVA-PA trunk and, then, of the PA. This is in line with previous studies ,8,12, whOn the other hand, regarding “technically easier” types of PA origin, the findings of the present study are also largely in line with previous work. Type III is considered probably the easiest type for PA catheterization because the obturator artery is almost always easy to catheterize and because of the favorable angle of PA origin from the obturator ,8. MoreoThere is a paucity of data regarding technical issues associated with type V ,14,15. IThis work has several limitations. It is a single-center, retrospective study and the number of patients is lower compared to that of some of the previous studies. Radiation data were not calculated separately for each pelvic side; as a result, it was not possible to study in detail the impact of each type on FT and DAP. Characterization of ‘’difficult’’ catheterizations was based exclusively on the need for additional dedicated devices; prolonged procedural times and maneuvers required in challenging cases were not taken into account. CBCT, which provides more detailed vascular imaging than CTA , was notThis is the first angiographic study of PA origin in Greece. It was demonstrated that types I and IV of PA origin were the most common and had the same prevalence (31% each). Supernumerary PAs and rare origins were detected more frequently than in many previous studies. Type I of PA origin showed significantly higher technical difficulty compared to the others, being associated with higher rates of difficult or failed catheterization and with higher radiation exposure. The negative effect of type I on the clinical outcome of PAE was not statistically significant, but probably merits further investigation.


Coronary atherosclerosis with a large necrotic core has been postulated to reduce the vasodilatory capacity of vascular tissue. In the present analysis, we explored whether total plaque volume and necrotic core volume on coronary computed tomography angiography (CCTA) are independently associated with myocardial ischaemia on positron emission tomography (PET).15O]H2O PET myocardial perfusion imaging, we quantitatively measured diameter stenosis, total and compositional plaque volumes on CCTA. Primary endpoint was myocardial ischaemia on PET, defined as an absolute stress myocardial blood flow ≤2.4 mL/g/min in ≥1 segment. Multivariable prediction models for myocardial ischaemia were consecutively created using logistic regression analysis . A total of 493 patients  underwent sequential CCTA/PET imaging. In 153 (31%) patients, myocardial ischaemia was detected on PET. Diameter stenosis ≥50% (P < 0.001) and necrotic core volume (P = 0.029) were independently associated with myocardial ischaemia, while total plaque volume showed borderline significance (P = 0.052). The plaque composition model (χ2 = 169) provided incremental value for the prediction of ischaemia when compared with the stenosis model  and plaque volume model .From a registry of symptomatic patients with suspected coronary artery disease and clinically indicated CCTA with sequential [The volume of necrotic core on CCTA independently and incrementally predicts myocardial ischaemia on PET, beyond diameter stenosis alone.  Particularly in coronary plaques with moderate stenosis  a high variability in myocardial perfusion has been described, reporting ischaemia in one-third of plaques.2–4 These observations have underscored the importance of identifying novel factors beyond coronary artery stenosis that may affect downstream myocardial perfusion.1 Recently, coronary computed tomography angiography (CCTA) has emerged as a non-invasive imaging modality that allows for the detailed volumetric measurement of different plaque components in coronary artery disease (CAD).6 Specifically, large volumes of vulnerable lipid-rich plaque—necrotic core—have been hypothesized to impair the vasodilatory response of vascular tissue, thereby inducing ischaemia.8 Hence, the present analysis sought to explore whether total plaque volume and necrotic core volume on CCTA are associated with myocardial ischaemia on positron emission tomography (PET), independent of diameter stenosis.Myocardial ischaemia occurs when the oxygen supply relative to the demand of the myocardium is insufficient, and this can be adequately assessed using non-invasive myocardial perfusion imaging or invasive fractional flow reserve. 15O]H2O PET myocardial perfusion imaging were recruited at the Turku University Hospital, Turku, Finland between 2007 and 2011. The study design has been reported earlier.9 In brief, a total of 922 patients were referred for CCTA, and those with a suspected obstructive stenosis on CCTA underwent subsequent PET myocardial perfusion imaging to assess the presence of myocardial ischaemia. The study protocol was approved by the ethics committee of the Hospital District of South-West Finland, and the need for written informed consent was waived. The study was performed in compliance with the Declaration of Helsinki. For the current analysis, exclusion criteria were absence of any CAD on CCTA (n = 261), impaired image quality (n = 153), non-adherence to the sequential imaging protocol (n = 14), and outlier results (n = 1). Thus, 493 patients were included .Consecutive symptomatic patients with suspected CAD and clinically indicated CCTA with sequential H2O  was injected as radiotracer bolus over 15 seconds.10 Intravenous adenosine (140 µg/kg/min) infusion was started 2 minutes prior to the stress scan to reach maximal coronary vasodilation and administered until the end of the scan. Stress scans were quantitatively analysed by an experienced reader  in accordance with the 17-segment American Heart Association model using specialized software .14 Absolute stress myocardial blood flow was provided for the individual myocardial segments and total left ventricular myocardium.In patients with a suspected obstructive stenosis on initial CCTA evaluation, stress PET myocardial perfusion imaging was performed using the same PET/CT scanner.9 Patients without a suspected obstructive stenosis on initial CCTA evaluation did not undergo subsequent PET myocardial perfusion imaging (per study design) and were assumed non-ischaemic.The primary endpoint was the presence of myocardial ischaemia on PET, defined as an absolute stress myocardial blood flow ≤2.4 mL/g/min in at least 1 of 17 segments.T test or Mann–Whitney U test. Categorical data were compared with the χ2 test. Uni- and multivariable logistic regression analyses were performed to assess the association between selected variables and myocardial ischaemia. The following models for the prediction of myocardial ischaemia were constructed: a stenosis model (diameter stenosis ≥50%), a plaque volume model , and a plaque composition model (plaque volume model + necrotic core volume). Particular focus was given to necrotic core volume as plaque composition, considering its link with local vasodilatory dysfunction.8 All models were adjusted for important clinical variables as chosen by domain expertise . Multicollinearity between variables was ruled out as calculated with the variance inflation factor . Measures of association were displayed as odds ratios with 95% confidence intervals (CIs). Area under the receiver-operating characteristic curves (AUCs) of the models were compared with the DeLong’s test to evaluate discriminatory ability. χ2’s of the models were compared with the likelihood ratio test to evaluate goodness of model fit. Effect modification of necrotic core volume on myocardial ischaemia by total plaque volume was tested with interaction terms. A two-sided P-value of <0.05 indicated statistical significance, and all statistical analyses were performed with R , SPSS , and STATA software .Continuous data are shown as mean ± standard deviations or medians with interquartile ranges (IQR), dependent on distribution. Categorical data are shown as absolute numbers with percentages. Continuous data were compared with the independent sample Figure S1). In 199 patients, an obstructive stenosis was excluded on CCTA, therefore they did not undergo PET myocardial perfusion imaging and were assumed non-ischaemic. In contrast, in 294 patients, an obstructive stenosis was suspected on CCTA, and in 153 (31% out of 493) patients, myocardial ischaemia was detected on subsequent PET (Table 1). Patients who showed myocardial ischaemia on PET were more often male  and more frequently had typical angina  compared with patients who did not show ischaemia. Moreover, cardiac risk factors including hypertension , dyslipidaemia , and diabetes mellitus  were more prevalent in patients with myocardial ischaemia.A total of 493 patients  underwent sequential CCTA/PET imaging for the assessment of CAD and myocardial ischaemia  patients, a diameter stenosis ≥50% was observed on CCTA. Patients with myocardial ischaemia demonstrated more often a diameter stenosis ≥50%  when compared with patients without ischaemia. Furthermore, total plaque volume  and all compositional plaque volumes (P < 0.001) were greater in patients with myocardial ischaemia. Also, greater necrotic core volumes were observed irrespective of their obstructive status in ischaemic patients .CCTA results of the study population are depicted in Table 2. A median of 9 segments (IQR 4–15 segments) was affected in patients with myocardial ischaemia. Patients with myocardial ischaemia demonstrated a lower global stress myocardial blood flow when compared with patients without ischaemia on subsequent PET . Within this group, perfusion defects fully matched the stenosis findings in 98 (64%) patients, while this was partially or not the case in 34 (22%) and 21 (14%) patients, respectively.PET myocardial perfusion imaging results of the study population are depicted in Table S1). Different multivariable prediction models were consecutively created: a stenosis model (diameter stenosis ≥50%), a plaque volume model  and a plaque composition model . In the plaque composition model, diameter stenosis ≥50% (P < 0.001) and necrotic core volume (P = 0.029) remained independently associated with myocardial ischaemia. Additionally, total plaque volume showed a borderline significant association (P = 0.052).Male sex, hypertension, dyslipidaemia, diabetes mellitus, number of cardiac risk factors, diameter stenosis ≥50%, total plaque volume, and all compositional plaque volumes were univariable predictors of myocardial ischaemia on PET (see Table 3). The plaque composition model had the highest AUC value, though this did not reach statistical significance compared with the plaque volume model (P > 0.05). However, the plaque composition model significantly increased the model fit, indicating that adding necrotic core volume to the model provided incremental predictive information  .A stepwise increase in AUC for discrimination of myocardial ischaemia was observed for the consecutive models: 0.802 (95% CI 0.758–0.845) for the stenosis model, 0.834 (95% CI 0.794–0.874) for the plaque volume model and 0.838 (95% CI 0.799–0.876) for the plaque composition model (P = 0.004) and in the adjusted (plaque composition) model . Notably, a greater necrotic core volume was associated with an increased risk of myocardial ischaemia. This effect was more pronounced in patients with a smaller total plaque volume and decreased with increasing total plaque volume .A significant interaction was demonstrated between total plaque volume and necrotic core volume, both in a crude model . Similar results were observed on a per-patient level: a greater modified Duke CAD index, integrating both the location and severity of stenosis, translated into a reduced stress myocardial blood flow  and myocardial flow reserve . Likewise, Lin et al.17 analysed 163 patients with suspected CAD who underwent CCTA and single photon emission computed tomography. Both the segment stenosis score (P = 0.008) and modified Duke CAD index (P = 0.02) were independently associated with severe abnormalities on single photon emission computed tomography. In addition, other studies employing an invasive fractional flow reserve ≤0.80 as reference standard for myocardial ischaemia, comparably revealed stenosis severity as a strong and independent predictor of ischaemia.19–23Prior studies have examined the effect of CCTA-derived stenosis on myocardial ischaemia using non-invasive myocardial perfusion imaging.2–4 Consequently, measures of vulnerable plaque have been proposed to potentially affect downstream myocardial perfusion in addition to coronary artery stenosis.1 Shmilovich et al.24 evaluated 49 patients with a focal diameter stenosis ≥70% on CCTA who consecutively underwent single photon emission computed tomography. In patients with severely stenotic plaques, the presence of necrotic core and positive remodelling on CCTA negatively impacted myocardial perfusion, both as an absolute and relative entity . Furthermore, Driessen et al.22 prospectively included 208 patients with suspected CAD who underwent CCTA and PET myocardial perfusion imaging. Next to stenosis severity, non-calcified plaque volume (integrating necrotic core volume) and the presence of positive remodelling were proved to be inversely related to stress myocardial blood flow. More specifically, a greater number of adverse plaque characteristics, including necrotic core, positive remodelling, spotty calcification, and napkin-ring sign, was associated with a stepwise decrease in stress myocardial blood flow. Various studies using an invasive reference standard for myocardial ischaemia showed similar observations.19–23 In agreement with our results, the majority of these studies demonstrated the independent and incremental predictive value of necrotic core volume for ischaemia.20–23Although CCTA-derived stenosis has a well-established effect on myocardial ischaemia, discordances between the two have frequently been described.8 First, it has been postulated that coronary plaques with lower HU on CCTA have a greater lipid-rich content, consequently inducing local oxidative stress, inflammation, and endothelial dysfunction.25–27 Second, histopathological studies have illustrated that coronary arteries are able to dilate in order to maintain the luminal dimensions.28 Coronary plaques with large necrotic cores often show positive remodelling, in which potentially the Glagovian limit is reached and no further compensation can occur that will preserve the blood flow to the myocardium.29 In the present analysis, however, no differences in remodelling index were observed between patients with and without myocardial ischaemia. To this end, it should also be mentioned that diffuse and heterogenous CAD may manifest as a continuous, graded pressure drop along the coronary arteries, thereby reducing the myocardial flow reserve and potentially contributing to downstream myocardial perfusion abnormalities.30–33 Yet, in the current analysis the myocardial flow reserve was not available, since in most patients only stress scans  were performed as part of the study protocol.While not yet elucidated, underlying mechanisms have been proposed as to how a large necrotic core can influence the vasodilatory response of vascular tissue.Our study had an observational design with inherent limitations, including confounding and selection bias. This was a single center registry of which only part of the patients underwent quantitative analysis of CCTA scans. Moreover, PET myocardial perfusion imaging was executed according to a sequential imaging protocol, and therefore not performed in patients without a suspected obstructive stenosis. Lastly, particular measurements, such as lesion length and calcified volume, were highly correlated with diameter stenosis or total plaque volume and could hence not be added to the multivariable analysis (because of multicollinearity).The volume of necrotic core on CCTA independently and incrementally predicts myocardial ischaemia on PET, with a more pronounced effect in patients with a smaller total plaque volume. This provides additional insight into novel factors beyond diameter stenosis that may affect downstream myocardial perfusion.European Heart Journal - Cardiovascular Imaging online.jeac130_Supplementary_DataClick here for additional data file.