key: cord-0996046-898h9rl1
authors: nan
title: Full Issue PDF
date: 2020-08-31
journal: JACC: Cardiovascular Imaging
DOI: 10.1016/s1936-878x(20)30581-7
sha: b6d5e7fae9cb10b697ee57a5099e4cec83141463
doc_id: 996046
cord_uid: 898h9rl1

nan

studies in patients with mitral valve disease have identified atrial fibrillation (AF) as a risk factor (6, 7) , others have found pulmonary artery systolic pressures (PASPs) to be the most powerful predictor of TR progression (4) . In a recent study (5) , neither increased PASP nor AF were associated with the rate of TR progression.

Cross-sectional studies suggest that TR is frequent, with a prevalence similar to that of aortic stenosis, and may represent a significant public health problem (8) . However, there are no studies that have explicitly measured the population burden of hemodynamically significant TR attributable to specific risk factors. Population burden measurements, for example, populationattributable fractions (PAFs) (9, 10) , are directly relevant to prevention and research prioritization because they estimate the number of events that may be preventable if the prevalence of a modifiable risk factor was reduced.

Therefore, this study sought to identify risk factors for the development of significant functional TR and their relative importance in a large cohort of patients with trivial or mild TR at baseline. To gain additional insight into the effect of various risk factors, the burden of TR that could be attributed to each risk factor also was estimated. A separate analysis was performed among subjects without valvular heart disease (VHD).

A retrospective cohort study was conducted using the presence of an RV pacemaker lead; and 6) additional valvular heart disease. Patients with organic tricuspid valve disease and in whom PASP was not adequately estimated were excluded. TR was quantified by an integrated approach (11) as described in previous studies (1, 2, (12) (13) (14) . First, TR was graded qualitatively by using color Doppler flow mapping. When more than mild TR was present, severity was determined by integrating data from the following parameters: the vena contracta width when feasible ($7 mm, denoting severe TR); the presence and degree of malcoaptation of the tricuspid leaflets; tenting distance; the presence of mid-to-late systolic flow reversal in the hepatic veins; and evaluation of right heart chambers (1, 11, 12, 14) .

LV ejection fraction (LVEF) and LA size were estimated by a combination of visual assessments and standard chamber measurements. The cutoff values for LVEF and LA size values were based on American Society of Echocardiography guidelines at the time the echocardiographic studies were performed (15) .

RV function was assessed qualitatively by integrating visual assessment of the contractility of the RV walls from different views and classified using an ordinal scale (normal or mildly, moderately, or severely reduced) (2, 13, 16) . The final RV chamber size and function were qualitatively graded as a binary variable (< or $ moderate). PASP was estimated from a clearly defined TR signal by continuous-wave Doppler and inferior vena cava size and respiratory variation (12) . Isolated significant TR was defined as previously described (1) . STUDY ENDPOINTS. The primary endpoint of the study was the progression of TR severity from trivial/ mild to moderate/severe. STATISTICAL ANALYSIS. Baseline characteristics of the groups were compared using an unpaired t-test for continuous variables and by the chi-square statistic for categorical variables.

Because the exact time of TR progression between the first and second echocardiographic examination was unknown, multivariate stepwise binary logistic regression models were fitted to determine independent predictors of progression to significant TR. were performed to provide additional information for the most predictive variables for TR progression (17) .

To estimate the potential contribution of various baseline risk factors to the burden of moderate or severe TR in the population, the PAFs were computed, expressed as a percentage for each primary risk exposure (9, 10) . Generally, the PAFs are the fractions of outcomes that would be prevented if the risk factors under consideration were removed, comparing current risk factor exposure to a counterfactual zero exposure. PAFs associated with independent risk factors for the development of moderate or severe TR were calculated using the Stata command punaf (18) . The PAFs presented are adjusted for confounders in a similar manner to the corresponding logistic regression. Continuous risk factors (age and PASP) were dichotomized at their median values for the PAFs calculations.

In step 2, the logistic model was specified using paired echocardiographic data to evaluate the combined effects of baseline predictors and the appearance of new predictors between the 2 echocardiograms. Logistic regression with robust clustered standard errors was used to adjust for within-subject repeated measures (19) . In this model, 

A total of 5,886 consecutive patients who met the study inclusion criteria were screened. Of these, 488 patients were excluded due to moderate or severe TR.

Of the remaining patients, 1,552 patients had at least 1 additional echocardiographic study (Supplemental Baseline demographic and echocardiographic characteristics of the study cohort are shown in Table 1 . Patients who progressed to moderate or severe TR were older, more likely to be female, and have more history of heart failure, AF, and a pacing lead. In addition, there was a higher frequency of all echocardiographic variables denoting left-sided myocardial or valvular disease among individuals with TR progression. The frequency of RV enlargement or dysfunction was low, albeit higher in subjects with TR progression ( Table 1) . Table 2 ). The c-index of the model was 0.78 (95% CI: 0.75 to 0.81), indicating good model discrimination. The incidence rates of progression to moderate or severe TR as a function of age are shown in Figure 1 . Similar results were obtained accounting for time in a competing risk regression model (Supplemental Table 3 ).

The predictive model for TR progression in patients without significant valvular disease at baseline The CART also demonstrated that, without the presence of these 4 parameters, the risk of developing significant TR was small, regardless of other risk factors. For example, a young person with a pacing lead but with normal PAP and normal LA size and no AF has a w3% probability of developing significant TR.

PAFs FOR SIGNIFICANT TR. The proportion of incident moderate or severe TR that could be attributed to each of the risk factors is shown in Figure 2 . Age associated with a more rapid progression to significant TR. However, in that study, there was no control group of patients without TR progression. In addition, 3 important predictors found in previous studies (4, 6, 7) , PH, AF, and left atrial size were not considered in that study (5) .

To the authors' knowledge, this is the largest study pertaining to TR progression. The present study provides a comprehensive assessment of all potential risk factors for TR progression in a large cohort of patients, providing insight into the pathogenesis of hemodynamically significant functional TR, both in terms of individual risk prediction and from the population perspective.

PH was the strongest risk factor to antedate the development of significant TR. The mechanisms by which PH promotes the development of TR have been previously reviewed (2, 20) . Importantly, however, the causes of PH in the contemporary population are primarily aging (21) and diastolic heart failure (22) , rather than VHD.

The present study explicitly calculated the population burden of TR attributable to various risk factors. In the overall study cohort, aging and PH had the highest PAF. By contrast, the PAF was substantially lower for pacing and even VHD. The low PAF of pacing and VHD may be partly due to the low prevalence of these risk factors but also due to the stronger effects of other risk factors. For example, left-sided VHD may lead to TR primarily through PH and AF, and pacing may depend on other concomitant risk factors to produce significant TR (e.g., tricuspid valve

[TV] annulus that is already dilated).

These results indicate that, even if left-sided VHD was eliminated, the incidence of moderate or severe TR would not be substantially reduced, given the strength of association and high prevalence of aging, PH, and AF in the population. Similarly, from the population perspective, strategies to mitigate TR post-pacemaker or -implantable cardioverterdefibrillator insertion are likely to have limited impact on the prevalence of significant TR.

The CART analysis also ranks covariates in terms of their importance in the tree (17, 23) . The analysis demonstrated that 4 variables (PH, LA size, age, and AF) provided prognostic information that was almost identical to the full 8 independent variables logistic regression model.

Interestingly, the CART analysis also provided a sensible interpretation of the most powerful predictors of TR progression that was consistent with our current mechanistic understanding (Central Illustration) (4) . Elevated PAP represent established LHD, where pulmonary pressures are already elevated due to a more advanced LV systolic or diastolic dysfunction or VHD, with or without AF. In turn, PH results in maladaptive RV remodeling, with further tricuspid valve tenting and tricuspid annular dilation (1, 20, 24) .

In the absence of elevated PAP, LA enlargement represents the same underlying conditions but at an earlier stage. An increase in LA size most commonly reflects increased LA pressure secondary to increased LV stiffness and diastolic dysfunction and is a marker of both the severity and the chronicity of diastolic dysfunction and magnitude of LA pressure elevation (25) . Over time, however, an enlarged LA portends pulmonary venous hypertension (26) and a higher incidence of AF (27) . AF with right atrial dilation and increased TV annular area appears to be sufficient to cause significant functional TR (28) . However, this condition occurs infrequently in the absence of PH and is often categorized under "idiopathic" TR (1, 3) . Note that the CART analysis is consistent with this concept, as a small number of patients with AF and normal PAP remain at substantial risk for TR progression.

The CART analysis is also useful in determining the need and intensity of follow-up in individuals with mild TR. In the absence of any of the 4 major risk factors (Central Illustration), progression to moderate or severe TR occurred in w3% of patients and therefore these patients can be followed at longer intervals. In patient with 1 or more of the 4 major risk factors, closer follow-up is justified and is often also dictated by the presence of significant LHD. Furthermore, based on the present study results and current mechanistic concepts (3, 20) , the best strategy to mitigate the progression of TR is to aggressively treat PH and AF and their causes.

TR IS LINKED TO LHD PROGRESSION. Previous studies of TR progression have generally studied risk variables at baseline data (4, 5) . The present results demonstrate that TR progression entails a striking increase in the associated left-sided cardiac comorbidities such that, at the time of the final echocardiographic study, LHD was far more advanced. Thus, in addition to a more severe LHD at baseline, patients whose TR progress represents a subset characterized by an accelerated course of LHD, including a more rapid increase in LA size, pulmonary pressures, and higher rates of new atrial fibrillation, reduction in LVEF, worsening valvular disease, and need for pacemaker or device therapy.

This finding further establishes the inextricable link between functional TR progression and LHD. (11) . Nonquantitative methods are accepted (11) and

have been used in multiple previous studies (2, 4, 12, 14, 24, 29) but may be less accurate.

Individual susceptibility to TR progression is deter- limited ability of conventional imaging modalities to assess its severity and define its pathophysiology (4, 5) .

Left-sided heart diseases and pulmonary hypertension (PH) (either pre-or post-capillary) are the most frequent causes of FTR (6) . Less common (although its prevalence increases with age) is FTR due to isolated tricuspid annular dilatation in the setting of aging or long-standing atrial fibrillation (AF) resulting in right atrial enlargement and tricuspid annular remodeling, whereas right ventricular (RV) shape and function remain normal (7) .

Another uncommon etiology of FTR is primary RV disease, including cardiomyopathies or RV infarction.

However, in a sizable number of cases, the etiology is uncertain, and the term "idiopathic" or "isolated" FTR has been suggested (8 that have been associated with increased risk for faster FTR progression (9) (10) (11) . In this issue of iJACC, [13] ) in a sizable number of patients. RV abnormalities were visually graded as a binary variable (less than moderate or moderate or greater), and the sizes of tricuspid annulus and right atrium were not contemplated, despite evidence suggesting that both can play a role in FTR development and progression (7) .

Retrospective studies based on clinically indicated tests suffer from obvious selection biases of the initial population, and subsequent follow-up tests are more likely in sicker or highly symptomatic patients.

Because patients with moderate FTR, and even a significant proportion of those with severe FTR, are completely asymptomatic, we cannot exclude that patients who underwent repeated echocardiography were those who had to follow-up their left heart disease or those who were symptomatic. In the reported study, only 2,040 patients (35%) of the initial cohort of 5,886 underwent repeated echocardiography.

Although Mutlak et al. (12) used an integrative approach to assess the severity of FTR, patients were selected on the basis of regurgitant jet area on color Doppler: trivial (jet area <1.0 cm 2 ), mild (jet area 1 to 5 cm 2 ), moderate (jet area 5 to 10 cm 2 ), and severe (jet area >10 cm 2 ) (14) . However, these are the criteria used to grade the severity of mitral regurgitation.

Using this metric to assess the severity of FTR is A rtificial intelligence broadly refers to algorithms that iteratively learn from plethora of clinical, imaging, and other diagnostic information to uncover patterns and make decisions from data (1) (2) (3) .

These techniques have empowered new discoveries to be made via modern bioinformatics approaches developed to achieve improved representations of complex disease processes (4) (5) (6) . An exemplar application is the "multiomics" approach for precision medicine, wherein patients are clustered or classified based on similarities in various clinical features to enable improved individual-level risk stratification (7) (8) (9) (10) (11) (12) (13) (14) .

Specifically, the "phenomics" approach in precision medicine allows for systematic dis- (15) . Although these methods have already been claimed to be useful in genomics and system biology (7, 13, 16) , there has been limited enthusiasm to address their application in clinical cardiovascular medicine.

The growth of cardiac imaging techniques has offered an ever-increasing array of measurements for understanding cardiac structure and function. For example, continuous technical developments and the evolution of novel parameters in echocardiography, ranging from 2-dimensional and Doppler-based measurements (17) to speckle tracking echocardiography (STE) (18) , vector flow mapping (VFM) (19) , and contrast particle imaging velocimetry-derived (19, 20) parameters of left ventricular (LV) muscle and blood VECTOR FLOW MAPPING. Images were analyzed using commercially available off-line software (DAS-RS1, Hitachi Aloka Medical Ltd., Tokyo, Japan). The LV endocardial border was manually traced at the onset of the QRS complex, which the software automatically tracked. We included a total of 24 parameters obtained from VFM to be consistently measured in most patients (>85%). These parameters have been previously described, and although validation studies are limited (22) (23) (24) , the published data suggest that these parameters may carry clinically useful information. They included: 1) indexes of vortex, such as vortex area, vortex core diameter, circulation, maximum vorticity, and boundary linear velocity from the flow-velocity curve (25) ; 2) energy loss (EL) (22, 26) ; and 3) the intraventricular pressure gradient (IVPG) (27) . The vortex was automatically tracked and analyzed throughout the cardiac cycle (28) . The ELs were calculated as the mean and peak values in systole and diastole (26) . IVPG was measured on a line that went through the center of the LV from the base to the apex (27 The illustration shows the steps involved in our study in which the data was extracted from the patient's electronic medical record. First, 2-dimensional and Doppler echocardiography, vector flow mapping of left ventricular (LV) muscle and blood flow mechanics, and LV and left atrial speckle-tracking parameters were obtained from patients. In the second step, unsupervised machine learning was used to generate patient similarity network and the subsequent 4 clusters were identified and validated across clinical parameters and outcomes. Finally, the data was used to train supervised learning models with cluster membership as target variable. Three separate models, namely, decision trees, ensemble, and Deepnets, were trained and tested to classify the patients to the correct group. LA ¼ left atrium.

Appendix. The STE and VFM analyses were performed by a single observer blinded to the patients' clinical information (J.S. Cho).

MACHINE LEARNING FRAMEWORK. We first used an unsupervised learning method that analyzes unlabeled points in multidimensional feature space to identify patient phenotypic clusters with similar features along a network (patient similarity network).

The clusters are then used as target for the supervised learning method to predict the patient groups. Unsupervised clustering prior to classification has been shown to improve the predictive capabilities of supervised learning models (29) (30) (31) . PATIENT Details of the baseline characteristics are described in Table 1 .

PATIENT-PATIENT SIMILARITY NETWORK. We integrated 42 complex echocardiographic variables (Table 2, Figure 1 ) to create a patient-patient similarity network. The network and the shape of the data that materialized was a loop with a side branch on the left of the loop ( Figure 2 ) using an automated platform with unsupervised machine learning.

Cluster I was found in the upper region of the loop.

The patients in cluster I were younger (age 38 AE 15 years; p < 0.001 vs. others) and had a lower prevalence of comorbidity than was found in the rest of the patients ( Table 1) . Typically, healthy volunteers (43, 61%) were grouped in this cluster.

Clusters II and III were in the right and bottom regions of the loop. Cluster II contained older patients (age 63 AE 13 years; p < 0.001) with a lower prevalence of comorbidities than those found in other clusters.

Compared with patients in clusters I and II, those in cluster III (age 59 AE 15 years; p < 0.001) presented a higher prevalence of comorbidities ( Table 1) .

Cluster IV was a side branch that included 69 patients. The patients in cluster IV were older (age 60 AE 13 years), were predominantly women (67%), and had a significantly higher prevalence of comorbidities than those found in other clusters (hypertension:

38%, atrial fibrillation: 35%, significant valvular heart disease: 26%, and cardiomyopathy: 51%; all p < 0.001 vs. others) ( Table 1) .

CONVENTIONAL ECHOCARDIOGRAPHIC PARAMETERS. figures, cluster I had the most preserved conventional echocardiographic features, including LVEF, eʹ, E/eʹ, and the LA volume index and LV mass index, each of which progressively worsened from cluster I to IV (p < 0.001 for all). Features such as E/A and LV volume showed a bimodal pattern in which the values decreased from cluster I to II and increased from cluster II to IV (p < 0.001 for both) ( Table 2) .

SPECKLE-TRACKING PARAMETERS. The STE analysis showed that most parameters (i.e., LV GLS, LV SRs, LV SRe, PALS, and LA SRs) progressively decreased in magnitude from clusters I to IV (p < 0.001 for all) ( Table 2) . However, in contrast to LV GLS, PALS showed a bimodal pattern in which it increased in magnitude from cluster I to II and then decreased in magnitude from cluster III to IV (p < 0.001) ( Figures 3C and 3D) .

VECTOR FLOW MAPPING. The majority of the VFM parameters, especially the early diastolic vortex area, core diameter, and circulation, showed a bimodal pattern in which they decreased from clusters I to II and subsequently increased toward clusters III and IV (p < 0.001 for all). However, maximum vorticity and boundary linear velocities decreased from clusters I to II and remained decreased in clusters III and IV, whereas the late diastolic vortex core diameter continuously increased from clusters I to IV (p < 0.001). The late diastolic vortex area, circulation, Figure 6 and Supplemental Table 2A LGE extent was visually defined as the number of segments that manifested LGE.

Interobserver and intraobserver variability for all CMR indexes used in the present registry are shown in Supplemental Tables 1A and 1B. ENDPOINT AND FOLLOW-UP. The only clinical endpoint of this registry was all-cause mortality.

Follow-up was centrally carried out by 4 cardiologists using the unified electronic regional health system registry. Adjudication of events was made by consensus of the 4 cardiologists authorized by the ethics committee for this purpose.

The specific objectives were to explore the potential of the extent of ischemic burden associated with the following: 1) long-term all-cause mortality; and 2) the effect of revascularization procedures prompted by the index vasodilator stress CMR study on longterm, all-cause mortality. Ischemic burden (segments with PD post-stress)

LGE segments)

Values are mean AE SD, n (%), and n (range Figure 2 ). Although LGE was not included in the multivariate analysis, its presence and extent were also associated with all-cause mortality in different ischemic burden populations (Supplemental Table 4 .

Variables used to obtain the propensity-matched population (n ¼ 1,032, 516 treated and 516 not treated with a CMR-related revascularization procedure) are displayed in Table 3 .

All-cause mortality occurred in 150 of the 1,032 patients included in this population (15%)-80 (15%) of non-revascularized cases and 70 (14%) of revascularized cases (p ¼ 0.40) ( Figure 3B ). Baseline and CMR characteristics of patients (treated and not treated) with a CMR-related revascularization procedure are listed in Table 4 .

The all-cause mortality rate in patients with and without CMR-related revascularization differed according to the extent of the ischemic burden. In non-revascularized patients, the all-cause mortality rate increased as the ischemic burden rose. However, this tendency did not occur in patients who underwent a CMR-related revascularization procedure ( Figure 3 , Central Illustration). Figure 3 illustrates the divergent effect of the ischemic burden on the allcause mortality risk depending on the use or not of CMR-related revascularization. We used a cutoff point of 5 segments with PD poststress to stratify patients into categories of extensive and nonextensive ischemic burden. This was the best cutoff point, which was derived from the Youden index, and applied to the receiver-operating curve analysis that explored the association of the extent of ischemic burden with all-cause mortality. In addition, this selection coincided with the point where the effects of the ischemic burden on all-cause mortality in revascularized and non-revascularized patients intersected ( Figure 3 ).

In the nonextensive ischemic burden group (#5 ischemic segments), patients who underwent a CMRrelated revascularization procedure displayed a significantly higher risk of all-cause mortality than those who did not (16% vs. 10%; p ¼ 0.01). In contrast, patients in the extensive ischemic burden group (>5 ischemic segments) treated with a CMR-related revascularization procedure displayed a lower risk of all-cause mortality than those who had CMRrelated revascularization was not done (10% vs. (Figures 4 and 5 LV end-systolic volume index was removed of multivariable analysis due to excessive co-linearity (Supplemental Table 2 ) and correlation (Supplemental Table 3 

The present registry demonstrated that in unselected patients with known or suspected SIHD who under- The propensity score, aimed at predicting the use of CMR-related revascularization, was obtained using a non-parsimonious model that included in model 1, those co-factors that were independently related to the occurrence of all-cause mortality (age, male sex, DM, current smoker, LVEF, and ischemic burden). The C-statistics of the resulting model was 0.807, indicating good discrimination. Then, the rest of variables associated with the use of CMR-related revascularization were also tested in model 2. None of these variables significantly improved the C-statistics of model 1. However, LGE extent was also used for selecting the 1:1 propensity scoreÀmatched population (final model) because of its potential relevance in indicating the use of CMR-related revascularization.

Abbreviations as in Table 1 All-cause mortality rates based on the extent of the ischemic burden in revascularized and non-revascularized patients in the (A) entire registry and in the (B) matched patients. HRs (with the respective 95% confidence intervals) of all-cause mortality increased in parallel with the extent of the ischemic burden in non-revascularized patients, but the opposite tendency occurred in patients who underwent CMR-related revascularization (p for interaction <0.001), both in the (C) entire registry and in the (D) matched patients. Cofactors independently associated with all-cause mortality in multivariable analysis (age, male, DM, current smoker, LVEF, and ischemic burden) and the propensity score to undergo CMR-related revascularization were used for adjustment in the (C) entire registry. Abbreviations as in Figures 1 and 2 . A physiology-based strategy (PCI only in lesions with fractional flow reserve <0.80) was superior to an anatomy-based strategy (PCI in lesions >50% by angiography) in the FAME trial (16) . In the FAME-2 (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) trial (17) , it was also more effective than optimal medical therapy alone in reducing the risk of a combined endpoint (but the benefit was restricted to the rate of unplanned revascularization 

LGE (no. of segments)

Values are mean AE SD, n (%), and n (range). All covariates had standardized mean difference (SMD) of <0.2, which was considered to be a sign of covariate balance.

Other abbreviations as in Table 1 . The currently recommended 10% threshold of ischemic myocardium is mainly derived from studies that used exercise combined with nuclear imaging (10, 11) . We based the analyses in our series on the extent (number of segments) of inducible PD. This is probably the most widely used and easily interpreted In summary, all these observations seem to suggest that to achieve a significant risk reduction in such a potent endpoint as all-cause mortality, an extensive ischemic burden by any of the available All-cause mortality was selected as the only endpoint. This is a verifiable and worrisome event, and the retrospective strategy for the revision of data within a unified electronic regional health system guaranteed the quality of information obtained.

Other events such as the cause of death, relief of symptoms, unplanned revascularization procedures, or re-infarctions could have contributed a more holistic vision of the course of patients. A trial fibrillation (AF) is often asymptomatic, and even more frequently asymptomatic with increasing age (1, 2) . In patients with stroke risk factors, continuous implantable monitoring reveals subclinical AF in w30% (2), whereas cohort studies have found subclinical AF in pacemaker patients to be associated with increased risk of stroke (3) . Systematic screening for AF is currently not supported, but reliable predictors of AF and possibly stroke may help in selecting patients for screening.

Assessment of left atrial late gadolinium enhancement (LA LGE) with cardiovascular magnetic resonance (CMR) imaging has primarily been used before or after AF ablations, and it is well established that the extent of LA LGE before ablation is inversely associated with procedural success (4) . Furthermore, stroke is associated with increased LA LGE (5,6), but only a few studies of LA LGE in patients without AF or stroke have been published (7) (8) (9) . Increased LA LGE has been found to be associated with future diagnosis of atrial arrhythmias in patients with preexisting cardiac disease (9) but no study has investigated the prognostic value of LA LGE in a population-based cohort or by use of continuous monitoring.

The aim of this study was to investigate the extent of LA LGE in a population with stroke risk factors but no history of AF and to investigate whether LA LGE was associated with incident AF as detected by continuous monitoring using an implantable loop recorder (ILR).

The study is part of the LOOP study (NCT02036450). A detailed description of the study design has previously been published (10) . In short, participants from the general population were randomly selected from civil registries and invited by mail. total of 3 study participants died during follow-up, all due to noncardiac causes.

In a total of 32 patients (47%), adjudicated incident AF episodes lasting $6 min were detected, and 16 experienced at least 1 AF episode lasting $5.5 h.

Among patients with AF, the mean AF burden was 3.87 AE 9.66%, median 0.20% (IQR: 0.06% to 1.43%).

When asked about symptoms, only 3 patients (9%) reported symptoms at AF debut and/or during AF.

Baseline characteristics are summarized in Table 1 , showing no differences between participants with and without AF. CMR parameters are summarized in Table 1 ). There was no difference in baseline demographic risk factors between men and women, but LV remodeling was more pronounced in men compared with women (Supplemental Table 1 ). Correlations between CMR variables Figure 4 ).

In this prospective study, we performed LA LGE scans in 68 patients followed by continuous monitoring for AF for more than 3 years. We found that, in addition to LA volumes and function, increased LA LGE was significantly associated with risk of AF. The long continuous monitoring enabled us to show that LA

LGE is associated not only with short episodes of AF ($6 min), but also with long episodes ($5.5 h), as well as high AF burden. Importantly, most of the patients (91%) were completely asymptomatic.

LA REMODELING AND AF. Markers of LA remodeling such as LA size and function have been linked in previous studies to the development of symptomatic AF (13, 14) . These studies all depend on a clinical diagnosis of AF and hence asymptomatic patients are not represented. Our study found that LA volume and ejection fraction were associated with incident AF, with similar hazard ratios as previously reported (13, 14) Asymptomatic AF arguably represents a phenotype with less atrial remodeling. 

Although AF has been shown to induce atrial fibrosis in animal models (15) , many of the participants in the current study with no detected AF displayed surprisingly large amounts of LA LGE ( Table 2) . A few other population-based studies have also found LA LGE in patients without AF (7, 8) , although these studies were not able to rule out subclinical AF. Hence, it appears that even relatively severe LA LGE is not strictly linked to AF, which speaks for atrial enhancement as an independent phenomenon from known risk factors for AF as part of a specific fibrotic atrial cardiomyopathy (16) , possibly with a bidirectional causality between AF and fibrosis (17) . In this context, it is important to remember that LA LGE may not be specific to atrial fibrosis. As LGE reflects accumulation of contrast, other causes of increased interstitial space, for example, inflammation, or blood stasis may also result in enhancement.

Prediction of AF is important because AF is often asymptomatic, even with long AF episodes (2, 18) .

Although subclinical AF is associated with an increased risk of stroke compared with no AF (3), it appears that shorter episodes are less hazardous (18) .

We found that LA LGE was strongly associated with longer episodes of AF ($5.5 h) with a higher hazard ratio than for AF episodes of any duration ( Figure 2) .

Similarly, we found that LA LGE was significantly higher in patients with a high AF burden ( Figure 3 ).

Our findings indicate that LA LGE may serve as a predictor of longer AF episodes and higher AF burden. We thus speculate that more widespread atrial fibrosis can sustain AF once it occurs.

Excessive atrial ectopic activity is strongly associated with incident stroke independently of manifest AF (19) and increased LA LGE has been found in patients with stroke of undetermined cause (6) .

Although LA LGE was significantly higher in the patients with incident AF during follow-up, some of the participants without AF also displayed extensive LA

LGE. As strokes are often temporarily discordant from AF (18) , it may very well be that remodeling of the left atria increases the risk of AF but also in itself constitutes an increased risk of stroke. As an alternative method of measuring fibrosis, ventricular native T1 relaxation times and extracellular volume have been associated with AF recurrence after ablation (20) . We were not able to confirm these findings with regard to incident screening-detected AF. This may be because the degree of diffuse fibrosis is lower before development of subclinical AF compared with the AF phenotype seen in patients undergoing ablation procedures.

Previous CMR studies have found correlations between LA LGE and age (5, 8) , hypertension (4), and female sex (5, 8, 21) . Similar to other previous CMR studies and studies on autopsy findings on atrial fibrosis (7,22), we could not confirm the associations with age and comorbidities. This was possibly because included participants were $70 years of age and had at least 1 of hypertension, heart failure, diabetes mellitus, and/or previous stroke, meaning that the healthiest among the participants were arguably those with only 1 risk factor (e.g., well-managed hypertension), whereas no participants were young or free of risk factors. As described, men displayed significantly more LA LGE than women in non-AF participants, although this was not the case in patients with AF. In general, men also displayed more LV remodeling as well as LV LGE (Supplemental Table 1 ) compared with women, which may be linked to the increased LA LGE in male participants. Finally, 

A U G U S T 2 0 2 0 : 1 6 9 0 -7 0 0 increased LA LGE in women compared with men has earlier been found to reverse with age (21) . STUDY LIMITATIONS. First, our study is limited by a modest cohort size. Out of ethical considerations, participants were to have an estimated glomerular filtration rate of at least 60 ml/min per 1.73 m 2 to be included in the study.

Second, LA LGE has well-known limitations.

However, as in a recent study (11) , we found good inter-and intraobserver reproducibility and the scan-rescan variability for LA LGE has recently been shown to be acceptable (23) . The upper IIR threshold used for LA LGE is well-described with data from healthy controls (11) and with reference to electroanatomic mapping (24) .

Because most of the patients were asymptomatic, we cannot exclude the presence of existing asymptomatic paroxysmal AF at inclusion. Nevertheless, the increasing incidence of AF throughout the entire follow-up period suggests that a substantial number of AF episodes were truly new-onset.

In this prospective cohort-based study, we found that LGE measured by CMR is predictive of future subclinical AF.

TRANSLATIONAL OUTLOOK: Future studies are needed to assess whether LA LGE is valuable in selecting patients for screening for AF or for stroke risk stratification. If reduction of LA

LGE is possible, this could potentially reduce AF burden and progression. cally, animal models support the relevance of clustered fibrosis in leading to re-entrant activations that sustain AF (5) . Additionally, it is known that AF itself can lead to tissue fibrosis, as illustrated by the fact that rapid atrial pacing induces fibrosis and AF (6) , and that atrial fibrosis and electric remodeling underlie the transition from paroxysmal to persistent AF and contribute to AF perpetuation (2) .

Therefore, the relationship between AF and fibrosis is clear. What is less clear is the direction of this relationship. AF and fibrosis go hand-in-hand, but which is the proverbial "chicken" and which is the "egg"? Is AF a consequence of fibrosis, is fibrosis the consequence of AF, or is the answer a combination of the 2?

Another clinical conundrum revolves around the mechanisms, determinants, and predictors of stroke in AF. The mechanistic paradigm of thrombus formation in the left atrial appendage (7) is undisputed and seems to be overwhelmingly predominant.

However, recent data seems to question its exclusiveness: the lack of temporal correlation between strokes and AF episodes-within the preceding month (8)-seems to suggest that additional mechanisms are operative, or that AF may be not only be a proximate risk factor for stroke, but also a marker of stroke risk from other mechanisms. And yet, the longer the AF episodes, the higher the risk of stroke (9) . How can this make sense? How can the presence of AF be associated with strokes even at times when AF does not happen? One fascinating hypothesis is that there is an underlying disease process that can both be a mechanism of stroke susceptibility and a mechanism of AF, and that both can occur independent of one 

published retrospective study identified an association between LA LGE and incident new-onset AF (14) .

In this issue of iJACC, Bertelsen et al. (15) Patients with 2 RFs were not enrolled in the study. Coronary CTA advanced plaque assessment was performed. Outcome measures were 3 combined endpoints: acute coronary syndrome (ACS), cardiac death þ ACS, and cardiac death þ ACS þ late revascularization.

RESULTS Among the 544 patients enrolled in the CAPIRE study, in 522 patients, a mean follow-up of 37 AE 10 months was obtained (16 patients were excluded due to 1 < segment involvement score <5 at core lab coronary CTA analysis and 6 patients were lost at follow-up). Higher atherosclerotic burden was found in patients with higher clinical risk, but prevalence of elevated noncalcified plaque volume did not significantly differ between low-versus high-risk patients.

Quantitative plaque parameters by coronary CTA were associated with composite endpoints at multivariable analysis when corrected for univariate predictors. Elevated noncalcified plaque volume, expressed as dichotomic variable, was associated with all combined endpoints. Even if the low absolute number of events represents a limitation to the present study, patients with low noncalcified plaque volume had similar risk of cardiac events independently from the presence of multivessel disease, while patients with high noncalcified plaque volume had higher rates of cardiac events. Continuous variables normally distributed were compared using the Student's t-test for independent 10.6 AE 6.8; p ¼ 0.014) ( Table 1) .

Medical therapy was more prevalent at baseline among patients with a higher clinical risk profile.

Plaque volume was analyzed both as continuous and as discrete dichotomic variables, using the HQ (75th percentile) among the entire population as cutoff values that resulted to be >300 mm 3 for total plaque volume, >80 mm 3 for noncalcified plaque volume, and >10 mm 3 for low-attenuation plaque. The same approach was used for SIS, SSS, and CT-adjusted Leaman score and the HQ cutoff resulted to be >7

for SIS, >13 for SSS, and >12 for the CT-adjusted Leaman score. The majority of coronary CTA data suggested higher atherosclerotic burden in patients with higher clinical risk; however, the prevalence of elevated noncalcified plaque volume when considered as a dichotomic variable did not significantly differ between low-risk versus high-risk patients ( Table 4) .

Concerning the advance CT plaque analysis, all qualitative high-risk plaque features were associated with all different combined endpoints (Table 4) .

Finally, the quantitative plaque parameters were associated to all the combined endpoints, both when Values are mean AE SD or n (%).

ACE ¼ angiotensin-converting enzyme; At1-blockers ¼ angiotensin receptor blockers; BMI ¼ body mass index; CAD ¼ coronary artery disease; Hb ¼ hemoglobin; HDL-C ¼ high-density lipoprotein cholesterol; hsTnT ¼ highsensitivity troponin T; LDL-C ¼ low-density lipoprotein cholesterol; PTX3 ¼ pentraxin-3; SCD ¼ sudden cardiac death; Total-C ¼ total cholesterol. considered as continuous or as dichotomic variables ( Table 6) .

Separate multivariable analysis in low-versus highrisk patients and excluding patients with diabetes confirmed plaque volume <150 HU as an independent predictor of events in both groups of patients (Supplemental Tables 1 and 2 ). Akaike information criterion was calculated and is reported in Supplemental Table 3 . Similarly, patients with low noncalcified plaque volume were almost free of events at follow-up even if the 10-year risk of heart attack (FRS) was more than 20% (100% and 99% ACS-free survival probability in patients with or without FRS >20%, respectively).

On the contrary, the subgroup of patients judged to Values are n (%) or mean AE SD.

CAD ¼ coronary artery disease; CT ¼ computed tomography; CTA ¼ computed tomography angiography; HPF ¼ high-risk plaque feature; HQ ¼ highest quartile; HU ¼ Hounsfield units; LAP ¼ low-attenuation plaque; LM ¼ left main disease; NRS ¼ napkin ring sign; Pl Vol ¼ plaque volume; RI ¼ remodeling index; SC ¼ spotty calcification; SIS ¼ segment involvement score; SSS ¼ segment stenosis score; other abbreviations as in Table 1. have a low or moderate clinical risk, but with coronary CTA showing high noncalcified plaque volume, has been reclassified by coronary CTA avoiding underestimation of their cardiovascular risk (80% MACE-free survival probability in patients with low FRS but with high noncalcified plaque volume; log-rank p < 0.001). Similar results were obtained when atherosclerotic cardiovascular disease risk score was used instead of FRS (Supplemental Figure 1 ).

The main finding of this analysis of CAPIRE study supports quantitative parameter of coronary CTA plaque assessment, more specifically the coronary plaque volume and particularly the noncalcific plaque volume, as the most powerful predictor of cardiovascular events at follow-up over lumen stenosis and clinical risk profile. Excluding patients with known heart disease enabled to specifically address the association between coronary atherosclerosis evaluated by coronary CTA and future acute coronary events; moreover, the peculiar study design, leading to a dichotomic distribution of traditional risk factors among our population, enabled us to demonstrate that the prevalence of elevated noncalcific plaque volume was not differently distributed in low-versus high-risk patients. The traditional approach to CAD is based on primary prevention for risk factor control in asymptomatic subjects and on myocardial Values are mean AE SD or n (%), unless otherwise indicated.

ACS ¼ acute coronary syndrome; CI ¼ confidence interval; HR: ¼ hazard ratio; other abbreviations as in Table 1 . Values are n (%), unless otherwise indicated.

Abbreviations as in Tables 1 to 3 . Notably, the multivariable analysis to predict cardiac events showed that the addition of MVD to the 

A U G U S T 2 0 2 0 : 1 7 1 8 -2 0

Editorial Comment body of published data evaluating whole-heart plaque quantification using coronary CTA. However, much work remains to be done before its routine clinical use ( Figure 1) During the administration of 20 mg of adenosine triphosphate (ATP) at 160 mg/kg/min for >3 min (11) Twenty-three patients were lost to follow-up; therefore, the final study population comprised 540 patients with suspected or known coronary artery disease. CT ¼ computed tomography. Table 1 shows baseline patient characteristics in all patients and those with suspected or known CAD. The dose-length products for CTA, CTP, and CTDE (15) 48 (14) 32 (15) Family history of CAD 101 (19) 52 (16) 49 (24) Body mass index >25 kg/m 2 177 (33) 112 (34) 65 (31) Echocardiography LVEF <50% 64 (12) 20 (6) 44 (21) Wall motion abnormality 168 (31) 50 (15) 118 (57) Symptom Typical 62 (11) 34 (10) 28 (13) Atypical 107 (20) 76 (23) 31 (15) Nonanginal 81 (15) 57 (17) 24 (12) Dyspnea 62 (11) 37 (11) 25 (12) History of CAD (20) Old myocardial infarction 108 (20) 0 (0) 108 (52) Values are n (%) or mean AE SD.

CABG ¼ coronary artery bypass grafting; CAD ¼ coronary artery disease; LVEF ¼ left ventricular ejection fraction; PCI ¼ percutaneous coronary intervention. 

Obstructive CAD 244 (45) 118 (36) 126 (61) Severe stenosis 142 (26) 68 (20) 74 (36) Multivessel disease 144 (27) 70 (21) 74 (36) Proximal LAD stenosis 117 (22) 44 (13) 73 (35) Stenosis score $6 155 (29) 55 (17) 100 (48) Dynamic CT perfusion Ischemic score $4* 169 (31) 88 (26) 81 (39) Ischemic score $8 79 (14) 38 (11) 41 (20) CT delayed enhancement

Myocardial scar 196 (36) 42 (13) 154 (74) $2 segments with scarring 150 (28) 26 (8) 124 (60) Scar score $4 126 (23) 20 (6) 106 (51) Scar score $8 73 (14) 8 (2) 65 (31) Values are n (%). *Ischemic perfusion defect was defined as ischemic score $4.

CAD ¼ coronary artery disease; CT ¼ computed tomography; LAD ¼ left anterior descending artery.

Ischemic score $4 was the strongest predictor of hard events (HR: 25.8; 95% CI: 3.3 to 204; p ¼ 0.002).

REGRESSION ANALYSIS. Models for multivariate analysis were created to evaluate whether IPD (ischemic score $4) was an independent predictor when adjusted for each of the predictors ( Table 4 ). In all patients, IPD was an independent predictor when adjusted for obstructive CAD, severe stenosis, proximal LAD stenosis, scar score $4, and wall motion abnormality. In these models, obstructive CAD, severe stenosis, proximal LAD stenosis, and myocardial scarring were also independent predictors against IPD, but wall motion abnormality was not. In patients with suspected CAD, IPD remained an independent predictor when adjusted for obstructive CAD, severe stenosis, proximal LAD stenosis, scar score $4, and CCS $400. In these models, obstructive CAD, severe stenosis, proximal LAD stenosis, scar score $4, and CCS $400 were independent predictors against IPD.

In patients with known CAD, IPD was an independent predictor when adjusted for obstructive CAD, severe stenosis, proximal LAD stenosis, multivessel disease, and scar score $4. In these models, multivessel disease and scar score $4 were independent predictors against IPD, whereas obstructive CAD, severe stenosis, and proximal LAD stenosis were not.

Multivariate analysis of predictors for hard events are listed in Supplemental Table 2 . IPD remained an independent predictor of hard events in all patients when adjusted for current smoker, wall motion abnormality, severe stenosis, and scar score $4. In these analysis, current smoker was an independent predictor against IPD, whereas wall motion abnormality, severe stenosis, and scar score $4 were not.

Kaplan-Meier curves by IPD ( Figure 3) showed that annualized event rates for MACEs were significantly different between patients with and without IPD among all patients (8.4% vs. 1.1%; p < 0.001) ( Figure 3A) and those with suspected (7.8% vs. 0.8%; p < 0.001) Nakamura et al. Annualized event rates for MACEs in patients with ischemic scores of #3, 4 to 7, and $8 were 1.1%, 6.3% and 11.3% respectively, in all patients (p < 0.001); 0.8%, 5.8%, and 11.1% in patients with suspected CAD respectively (p < 0.001); and 1.9%, 6.7%, and 11.0% in patients with known CAD, respectively (p < 0.001) (Supplemental Figure 1 ).

OBSTRUCTIVE CAD. To evaluate the incremental prognostic value of IPD over obstructive CAD, global chi-square scores and concordance index were calculated ( Figure 4) . Figure 4A shows that, by adding IPD to obstructive CAD, global chi-square scores increased significantly from 25.1 to 59.5 in all patients (p < 0.001), from 17.5 to 37.9 in patients with suspected CAD (p < 0.001), and from 5.0 to 18.6 in patients with known CAD (p ¼ 0.001).

ROC curve analysis for prediction of MACEs ( Figure 4B ) showed that the concordance index after adding IPD to obstructive CAD was significantly higher than that in obstructive CAD alone in all patients and in those with suspected and known CAD. Figure 5A shows that, among patients with stents who had no CABG, a significant difference in annualized event rates was apparent between patients with and without IPD (11.5% vs. 2.6%; p < 0.001).

In patients with heavy calcification, among those with suspected CAD, IPD had a significant association with poor prognosis. Annualized event rates for MACEs were significantly higher in patients with IPD than in those without among patients with a calcium score 400 (13.3% vs. 3.1%; p < 0.001) ( Figure 5B ).

DEGREE OF STENOSIS. Kaplan-Meier curves by IPD according to CTA results ( Figure 6 ) showed that patients with IPD had a worse prognosis than those without IPD among those with moderate (50% to 69%) stenosis but no severe ($70%) stenosis (annualized event rate: 8.8% vs. 1.0%; p < 0.001) Tables 1 and 2 . who had undergone bypass grafting were excluded. Abbreviations as in Figure 3 . Prognostic Value of Stress Dynamic CTP With CTDE in patients with IPD (þ) and scar score $4, with IPD (þ) and scar score <4, with IPD(-) and scar score $4, and with IPD(-) and scar score <4, respectively (p < 0.001). In Figure 7B , global chisquare tests showed that IPD and scar score $4 had incremental prognostic value over each other (p < 0.001). Details of events in patients with IPD or scarring are given in Supplemental Table 3 . There was no significant difference in the number of each event between IPD and scar score $4.

The main findings of the present study were that: 1) Figure 3 . Nakamura et al. fibrosis associated with abnormally increased extracellular volume (ECV). In the left anterior descending coronary artery (LAD), a stent is represented in its midportion, characterized as patent by CTA, without significant pressure drop by CT FFR (negative), but associated with a previous distal myocardial infarct, characterized by CT DE. Moreover, the stented lesion is also associated with a distal fixed perfusion defect due to reduced capillary density in the scar, which commonly extends to its peri-infarct border caused by lower capillary density (mixed normal and scarred myocardium) combined or not with microvascular dysfunction. CT ECV is greatly increased in the scar, as expected, and possibly increased in the peri-infarcted region as well because of tissue mixing or repeated ischemia and apoptosis. The heart cartoon also shows a first large LAD diagonal affected by diffuse atherosclerosis but with no significant morphological stenosis, as demonstrated by CTA. CT FFR can be abnormal if too many lesions in series lead to an overall pressure drop across the entire epicardial vessel length. CTP may be normal or abnormal because of microvascular disease and dysfunction. Finally, although CT DE is most often negative for myocardial scar, CT ECV can be increased because of chronic ischemia from microvascular disease with interstitial fibrogenesis. Importantly, the cartoon illustrates that multiple scenarios due to different combinations of macrovascular and microvascular disease can occur, and very frequently do, in the same heart in a patient with CAD, particularly in those with advanced ischemic heart disease. In this regard, although computed tomographic replacement fibrosis phenotyping through delayed enhancement is more than a decade old (14), the recently demonstrated ability to quantify interstitial myocardial fibrosis by CT (15) could provide additional insight into the pathogenesis of heart failure in patients with preserved ejection fraction (16) . Given that heart failure in general and heart failure with preserved ejection fraction specifically are frequently associated with macrovascular atherosclerosis and microvascular ischemic heart disease (17, 18) , such avenues for further investigation may prove uniquely important to patients with heart disease in the future.

In summary, the work by Nakamura et al. (9) demonstrates an important option to physicians who seek to detail the prognostic paths their patients with Table 1 . Overall, baseline characteristics in the two groups were mostly balanced. The majority of patients (58%) had pacemakers, 25% had ICDs, 16% underwent cardiac resynchronization therapy (CRT), either with a pacemaker or a defibrillator, and 1% had an epicardial lead. Implanted prosthetic heart valves were present in 17.5% of the study population.

Overall, the most prevalent pathogens causing CDRIE were staphylococci organisms (35%). Values are n (%). *Cox proportional hazards analyses were applied to calculate hazard ratios (HRs) and 95% confidence intervals (CIs); for the in-hospital mortality, and new heart rhythm and conduction disturbance odds ratios (ORs) with 95% CI were calculated instead. Values in bold indicate statistical significance. The In the analysis patients with positive 99m Tc-HMPAO-SPECT/CT scans for CDRIE had higher in-hospital mortality rates than those with negative 99 mTc-HMPAO-SPECT/CT results (11.4% vs. 0%, respectively; p ¼ 0.04). p < 0.05 were considered statistically significant. Abbreviations are as in Figure 1 . and log-rank test results. p < 0.05 were considered statistically significant. Abbreviations are as in Figure 1 .

Holcman et al. The total incremental admission mortality rate for patients with CDRIE varies from 4.7% to 11.5%, depending on the CIED type and the patient's status (21 uncontrolled infection, renal replacement therapy, reoperation due to CDRIE, new heart rhythm, and conduction disturbances. p < 0.05 were considered statistically significant. Abbreviations are as in Figure 1 . Abbreviations are as in Table 1 .

Holcman et al. Abbreviations as in Table 1 . Table 1) .

Holcman and colleagues in this issue (16) This has already been part of clinical routine in cancer Subsequently, endocardial and epicardial contours of the short-axis LGE images were traced manually.

Myocardial scar core size was automatically quantified using the full-width at half-maximum method, which defines scar as myocardium with signal intensity >50% of the maximum signal intensity in the hyperenhanced area. In addition, scar border zone was defined as myocardium with signal intensity >35%, but <50% of the maximum signal intensity in the hyperenhanced area, as described previously (10) .

Total scar size, scar core size, and border zone size were expressed as grams and percentages of the total LV mass. In addition, transmurality of scar core was evaluated, and segments were characterized as 1% to 25%, 25% to 50%, 50% to 75%, and 75% to 100% transmurality. ACE ¼ angiotensin converting enzyme; ARB ¼ angiotensin-II-receptor blockers; Ca ¼ calcium; CABG ¼ coronary arterial bypass graft; CRT-D ¼ resynchronization therapy; NT-proBNP ¼ N-terminal prohormone of brain natriuretic peptide; NYHA ¼ New York Heart Association; PCI ¼ percutaneous coronary intervention; VA ¼ ventricular arrhythmia.

For [ 11 C]HED image analysis, plasma parent fractions, and ratios of plasma to whole-blood concentrations derived from manual arterial blood samples were fitted to a sigmoid function (13) . Subsequently, the arterial whole-blood TAC was multiplied by the There were no significant differences in clinical characteristics between patients with or without VA, but patients who showed VA tended to be younger (63 AE 8 vs. 67 AE 9 years; p ¼ 0.06). Figure 2 shows an example of CMR and PET imaging in a patient who remained free of VA.

CHARACTERISTICS. The results of CMR imaging are presented in Table 2 and Figure 3 . The current study indicated that the amount of scar border zone was associated with VA, whereas scar core was not. Previous studies demonstrated that myocardial scar is strongly associated with SCD in patients with ischemic cardiomyopathy (17, 18) .

Studies evaluating both scar core and border zone in patients with coronary artery disease often indicate that scar border zone might be a better predictor for VA than scar core mass alone (10, 14, 19, 20) . Our results are consistent with findings of Roes et al.

(2009), who showed that scar border zone was the strongest predictor for VA, whereas scar core and total infarct zone were not associated with VA (10).

The infarct border zone often comprises a mixture of viable and nonviable tissue with heterogeneous conduction times, which may give rise to re-entry pathways and provide substrate for VA (21) . However, a recent study of Acosta et al. (3) evaluated 217 patients with ischemic and nonischemic cardiomyopathy and concluded that both scar mass and border zone were independently associated with VA. These inconsistent findings may partly be explained by sample-size differences and the use of different methods for defining scar core area (3, 19) . In the current study, the full width at half maximum method was used to define scar areas, as this method has been shown to provide the most reproducible results (22) .

This study failed to show an association between quantitatively assessed myocardial perfusion using PET and the occurrence of VA. In this same patient cohort, however, an independent relationship between impaired global hyperemic MBF and inducibility of VA was demonstrated using an electrophysiological study (6) . Previous studies that 

A U G U S T 2 0 2 0 : 1 7 5 5 -6 6 been linked to electric instability, as areas of denervated myocardium show prolonged refractory periods and supersensitivity to cathecholamines (27) (28) (29) . In a previous study, the size of sympathetic denervated myocardium was found to be larger in patients with inducible VA (9) . In addition, the

Positron Emission Tomography) study revealed that total sympathetic denervation size independently predicts appropriate ICD therapy for fast VA (7 ACE ¼ angiotensin converting enzyme; ARB ¼ angiotensin-II-receptor blocker; CFR ¼ coronary flow reserve; CI ¼ confidence interval; HED ¼ hydroxyephedrine; HR ¼ hazard ratio; LVEDVi ¼ leftventricular end-diastolic volume index; LVEF ¼ left-ventricular ejection fraction; MBF ¼ myocardial blood flow; NT-proBNP ¼ N-terminal prohormone of brain natriuretic peptide; NYHA ¼ New York Heart Association; RI ¼ retention index. may be hemodynamically tolerated or self-limiting (33) . It is therefore possible that the role of our imaging parameters on the effect of SCD was overemphasized.

ICDs for primary prevention of SCD, increased 

Current problem: Primary prevention ICD patients experience a low incidence of appropriate ICD therapy. Improved risk stratification of SCD is important to identify patients who could benefit of ICD implantation. compromising the high frame rate (24) . Consequently, blood and tissue motion in addition to tissue structure may now be explored using high frame rate ultrasound imaging (Central Illustration).

Ultrafast Doppler imaging. Conventionally, blood flow is detected with Doppler ultrasound by discriminating signals according to their temporal characteristics based on Doppler frequency (25) . Because red blood cells tend to move faster than the surrounding tissue, their Doppler frequency is generally higher, and the 2 signals can be separated by applying a temporal filter. In cardiac imaging, myocardial tissue also moves, which can make blood flow detection more challenging. In ultrafast ultrasound, all the pixels (or voxels) in a frame (or in a volume) are analyzed simultaneously, and both the temporal and spatial characteristics of the incoming signals can be exploited (26) . Tissue is known to be more spatially coherent than blood and is far less deformable than blood. This results in the signals from neighboring pixels or voxels inside a tissue area to be more likely correlated to one another. This additional spatial information allows the use of spatiotemporal filters, which dramatically improve blood detection (27) . Hence, ultrafast ultrasound not only brings the possibility of imaging high velocity flow but also the ability to efficiently discriminate blood flow from tissue movement (Video 1).

Coronary ultrafast Doppler angiography. Flow detection in the coronary circulation requires distinguishing the blood signal from myocardial movement. This becomes even more challenging for imaging the coronary microvasculature (with a diameter <100 mm).

The use of specific and adaptive spatiotemporal filters 

Assessment of myocardial stiffness.

Assessment of myocardial stiffness using acoustic radiation force.

Link between mechanical activation and electrical stimulation.

Speckle tracking of intraventricular blood flow. Wall shear stress (WSS).

Standard Doppler techniques using in high frame rate.

Tissue structure

Backscatter tensor imaging (BTI) Elastic tensor imaging (ETI) Villemain Here, the shear wave is generated by an internal stimulus (valve closure) and the ultrafast imaging allows to see its propagation. On M-mode acquisition along the midline of the left ventricular septum, a spatiotemporal representation of the local tissue acceleration is obtained and allows to estimate the shear wave speed.

Adapted with permission from Petrescu (50) . CA ¼ cardiac amyloidosis; HV ¼ healthy volunteer; other abbreviation as in Figure 2 .

Villemain et al. (18).

From a practical point of view, the variation of frame rate (from conventional to ultrafast) does not change the clinical constraints of pediatric cardiology.

Indeed, the transmission/reception frequency, allowing optimization of the spatial resolution and thus adaptation of the anatomy explored, will be generally the same whatever the frame rate. In addition, the type of probe (phased array or linear) and angular dependency remains the same. In the future, the manufacturer (and not the practitioner) will need to adapt its systems and "probe to system" transmissions to allow the application of ultrafast imaging in pediatrics (as in adult cardiology).

For this reason, few details will be discussed in this section on the type of equipment, type of probe, or emission/reception frequencies because these parameters will be broadly comparable to daily clinical practice. In the case of an exception (e.g., for coronary ultrafast Doppler angiography [CUDA] only demonstrated with a linear probe for technical reasons), precision will be provided.

In this paper, the applications will therefore be grouped by type of disease and not by age group (as traditionally used in pediatrics) because all the techniques presented do not have specific limits according to the patient's age or weight. In addition, they showed, using ETI (previously compared with histology [17] ), that the fractional anisotropy was different between healthy volunteers Ultimately, BTI could alter our comprehension of the The importance of quantitative CVP assessment is well described for prognostication of PAH patients (86) . However, in pediatrics, because of a lack of reliable tools, this parameter is not widely used to evaluate PAH. Likewise, the assessment of filling pressures in the functionally univentricular heart is limited, but important because of the preload dependence of the Fontan circulation. In addition, the significant risks of long-term hepatic impairment in patients with a functionally univentricular heart is emerging as an increasingly important prognostic factor (87, 88) . Therefore, better diagnostic tools to characterize liver morphology, stiffness, and their relationship to the cardiac status and pulmonary arterial pressures in the Fontan circulation is needed. Noninvasive quantitative evaluation of right heart filling pressures was very limited before the advent of LS (21) . Therefore, quantitative assessment of CVP by SWE in this population deserves further study.

Nevertheless, the parameters that can influence LS (notably fibrosis, inflammation, or cholestasis) can complicate its interpretation at the patient's bedside. Therefore, myocardial stiffness must be analyzed in terms of contractile stress properties. ESPVR is a linear parameter ( Figure 12 ) and can be characterized by a slope (E es , end-systolic elastance) and a volume axis intercept (V o ), so that:

where P es and V es are end-systolic pressure and volume, respectively. Importantly, this relationship was initially shown to be independent of afterload (106) . Ultimately, the ESPVR characterizes properties of the ventricular chamber when the myocardium is at maximal activation at a given contractile state. The stakes will be the same for ultrafast imaging. The development of a 2D multiplane analysis, or more generally a 3D ultrafast imaging approach, will probably be necessary to analyze the heart as a whole.

Initial preclinical studies are beginning to open this possibility (113, 114) , clinical proof of concept is now the next step.

Last, and more specifically, concerning natural shear waves generated by the mitral valve, the electrical conduction through the myocardium leads to 

Ultrafast ultrasound imaging could be a central noninvasive imaging tool, particularly in congenital and pediatric cardiology.

Myocardial stiffness assessment by ultrafast ultrasound imaging has the potential to become a cornerstone of ultrasound imaging in cardiology, particularly for the noninvasive assessment of systolic and diastolic physiology.

Further clinical developments could potentially reduce the need for cardiac magnetic resonance or imaging techniques requiring radiation. 

The pathogenesis of COVID-19 is characterized by 2 distinctive but synergistic mechanisms, the first (10) . The extent to which these finding may also apply to SARS-CoV-2 is unknown. To date, no cases of SARS-CoV-2 nucleic acid isolation from myocardial specimens have been described.

However, several cases have reported on the occurrence of severe myocarditis during laboratory-proven COVID-19 (11) (12) (13) (14) (15) . In all these cases, myocarditis 

A U G U S T 2 0 2 0 : 1 7 9 2 -8 0 8 procoagulant state with increased risk for arterial and venous acute thrombotic events, including type 1 myocardial infarction (MI) and pulmonary embolism (PE). Indeed, there is increasing concern that patients with COVID-19 are more prone to develop thromboembolic venous events and disseminated intravascular coagulation (18, 19) . Secondary cardiac involvement may also be the consequence of COVID-19 pneumonia is characterized by initial interstitial damage with a bilateral, peripheral, and posterior distribution followed by parenchymal involvement (34) . LUS effectively detects the areas Pleural effusion is rare *The term "ground-glass opacities" is also used in CXR to refer to areas of blurred opacities. LUS score, validated with chest CT comparison, provides a numeric assessment of regional loss of aeration that can be used to assess the response to treatments (33) (Figure 3) . Table 3 . Values are n/N (%) or median (interquartile range). *RV dilatation has been defined as RV mid diameter >35 mm. †RV dysfunction has been defined as either tricuspid annular plane systolic excursion <17 mm or Doppler tissue imaging S wave (S 0 wave) <9.5 cm/s. ‡PH has been defined as sPAP >35 mm Hg.

CVP ¼ central venous pressure; LVEF ¼ left ventricular ejection fraction; PH ¼ pulmonary hypertension; RV ¼ right ventricular; RWMA ¼ regional wall motion abnormality; sPAP ¼ systolic pulmonary arterial pressure. and 2 were assigned if parenchymal opacification involved 0%, <50%, and $50%, respectively, of each region (severity score range 0 to 40). The individual scores for each lung as well as the total score were significantly higher in patients with clinically severe COVID-19 compared with mild cases. A severity score <19.5 was highly effective in ruling out severe COVID-19 pneumonia, with a negative predictive value of 96.3% (31).

In the same way LUS could be effective in evaluating COVID-19 pneumonia severity and monitoring its modifications over time. For this purpose the numeric assessment of regional loss of aeration measured by global LUS score could represent a useful tool (33) . The global LUS score can be calculated as the sum of regional aeration scores attributed to each lung region during a standard 12-zone examination:

involving #50% of the pleura, 2 ¼ B-lines becoming coalescent or involving >50% of the pleura, and 3 ¼ tissue-like pattern (33) (Figure 3) . The global LUS score showed a good correlation with lung density as assessed on CT and has been applied in the ICU setting to quantify and monitor lung aeration in weaning from mechanical ventilation and in patients with ARDS on extracorporeal membrane oxygenation (33) . So far, the implementation of the global LUS score to monitor disease evolution and to guide decision making in patients with COVID-19 has not been systematically investigated. 

Cardiac involvement is present in up to 12% of patients with COVID-19.

Multimodality imaging is essential in different clinical settings in COVID-19.

Multimodality imaging is useful in diagnosis, risk stratification, and management.

Strategies for preventing viral transmission during examinations must be adopted.

The T he highly anticipated ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, the largest study to-date conducted to assess for the incremental clinical benefits of an initial invasive management strategy over an initial medical therapy strategy in patients with stable ischemic heart disease (SIHD), was just published (1). This study has important implications for the field of imaging as well as coronary interventions-how the trial will change these fields and each modality will be debated fiercely over the next many months. We want to pro- SUMMARY. Stress testing remains a vital diagnostic option for patients with ischemic heart disease.

In particular, with its extensive evidence-base Clear, focused, and clinically relevant study Elegant study design: large, randomized, multicenter, international recruitment Robust outcome measures Well-powered study (>80% power to detect an 18.5% relative reduction in the primary endpoint assuming an aggregate 4-yr cumulative event rate of approximately 14%) Excellent follow-up: >99% complete follow-up Outstanding optimal medical therapy (w95% statin use, 70% angiotensin-converting enzyme or angiotensin-converting enzyme inhibitor use, 96% aspirin use) Excellent risk factor control (nearly 90% nonsmokers, and 77% with well controlled systolic blood pressure <140 mm Hg).

A lack of equipoise; published data was conflicting, and physicians were not willing to randomize all patients with more than moderate ischemia. We do not know the percentage of patients screened who were eventually enrolled. Some sites report this to be 10% of patients who were identified as having moderate to severe ischemia, where there was a negative bias toward enrolling patients in the trial particularly when ischemia was more severe. Thus, the generalizability may be difficult to ascertain. Smaller numbers of women, nonwhite, and Hispanic participants. Only 23% (1,168 of 5,179) of the randomized cohort comprised women. Women more often manifested symptoms, and ischemic changes in the absence of obstructive CAD (women comprised 66% of the cohort excluded for nonobstructive CAD). Smaller cohorts of nonwhite (33.7%) and Hispanic (15.5%) patients were included (23) . Heterogeneity in patients enrolled, revascularization practices, and the definition of ischemia. B 348 sites (320 randomizing sites) from 38 countries recruited subjects into this study. This has added heterogeneity in patient characteristics (23) , and practice patterns, as free stents and free medicines were provided to some of the international sites, which may have affected subject selection for study enrollment, revascularization method selection in the invasive arm, as well as cross over from the conservative to invasive arm. B Ischemia tests included electrocardiographic ischemia, radionuclide/cardiac magnetic resonance myocardial perfusion abnormalities, and ischemic wall motion abnormalities, which may have different implications for burden of ischemia and prognosis. Due to slow recruitment, study inclusion criteria were amended to include patients based on exercise stress test evidence of ischemia, the study primary endpoint was amended as pre-specified into the study, and follow-up was reduced in 2014. Inclusion of exercise stress alone cohort is problematic as the magnitude of electrocardiography changes do not correlate to the extent and severity of ischemia. It added heterogeneity to the patient cohort and may have diminished the study power for drawing conclusions for the imaging-based ischemia alone. Whether this exercise stress-only cohort underwent fewer revascularizations is not clear. The exercise stress-only cohort had a stricter cutoff of 70% stenosis in a coronary artery serving a large myocardial region before randomization (23) . It is not surprising then that the exercise stress-only cohort had greater frequency of severe ischemia (83% vs. 44.8% for imaging stress test) (23), greater frequency of 3-vessel CAD, LAD, and proximal LAD stenosis than participants undergoing stress imaging. On the other hand, they were also younger, less often white, with lower prevalence of hypertension and prior PCI or CABG, stroke, or MI (23) . Exercise stress-only cohort made up 25% of all patients enrolled. All eligible stress-only patients were assigned to the severe category, thus accounting for 50% of severe ischemia, a disproportionate portion of patients that may have diluted the severe ischemia cohort defined on imaging. It is well-recognized that high-risk ischemic features on nuclear imaging (transient ischemic dilation, heart to lung ratio, right ventricular tracer uptake, left ventricular ejection fraction, and myocardial blood flow values by positron emission tomography) portend greater risk. It is not clear if these were considered and we await the subanalyses. Unblinded study without sham procedure for revascularization. This may have potentially increased hospitalization for unstable angina or heart failure and cross over from conservative to invasive arm (24) . Completeness of revascularization has not been reported yet, but chronic totally occluded coronary arteries were common and frequently not revascularized. At this time, we do not know if the revascularization was directed to the coronary stenoses that subtended ischemic territories. The study was underpowered to evaluate CABG vs. PCI separately. Invasive patients may have been treated according to local practices. This may have made the selection of all invasive modalities (PCI and CABG) suboptimal and, as such, appear no better than medical therapy (paraphrased from communication with M. Ruel, MD) (pending citation).

CABG ¼ coronary artery bypass surgery; CAD ¼ coronary artery disease; LAD ¼ left anterior descending; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention.

substantiating its utility and versatility and continued refinements in its diagnostic precision, stress echocardiography will retain a prominent role as a robust tool for assessment of patients with ischemic heart disease. The ISCHEMIA study has several strengths and weaknesses ( Table 1) . DO Results interpretation and concern of extrapolating from ISCHEMIA. As with many trials, there are differences in the interpretation of the ISCHEMIA results, and various attempts will be made at extrapolating beyond the data provided and questions asked in the trial.

A problematic interpretation by some is that the Given the astronomical financial losses faced by our health systems, will our careers face major hurdles in turn affecting our lives? These are but a few of the stressors that we continue to face in these challenging times.

Across our hospitals, nearly all elective procedures, including a large volume of patients with planned stress tests, were deferred, and most were rescheduled into June or later (Figure 1) . interactions often left us feeling that many questions were unanswered and with residual concern about the patient's state and need for intensified cardiovascular care, which we were unprepared to provide.

At its onset, COVID-19 was deemed primarily a respiratory disease, but we rapidly recognized multiorgan involvement with distinct and devastating cardiovascular manifestations. For the sickest patients, acute cardiac decompensation was observed, whereas others had elevated troponin levels, raising concern for an initial diagnosis of acute myocardial What has happened over the past few months is unimaginable, and its emotional toll on our lives has yet to be fully realized. There are so many ways that these challenges have added stress to our day, for example, anxiety related to the potential shortages of personal protective equipment, concern over cut- other studies, which reported that a worse baseline LVGLS was associated with negative outcomes (4-6).

A total of 4 studies generated receiver-operating characteristic curves (2, 3, 5, 6) . In 3 studies, the cutoff value of LVGLS was found to be À18%, À18.4%, and À18.1%, which could be used to predict worse outcomes in patients with chronic primary MR undergoing mitral valve surgeries (2, 5, 6) . 10

Stress single-photon emission computed tomography (SPECT) incurred higher 12-months cost for ischemic heart disease testing versus stress cardiac magnetic resonance (CMR) across a range of Duke Activity Status Indexes (DASI) (p < 0.01). (Table) VT optimal cutoff points. We studied 546 subjects (55% were men; age 29.5 AE Table 1 ;

intraclass correlation coefficient values for all measurements were good to excellent (0.88 to 0.99). With To our knowledge, this was the largest prospective rTOF CMR study of high-risk patients with significant PR. Our multinational cohort consisted of a balanced representation of children, young adults, middleaged adults, and older adults across the 4 age quartiles, which enhanced generalizability (as opposed to previous data reported from a single country with younger subjects) (2). Our results confirmed that male and female hearts with rTOF were distinct, and adaptive response of cardiac dimensions and systolic function to chronic volume overload appeared to vary according to age and by sex.

At more advanced ages, women displayed more extensive change within the right heart. Older adult women had larger RV volumes, whereas the extent of RV dilation did not differ significantly in older males versus younger males, which suggested that age might be a more important consideration for timing of PV intervention in females to mitigate irreversible RV remodeling in older women with larger RV volumes. approach. With the knowledge that females with rTOF have smaller hearts at baseline but may be more susceptible to RV enlargement and RV systolic dysfunction with advancing age, one must question whether referral for intervention should incorporate sex and age variables. We suggest that our data may carry the potential to further inform risk stratification and timing of PV intervention in rTOF. Interclass correlation coefficients (ICC) with 95% confidence intervals (CIs) were performed to test intrareader and inter-reader consistency of agreement, and mean differences (and 95% CI) were estimated. LGE was quantified using a threshold of 6 SDs above the mean signal intensity of the reference myocardium.

The median duration of follow-up was 37 months year; 95% CI: 0.3% to 1.9%; p ¼ 0.005). T1 decreased over time in men not on ERT (À7.6 ms per year; 95% CI: À12.6 to À2.5; p ¼ 0.003), although there was a tendency to a smaller reduction on ERT (À2.4 ms; 95% CI: À4.6 to À0.1; p ¼ 0.039; between groups: p ¼ 0.064). However, in women, T1 decreased over time in those not on ERT (À8.3 ms per year; 95% CI:

À12.6 to À3.9; p < 0.001) but increased in the ERT group (þ6.2 ms per year; 95% CI: 2.0 to 10.4; p ¼ 0.004; between groups: p < 0.001).

This longitudinal CMR study was consistent with a sex-specific myocardial response in FD. Men had more advanced cardiac involvement at baseline and progressed at a greater rate than women, despite use Figures 1H and 1I A plaque in the right coronary artery (RCA) without high-risk plaque (HRP) features progressed into an obstructive lesion at follow-up, whereas a plaque in the left anterior descending (LAD) artery with HRP features at baseline remained nonobstructive at follow-up. The diameter stenosis was similar between the 2 lesions, but total percent atheroma value (PAV) was greater in the RCA lesion without HRP features than the LAD lesion with HRP features. In multivariate analysis that adjusted clinical risk factors and baseline PAV, diameter stenosis, and the presence of HRP, both PAV and percent diameter stenosis were significant risk factors for the development of obstructive lesions, but HRP was not.

Subclinical atrial fibrillation in older patients

Subclinical device-detected atrial fibrillation and stroke risk: a systematic review and meta-analysis

Challenges in infective endocarditis

Complications of cardiac implants: handling device infections

ESC Guidelines for the management of infective endocarditis

16-year trends in the infection burden for pacemakers and implantable cardioverter-defibrillators in the United States

Clinical presentation, aetiology and outcome of infective endocarditis. Results of the ESC-EORP EUROENDO (European infective endocarditis) registry: a prospective cohort study

Increased longterm mortality in patients with cardiovascular implantable electronic device infections

Early diagnosis of cardiac implantable electronic device generator pocket infection using 18F-FDGPET/CT

Rising rates of cardiac rhythm management device infections in the United States: 1996 through

Guidelines for the labelling of leukocyteswith 99mTc-HMPAO

Added value of 99mTc-HMPAO-labeled leukocyte SPECT/CT imaging in the characterization and management of patients with infectious endocarditis

Clinical indications, image acquisition and data interpretation for white blood cells and anti-granulocyte monoclonal antibody scintigraphy

Added value of 99mTc-HMPAO-labeled leukocyte SPECT/CT imaging in the characterization and management of patients with infectious endocarditis

The role of 99mTc-HMPAO-labelled white blood cell scintigraphy in the diagnosis of cardiac device-related infective endocarditis

99mTc-HMPAO-labeled leukocyte SPECT/CT and transthoracic echocardiography diagnostic value in infective endocarditis

EuroEcho-imaging 2017:highlights

Inflammatory markers and 99mTc-HMPAO-labeled leukocyte SPECT/CT results in suspected infective endocarditis

Role of radiolabelled leucocyte scintigraphy in patients with a suspicion of prosthetic valve endocarditis and inconclusive echocardiography

Recommendations for the practice of echocardiography in infective endocarditis

Management of cardiac implantable electronic device infection

The European Lead Extraction ConTRolled (ELECTRa) study: a European Heart Rhythm Association (EHRA) registry of transvenous lead extraction outcomes

Mortality and cost associated with cardiovascular implantable electronic device infections

Incidence of device-related infection in 97 750 patients: clinical data from the complete Danish device-cohort (1982-2018)

Clinical utility of 18F-FDG positron emission tomography/ computed tomography scan vs. 99mTc-HMPAO white blood cell single-photon emission computed tomography in extra-cardiac work-up of infective endocarditis

Infective endocarditis -Cinderella in cardiology

Contribution of PET imaging to the diagnosis of septic embolism in patients with pacing lead endocarditis

Molecular Imaging for the diagnosis of infective endocarditis: a systematic literature review and meta-analysis

Detection of device infection using nuclear cardiology imaging

Comprehensive metaanalysis on [18F]FDGPET/CT and radiolabelled leukocyte SPECT-SPECT/CT imaging in infectious endocarditis and cardiovascular implantable electronic device infections

Radiolabeled WBC scintigraphy in the diagnostic workup of patients with suspected device-related infections

Prognostic Value of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Infective Endocarditis

Contribution of PET imaging to mortality risk stratification in candidates to lead extraction for pacemaker or defibrillator infection

Clinical presentation, aetiology and outcome of infective endocarditis. Results of the ESC-EORP EURO-ENDO (European infective endocarditis) registry: a prospective cohort study

Recommendations on nuclear and multimodality imaging in IE and CIED infections

The "3M" approach to cardiovascular infections: multimodality, multitracers, and multidisciplinary

Positron emission tomography/computed tomography for diagnosis of prosthetic valve endocarditis: increased valvular 18F-fluorodeoxyglucose uptake as a novel major criterion

multimodality imaging in infective endocarditis: an imaging team within the endocarditis team

Prognostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in infective endocarditis

The role of FDG-PET/CT imaging in early detection of extra-cardiac complications of infective endocarditis

Improving the diagnosis of infective endocarditis in prosthetic valves and intracardiac devices with 18F-fluordeoxyglucose positron emission tomography/computed tomography angiography: initial results at an infective endocarditis referral center

CT angiography for the diagnosis of infective endocarditis

Added value of 99mTc-HMPAO-labeled leukocyte SPECT/CT in the characterization and management of patients with infectious endocarditis

99mTc-HMPAO-labeled leukocyte SPECT/CT and transthoracic echocardiography diagnostic value in infective endocarditis

Whole body [(18) F]fluorodeoxyglucose positron emission tomography imaging for the diagnosis of pacemaker or implantable cardioverter defibrillator infection: a preliminary prospective study

Usefulness of fluorine-18 positron emission tomography/computed tomography for identification of cardiovascular implantable electronic device infections

Diagnostic yield of FDG positron-emission tomography/computed tomography in patients with CEID infection: a pilot study

The prognostic value of 99 mTc-HMPAO-labeled leupredictors, and survival impact

Sudden cardiac death (SCD) -risk stratification and prediction with molecular biomarkers

Sudden cardiac death prediction and prevention: report from a National Heart, Lung, and Blood Institute and Heart Rhythm Society Workshop

Relationship of non-invasive quantification of myocardial blood flow to arrhythmic events in patients with implantable cardiac defibrillators

Myocardial scar but not ischemia is associated with defibrillator shocks and sudden cardiac death in stable patients with reduced left ventricular ejection fraction

Frequency and implications of ischemia prior to ventricular tachyarrhythmia in patients treated with a wearable cardioverter defibrillator following myocardial infarction

CMR for sudden cardiac death risk stratification: are we there yet?

Scar characterization to predict life-threatening arrhythmic events and sudden cardiac death in patients with cardiac resynchronization therapy: the GAUDI-CRT study

Scar extent, left ventricular end-diastolic volume, and wall motion abnormalities identify high-risk patients with previous myocardial infarction: a multiparametric approach for prognostic stratification

Cardiac sympathetic denervation assessed with 123-iodine metaiodobenzylguanidine imaging predicts ventricular arrhythmias in implantable cardioverter-defibrillator patients

Regional myocardial sympathetic denervation predicts the risk of sudden cardiac arrest in ischemic cardiomyopathy

Value of CMR and PET in predicting ventricular arrhythmias in ischemic cardiomyopathy patients eligible for ICD

Recent evolutions in pediatric and congenital echocardiography

Echocardiography in Pediatric and Congenital Heart Disease: From Fetus to Adult

Speckle tracking echocardiography in pediatric and congenital heart disease

Threedimensional echocardiography in congenital heart disease: an expert consensus document from the European Association of Cardiovascular Imaging and the American Society of Echocardiography

Pediatric echocardiographic nomograms: what has been done and what still needs to be done

Ultrafast imaging in biomedical ultrasound

Ultrafast harmonic coherent compound (UHCC) imaging for high frame rate echocardiography and Shear Wave Elastography

Myocardial stiffness assessment using shear wave imaging in pediatric hypertrophic cardiomyopathy

Pediatric cardiac shear wave elastography for quantitative assessment of myocardial stiffness: a pilot study in healthy controls

Noninvasive imaging of the coronary vasculature using ultrafast ultrasound

Transthoracic ultrafast Doppler imaging of human left ventricular hemodynamic function

New developments in paediatric cardiac functional ultrasound imaging

Assessing the performance of ultrafast vector flow imaging in the neonatal heart via multiphysics modeling and in vitro experiments

ECG-gated, mechanical and electromechanical wave imaging of cardiovascular tissues in vivo

A clinical feasibility study of atrial and ventricular electromechanical wave imaging

Imaging the dynamics of cardiac fiber orientation in vivo using 3D ultrasound backscatter tensor imaging

Mapping myocardial fiber orientation using echocardiography-based shear wave imaging

3D elastic tensor imaging in weakly transversely isotropic soft tissues

Toward noninvasive assessment of CVP variations using real-time and quantitative liver stiffness estimation

Liver stiffness measurements for evaluation of central venous pressure in congenital heart diseases

Stone liver, heart in danger. Could the liver stiffness assessment improve the management of patients with heart failure?

Ultrafast Doppler reveals the mapping of cerebral vascular resistivity in neonates

Exposure to low-dose ionizing radiation from cardiac procedures and malignancy risk in adults with congenital heart disease

Coherent plane-wave compounding for very high frame rate ultrasonography and transient elastography

Real-time two-dimensional Doppler echocardiographic flow mapping

Ultrafast Doppler imaging of blood flow dynamics in the myocardium

Spatiotemporal clutter filtering of ultrafast ultrasound data highly increases Doppler and fultrasound sensitivity

Adaptive spatiotemporal filtering for coronary ultrafast Doppler angiography

Development and validation of echo PIV

Vector velocity estimation of blood flow -a new application in medical ultrasound

4D ultrafast ultrasound flow imaging: in vivo quanti

Robust angle-independent blood velocity estimation based on dual-angle plane wave imaging

D intracardiac ultrasound vector flow imagingfeasibility and comparison to phase-contrast MRI

Intracardiac flow analysis: techniques and potential clinical applications

Cardiac excitation-contraction coupling

Transmural heterogeneity of calcium activity and mechanical function in the canine left ventricle

Imaging the electromechanical activity of the heart in vivo

Shear modulus imaging with 2-D transient elastography

Supersonic shear imaging: a new technique for soft tissue elasticity mapping

Theory and Elasticity

Shear wave elasticity imaging: a new ultrasonic technology of medical diagnostics

Real-time assessment of myocardial contractility using shear wave imaging

Titins: giant proteins in charge of muscle ultrastructure and elasticity

In vivo quantitative mapping of myocardial stiffening and transmural anisotropy during the cardiac cycle

Propagation of spontaneously actuated pulsive vibration in human heart wall and in vivo viscoelasticity estimation

Wave propagation of myocardial stretch: correlation with myocardial stiffness

Intrinsic wave propagation of myocardial stretch, a new tool to evaluate myocardial stiffness: a pilot study in patients with aortic stenosis and mitral regurgitation

Increased myocardial stiffness detected by intrinsic cardiac elastography in patients with amyloidosis: impact on outcomes

Velocities of naturally occurring myocardial shear waves increase with age and in cardiac amyloidosis

In the heart of stiffness: are natural heart vibrations reliable to assess myocardial stiffness, the new holy grail in echocardiography?

Prospects for elasticity reconstruction in the heart

Ultrasound elastography: principles and techniques

Computational mechanics of the heart

Non-invasive myocardial shear wave elastography device for clinical applications in cardiology

An in silico framework to analyze the anisotropic shear wave mechanics in cardiac shear wave elastography

Ultrasound backscatter tensor imaging (BTI): analysis of the spatial coherence of ultrasonic speckle in anisotropic soft tissues

Motion correction for 3D ultrafast ultrasound: application to 3D backscattered tensor Imaging of soft tissues anisotropy

Ultrasound imaging of cardiac fiber orientation: what are we looking at? In

Interpretation of left ventricular diastolic dysfunction in children with cardiomyopathy by echocardiography: clinical perspective

Tissue velocities, strain, and strain rate for echocardiographic assessment of ventricular function in congenital heart disease

Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council

Dissipative energy loss within the left ventricle detected by vector flow mapping in diabetic patients with controlled and uncontrolled blood glucose levels

Diagnostic errors in pediatric echocardiography: development of taxonomy and identification of risk factors

Shunt flow evaluation in congenital heart disease based on two-dimensional speckle tracking

Pediatric transthoracic cardiac vector flow imaging -a preliminary pictorial study

The powervelocity integral at the vena contracta

The right ventricle in pulmonary arterial hypertension

Pathophysiology, adaptation, and imaging of the right ventricle in Fontan

Right versus left ventricular failure: differences, similarities, and interactions

Potential pediatric applications of PET/MR

Myocardial stiffness evaluation using noninvasive shear wave imaging in healthy and hypertrophic cardiomyopathic adults

Hypertrophic cardiomyopathy

Pathologic fibrosis and matrix connective tissue in the subaortic myocardium of patients with hypertrophic cardiomyopa

Embryological origins: how does the right ventricle form

Right ventricular physiology, adaptation and failure in congenital and acquired heart disease

Assessment of vascular /or stent implantation: relationship to central haemodynamics and left ventricular mass

Arterial stiffness estimation by shear wave elastography: validation in phantoms with mechanical testing

Arterial Stiffness Assessment by Shear Wave Elastography and Ultrafast Pulse Wave Imaging: Comparison with Reference Techniques in Normotensives and Hypertensives

Evaluation of materials used for vascular anastomoses using shear wave elastography

Shear wave elastography imaging of carotid plaques: feasible, reproducible and of clinical potential

Liver stiffness is directly influenced by central venous pressure

ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension

Diagnosis and management of noncardiac complications in adults with congenital heart disease: a scientific statement from the

Fontan-associated liver disease

Instantaneous pressurevolume relationships and their ratio in the excised, supported canine left ventricle

Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: a guide for clinical, translational, and basic researchers

Doppler-derived myocardial systolic strain rate is a strong index of left ventricular contractility

Myocardial strain: can we finally measure contractility?

New concepts in diastolic dysfunction and diastolic heart failure: part I: diagnosis, prognosis, and measurements of diastolic function

Cardiomyocyte stiffness in diastolic heart failure

General index for the assessment of cardiac function

Passive elasticity of the human left ventricle. The parallel elastic element

Diastolic heart failure-abnormalities in active relaxation and passive stiffness of the left ventricle

Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy

HFSA focused update of the 2013 ACCF/ AHA guideline for the management of heart failure

Shear wave imaging of passive diastolic myocardial stiffness: stunned versus infarcted myocardium

Quantitative assessment of left ventricular diastolic stiffness using cardiac shear wave elastography

Echocardiographic reference ranges for normal cardiac Doppler data: results from the NORRE Study

Cardiac shear wave elastography using a clinical ultrasound system

Matrix elasticity regulates the optimal cardiac myocyte shape for contractility

End-systolic pressure/volume ratio: a new index of ventricular contractility

Contraction and resting stiffness of isolated cardiac muscle: effects of inotropic agents

The cardiovascular effects of adrenaline, dobutamine and milrinone in rabbits using pressurevolume loops and guinea pig isolated atrial tissue

The development of the entire end-systolic pressure-volume and ejection fraction-afterload relations: a new concept of systolic myocardial stiffness

Accounting for the Gregg effect in tetanised coronary arterial pressure-flow relationships

Quantifying myocardial contractility changes using ultrasoundbased shear wave elastography

4-D ultrafast shear-wave imaging

Clinical characteristics of coronavirus disease 2019 in China

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19)

Association of coronavirus disease

COVID-19 infection: the perspectives on immune responses

COVID-19 illness in native and immunosuppressed states: a clinicaltherapeutic staging proposal

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Risk factors associ-Wuhan, China

Coronavirus disease 2019 (COVID-19) and cardiovascular disease

SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS

Lifethreatening cardiac tamponade complicating myopericarditis in COVID-19

Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19)

Myocarditis in a patient with COVID-19: a cause of raised troponin and ECG changes

Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

The inflammatory response in myocardial injury, repair, and remodelling

NLRP3 inflammasome and the IL-1 pathway in atherosclerosis

Acute pulmonary embolism and COVID-19 pneumonia: a random association?

ESC working group position paper on myocardial infarction with non-obstructive coronary arteries

Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China

Association of influenza-like illness activity with hospitalizations for heart failure: the Atherosclerosis Risk in Communities Study

Advocacy-and-Economics/ACR-Position-Statements/ Recommendations-for-Chest-Radiography-and-CT-for-Suspected-COVID19-Infection

Frequency and distribution of chest radiographic findings in COVID-19 positive patients

Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases

Chest radiographic and CT findings of the 2019 novel coronavirus disease (COVID-19): analysis of nine patients treated in Korea

Chest x-ray findings in asymptomatic and minimally symptomatic quarantined patients in

Time course of lung changes on chest CT during recovery from 2019 novel coronavirus (COVID-19) pneumonia

Temporal changes of CT findings in 90 patients with COVID-19 pneumonia: a longitudinal study

Patients with RT-PCR confirmed COVID-19 and normal chest CT

Chest CT severity score: an imaging tool for assessing severe COVID

International evidence-based recommendations for point-of-care lung ultrasound

Assessment of lung aeration and recruitment by CT scan and ultrasound in acute respiratory distress syndrome patients

Is there a role for lung ultrasound during the COVID-19 pandemic?

COVID-19 pandemic and cardiac imaging: EACVI recommendations on precautions, indications, prioritization, and protection for patients and healthcare personnel

ASE statement on protection of patients and echocardiography service providers during the 2019 novel coronavirus outbreak

Focused cardiac ultrasonography

Echocardiography in the time of COVID-19

Coronary CT angiography versus standard evaluation in acute chest pain

Triple rule out versus coronary CT angiography in patients with acute chest pain results from the ACIC consortium

Cardiac computed tomography in troponin-positive chest pain: sometimes the answer lies in the late iodine enhancement or extracellular volume fraction map

Quadruple rule out" with cardiac computed tomography in COVID-19 patient with equivocal acute coronary syndrome presentation

Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations

Early T1 myocardial MRI mapping: value in detecting myocardial hyperemia in acute myocarditis

Guidance and best practices for nuclear cardiology laboratories during the coronavirus disease 2019 (COVID-19) pandemic: an information statement from ASNC and SNMMI 2020

Management of acute myocardial infarction during the COVID-19 pandemic

Virtually perfect? Telemedicine for COVID-19

Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease

Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility

Echocardiography in pandemic: front-line perspective, expanding role of ultrasound, and ethics of resource allocation

From the a Department of Radiology, New York-Presbyterian Hospital and Weill Cornell Medicine

Division of Cardiology

r Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Cardiac Amyloidosis Program, Division of Cardiology, Department of Medicine, Brigham and Women's Hospital

Division of Cardiology

North Carolina; aa Appalachian Regional Healthcare System

Initial invasive or conservative strategy for stable coronary disease

Optimal medical therapy with or without PCI for stable coronary disease

Utilization and outcomes of measuring fractional flow reserve in patients with stable ischemic heart disease

ESC guidelines for the diagnosis and management of chronic coronary syndromes

Should NICE guidelines be universally accepted for the evaluation of stable coronary disease? A debate

Prospective comparison of FFR derived from coronary CT angiography with SPECT perfusion imaging in stable coronary artery disease: the ReASSESS study

Prediction of coronary revascularization in stable angina: comparison of FFRCT with CMR stress perfusion imaging

A clinical prediction rule for the diagnosis of coronary artery disease: validation, updating, and extension

for the SCOT-HEART Investigators. Coronary CT angiography and 5-year risk of myocardial infarction

Improved cardiac risk assessment with noninvasive measures of coronary flow reserve

Long-term prognosis after a normal exercise stress Tc-99m sestamibi SPECT study

Cardiac magnetic resonance stress perfusion imaging for evaluation of patients with chest pain

Magnetic Resonance perfusion or fractional flow reserve in coronary disease

Comprehensive cardiac CT with myocardial perfusion imaging versus functional testing in suspected coronary artery disease: the multicenter, randomized CRESCENT-II Trial

Prognostic value of coronary CT angiography with selective pet perfusion imaging in coronary artery disease

Multicentre multi-device hybrid imaging study of coronary artery disease: results from the EValuation of INtegrated Cardiac Imaging for the Detection and Characterization of Ischaemic Heart Disease (EVINCI) hybrid imaging population

Diagnostic performance of hybrid cardiac imaging methods for assessment of obstructive coronary artery disease compared with stand-alone coronary computed tomography angiography: a meta-analysis

Anatomical and functional computed tomography for diagnosing hemodynamically significant coronary artery disease: a meta-analysis

Guidelines for performance, interpretation, and application of stress echocardiography in ischemic heart disease: from the American Society of Echocardiography

The clinical use of stress echocardiography in nonischaemic heart disease: recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography

Baseline characteristics and risk profiles of participants in the ISCHEMIA randomized clinical trial

ISCHEMIA: a search for clarity and why we may not find it

for the FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention

Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study

for the Consortium CAD. A clinical prediction rule for the diagnosis of coronary artery disease: validation, updating, and extension

ESC Guidelines for the diagnosis and management of chronic coronary syndromes: the Task Force for the Diagnosis and Management of Chronic Coronary Syndromes of the European Society of Cardiology (ESC)

of care: a meta-analysis of randomised clinical trials

for the PROMISE Investigators. Outcomes of anatomical versus functional testing for coronary artery disease

for the COURAGE Investigators. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy

Healthstatus outcomes with invasive or conservative care in coronary disease

Trends in characteristics and outcomes of patients undergoing coronary revascularization in the United States

Global, regional, and national burden of cardiovascular diseases for 10 causes

Fractional flow reserve versus angiography for guiding percutaneous coronary interventional in patients with multivessel coronary artery disease

Fractional flow reserve-guided PCI for stable coronary artery disease

Fiveyear outcomes with PCI guided by fractional flow reserve

Timing of first postdischarge follow-up and medication adherence after acute myocardial infarction

Quality of life versus length of life considerations in cancer patients: A systematic literature review

Appropriateness of percutaneous coronary intervention

Patient selection for diagnostic angiography and hospital-level percutaneous coronary intervention appropriateness: insights from the National Cardiovascular Data Registry

Fighting the oculostenotic reflex

Ischemia trial: implications for coronary CT angiography

Prognostic value of coronary artery calcium in the PROMISE study (Prospective Multicenter Imaging Study for Evaluation of Chest Pain)

Preserved coronary flow reserve effectively excludes high-risk coronary artery disease on angiography

Realworld clinical utility and impact on clinical decision-making of coronary computed tomography angiography-derived fractional flow reserve: lessons from the ADVANCE Registry

Global coronary flow reserve is associated with adverse cardiovascular events independently of luminal angiographic severity and modifies the effect of early revascularization

for the COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease

for the BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease

for the Scottish COmputed Tomography of the HEART (SCOT-HEART) Trial Investigators. Symptoms and quality of life in patients with suspected angina undergoing CT coronary angiography: a randomised controlled trial

for the MR-INFORM Investigators. Magnetic resonance perfusion or fractional flow reserve in coronary disease

Cardiovascular magnetic resonance and singlephoton emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial

for the CE-MARC 2 Investigators. Effect of care guided by cardiovascular magnetic resonance, myocardial perfusion scintigraphy, or NICE guidelines on subsequent unnecessary angiography rates: the CE-MARC 2 randomized clinical trial

Prognostic value of CMR and SPECT in suspected coronary heart disease: long term follow-up of the CE-MARC Study

Cost effectiveness analysis of stress magnetic resonance imaging for stable chest pain syndromes

Automated pixel-wise quantitative myocardial perfusion mapping by CMR to detect obstructive coronary artery disease and coronary microvascular dysfunction: validation against invasive coronary physiology

Microvascular angina diagnosed by absolute PET myocardial blood flow quantification

Association of sex with severity of coronary artery disease, ischemia, and symptom burden in patients with moderate or severe ischemia: secondary analysis of the ISCHEMIA Randomized clinical trial

Echocardiographic predictors of left ventricular function and clinical outcomes after successful mitral valve repair: conventional two-dimensional versus speckle-tracking parameters

Assessment of longitudinal

Twist deformation for predicting postoperative left ventricular function in patients with mitral regurgitation: a speckle tracking echocardiography study

Myocardial strain in prediction of outcomes after surgery for severe mitral regurgitation

Prognostic value of global longitudinal strain and etiology after surgery for primary mitral regurgitation

Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial

Diagnostic performance of treadmill exercise cardiac magnetic resonance: the prospective, multicenter Exercise CMR's Accuracy for Cardiovascular Stress Testing (EXACT) trial

ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines)

Magnetic resonance perfusion or fractional flow reserve in coronary disease

Research-Statistics-Data-and-Systems/Research-Statistics-Data-and-Systems

Morphofunctional abnormalities of mitral annulus and arrhythmic mitral valve prolapse

The Pickelhaube sign: novel echocardiographic risk marker for malignant mitral valve prolapse syndrome

Interactions between mitral valve and left ventricle analysed by 2D speckle tracking in patients with mitral valve prolapse: one more piece to the puzzle

Impact of gender and age on cardiovascular function late after repair of tetralogy of Fallot: percentiles based on cardiac magnetic resonance

AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: Executive Summary

Lower extremity revascularization in end-stage renal disease

Ferumoxytol magnetic resonance angiography: a dose-finding study in patients with chronic kidney disease

Methodology for fully automated segmentation and plaque characterization in intracoronary optical coherence tomography images

Convolutional neural network based automatic plaque characterization from intracoronary optical coherence tomography images

Depth-resolved modelbased reconstruction of attenuation coefficients in optical coherence tomography

Characterization of Human atherosclerosis by optical coherence tomography

Hughes has been a consultant and has received honoraria from Takeda, Sanofi, and Amicus. Dr. Geberhiwot has been a consultant and has received an unrestricted research grant from Sanofi-Genzyme and Takeda. the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information

Diagnosis and treatment of the cardiovascular consequences of Fabry disease

Onset and progression of the Anderson-Fabry disease related cardiomyopathy

Proposed stages of myocardial phenotype development in Fabry disease

or median (interquartile range). *Frequency of LV lead placed in the lateral wall was calculated for 138 patients with known LV lead position. †Values of CW and WW of the septum and lateral wall were compared in 115 patients (CRT responders n ¼ 69, 60%) in which assessment of MW indices was feasible immediately after CRT implantation

6MWT ¼ 6-min walk test

GFR ¼ glomerular filtration rate

LBBB ¼ left bundle branch block

LVEDV ¼ left ventricular enddiastolic volume

LVEF ¼ left ventricular ejection fraction

LVESV ¼ left ventricular end-systolic volume

Pi ¼ postimplantation

WW ¼ wasted work

A novel clinical method for quantification of regional left ventricular pressure-strain loop area: a non-invasive index of myocardial work

Left ventricular contractile reserve by stress echocardiography as a predictor of response to cardiac resynchronization therapy in heart failure: a systematic review and meta-analysis

Role of myocardial constructive work in the identification of responders to CRT

Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: early experience and forecast during an emergency response

Cardiac CT with delayed enhancement in the characterization of ventricular tachycardia structural substrate: relationship between CT-segmented scar and electro-anatomic mapping

Management of COVID-19 respiratory distress

Acute respiratory distress syndrome: the heart side of the moon

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19)

Changes in arterial pressure during mechanical ventilation

Echocardiographic findings in Covid-19 pneumonia

The spectrum of cardiac manifestations in coronavirus disease 2019 (COVID-19)-a systematic echocardiographic study

Prognostic value of right ventricular longitudinal strain in patients with COVID-19

Risk stratification in patients with aortic stenosis: pay more attention to the right-side unit!

Right ventricle to pulmonary artery coupling in patients undergoing transcatheter aortic valve implantation

RV contractile function and its coupling to pulmonary circulation in heart failure with preserved ejection fraction: stratification of clinical phenotypes and outcomes

Prognostic value of right ventricular longitudinal strain in patients with COVID-19

Moderate and severe acute respiratory distress syndrome: Hemodynamic and cardiac effects of an open lung strategy with recruitment maneuver analyzed using echocardiography

Prognostic value of right ventricular longitudinal strain in patients with COVID-19

Abnormal right ventricularpulmonary artery coupling with exercise in heart failure with preserved ejection fraction

Lack of a tricuspid regurgitation doppler signal and pulmonary hypertension by invasive measurement

Diagnosis of pulmonary embolism with use of computed tomographic angiography

Pulmonary embolism and coexisting deep vein thrombosis: a detrimental association?

Hoyt have filed for a patent for the AI algorithm. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Cardiovascular Imaging author instructions page.

We thank Drs. Tsolaki and Zakynthinos for their in- 

We appreciate the comments by Dr. Fukui and colleagues about our paper (1), and we fully agree with some of their views. However, there are some issues that need to be clarified and discussed.We acknowledge and agree that right ventricular (RV) function is closely linked with the afterload. In Among them, the majority was mild or trivial TR, which may affect the accuracy of PASP assessment. As the right heart catheterization was not available in our designated treatment hospital, PASP derived from