key: cord-0832649-ne60eiss
authors: nan
title: Full Issue PDF
date: 2020-03-31
journal: JACC: Cardiovascular Imaging
DOI: 10.1016/s1936-878x(20)30146-7
sha: a259df2417194c1c5b92ada1560e58c04b34ab76
doc_id: 832649
cord_uid: ne60eiss

nan

U ltrasound (US) has a wide variety of biological effects. The ability of US to increase tissue blood flow in a non-thermal manner occurs, in part, through acoustically driven vascular shear and convective motion, thereby initiating endogenous endothelial-dependent vasodilatory pathways (1, 2) . Encapsulated microbubble (MB) contrast agents exposed to US undergo volumetric oscillation, called cavitation, which produces high local shear forces.

Accordingly, MB inertial cavitation (destruction) increases tissue perfusion to a much greater extent than US alone (3, 4) . The molecular mechanism by which contrast-enhanced US (CEU) augments flow is through release of adenosine triphosphate (ATP) and subsequent purinergic signaling that leads to production of nitric oxide, prostaglandins, and adenosine (5) .

The therapeutic potential of MB cavitation using US frequencies and pressures within the diagnostic range has been demonstrated in animal models of acute myocardial infarction and peripheral artery disease (PAD) where tissue ischemia could be either fully or partially reversed (3, 5) . It has been observed that this beneficial effect can last long after completion of CEU, which is thought to represent a sustained ATP release that occurs from not only acute cellular microporation but also from purinergic channel activation (5) . In this study, we investigated how limb flow augmentation and ATP release in mice could be optimized by modifying US transmit settings (line density, pulse duration) that influence the pressure and shear conditions during MB inertial cavitation. We then applied this knowledge in a first-in-human trial to test the hypothesis that augmentation in limb blood flow could be achieved by CEU performed with short-duration MB cavitation protocols in normal human subjects and in patients with PAD. We also tested whether flow augmentation occurs remotely from the US-exposed region based on the potential of cavitation to increase systemic concentrations of ATP or vasodilators. has been shown not to produce any detectable changes in perfusion (4) . MBs were infused at a rate of 1 Â 10 7 min -1 . Time-intensity data at a frame rate of 5 Hz were acquired after a high-power (MI 1.0) 5frame sequence and were fit to the function: y ¼ A(1Àe bt ); using non-linear least-squares regression, where y is intensity at time t, A is the plateau intensity representing relative microvascular blood volume, and the rate constant b is the microvascular flux rate (7) . Microvascular blood flow was quantified by the product of A and b (7) . differences were assessed using unpaired Student's t-test, or using Mann-Whitney U test for data that were determined to be non-normally distributed using D'Agostino and Pearson omnibus test. Comparisons within a group (i.e., change in perfusion from baseline) was evaluated using paired Student's t-test or Wilcoxon test. Bonferroni's correction was used for comparisons for more than 2 conditions. Differences were considered significant at p < 0.05 (2-sided) .

PROGRAMMED US FIELDS. Calibrated hydrophone measurements demonstrated that the clinical imaging probe could achieve peak negative acoustic pressures ranging from 20 kPa to 4.0 MPa (MI 0.03 to 3.44) , and were largely independent of pulse length.

Output conditions were then set to achieve a peak negative acoustic pressure of 1.5 MPa to approximate that previously used to augment tissue flow in mice (8) . Computer-simulated field assessment for the different programmed line densities showed excellent agreement with hydrophone data, with beam widths measured to within 5% agreement ( Figure 1B) . 

Of the non-thermal bioeffects produced by US, shear forces that occur from convective motion, microstreaming, or shock wave formation are thought to be important for therapeutic augmentation of tissue perfusion. The effects of US on microvascular resistance are amplified several-fold by the presence of MB contrast agents, including those that are approved for diagnostic use in humans (4, 9) . In this study, we have tested the vascular effects of different acoustic settings within regulatory pressure limits that can be implemented on a clinical scanner and tested efficacy in humans to show that a >2 fold increase in limb blood flow is achievable in normal subjects and patients with PAD. Our preclinical studies focused entirely on MB cavitation because we have previously demonstrated that limb flow augmentation is much less with US alone compared with CEU, despite a duty factor (duration of US exposure) that is several orders of magnitude higher (4) . It is also known that limb flow augmentation produced by inertial cavitation increases with the acoustic pressures up to the limits of a clinical scanner without causing adverse bioeffects (4) . Accordingly, the examination of line density in the current study was intended to find a balance between: 1) avoiding "between-line gaps" at low line density, which results in a situation where some MBs are not exposed to high acoustic pressures; and 2) avoiding MB cavitation by a neighboring line at high line density, which would destroy MBs before exposure to the intended high acoustic pressures ( Figure 1A) . Pulse duration was also studied based on the knowledge that MBs can undergo sustained cavitation with long pulses, probably through the continued acoustic activity of free gas released from the shell boundaries (10, 11) . For the long pulse durations, we compared continuous 40-cycle to segmented 8 Â 5-cycle scheme because previous studies have been performed with the latter and yet sustained cavitation without cycle interruption may In vivo studies have indicated that the release of ATP is a key process in CEU-mediated flow augmentation (Central Illustration), acting secondarily through a variety of vasodilators including nitric oxide, adenosine, and prostanoids (5) . In the current study, settings that were most reliable for increasing flow also produced the greatest ATP signal at the USexposed site. However, our findings also indicate that ATP signal is not proportionally related to flow augmentation. This phenomenon could be explained by existence of a threshold concentration over which ATP does not further increase flow, or because purinegic signaling is likely to be dominated by ATP transiently released from shear forces on red blood cells during US (5, 12) . Also, signal on optical imaging is unlikely to be only from intravascular ATP, which mediates vasodilation, but can also reflect interstitial ATP, which can produce neurogenic vasoconstriction (13, 14) .

The first evidence that limb blood flow in humans could be increased by MB cavitation was described in a study where CEU was being used to assess skeletal This finding is remarkable because only a small volume of the calf was exposed to US. Unlike in murine models of PAD where 10 min CEU exposure can reverse ischemia for >24 h (5), the duration of effect was limited in humans. This finding likely reflects major differences in the proportion of the limb that was exposed to US. We believe therapeutic effect will be augmented by 3-D US that can be programmed on US+MB (n = 10) Contralateral (n = 9)

the existing system, using spatial data on cavitation on this study to design elevational spacing.

Although the study was performed in patients primarily with intermittent claudication, the implication of our results is that therapeutic CEU could be used in those with more severe disease to accelerate wound healing or for limb salvage in those with critical limb-threatening ischemia who require a delay in definitive therapy. Successful implementation of such a strategy will require further investigation into protocol changes that could produce a longer duration of effect. According to murine data, this may be possible with greater spatial extent of cavitation, or with MB agents that circulate for a long duration before clearance, thereby increasing the potential duration of therapy. Cavitation of MBs is also being explored for its ability to accelerate clot lysis in acute MI and in peripheral thrombotic events (15) (16) (17) . The ability to increase tissue perfusion independent of sonothrombolysis needs to be considered when examining the efficacy of these therapies. has been used to transiently open the blood-brain barrier for drug delivery (4, 5) ; deliver therapeutic RNAs directly into target cells (sonoporation) (6,7); rescue tissue flow in the setting of microvascular obstruction (8) ; recanalize acutely thrombosed epicardial coronary or cranial arteries (sonothrombolysis) (9) ; and decrease brain beta-amyloid accumulation and cognitive dysfunction in patients with Alzheimer disease (10) . More recently, early clinical trials using UTMC to treat glioblastoma (11) and Alzheimer disease (12) , and to supplement primary stenting in acute myocardial infarction (13) , have been reported.

In this issue of iJACC, Mason et al. (14) describe another therapeutic application of UTMC:

ultrasound-induced destruction (inertial cavitation) of microbubbles to augment skeletal muscle blood flow for treatment of limb ischemia. Previous studies demonstrated that UTMC causes vasodilation and release of nitric oxide (15, 16) , prostanoids, and adenosine, possibly via increased adenosine triphosphate (ATP) release (15) . The study by Mason et al. (14) takes the next clinical translational step by demonstrating that UTMC causes transient skeletal muscle hyperemia in human subjects, both with and without peripheral arterial disease. In an illustration of the beauty of ultrasound "theranostics," ultrasound and microbubbles were used both to provide the therapy to skeletal muscle as well as to image the hyperemic effect of that therapy.

A fundamental question posed by the current study (14) and other studies of UTMC therapeutics is:

What is "the best" acoustic regime for achieving the This study highlights the complex parameter space that we must deal with in order to intelligently select the acoustic conditions that maximize the desired effect of UTMC-mediated flow augmentation.

Although the need to understand these complicated interrelationships may be a challenge, the data also suggest that the desired result can be achieved using various ultrasound settings; that is, there can be crisscrossing highways, but there is more than one way to get to the same destination. In this regard, we have more freedom to operate with respect to defining "optimal" acoustic regimens to serve clinical translation, and this is a good thing.

That more than one acoustic "recipe" may be able to induce the same hindlimb flow augmentation highlights the need to probe more deeply to identify the governing biophysical principles that drive the phenomenon of shear stress-induced hyperemia.

Helfield et al. (17) reported that sonoporation can be triggered by a wide range of acoustic pressures and ultrasound frequencies, but the unifying physical principle was the requirement for a microbubble to radially expand beyond an absolute threshold amount to confer a local threshold shear stress, beyond which cell membrane breach, or sonoporation, occurs. These "desired" acoustic behaviors were elicited by numerous stable and inertial cavitation regimens. If such findings were to be extended-and as suggested by the current study-it may be that many different acoustic regimens effectively drive skeletal muscle hyperemia, but they may act via a unifying biophysical mechanism that still remains incompletely understood.

Another interesting finding of this study is the absence of a direct correlation between the magni- Current guidelines for risk stratification in AS suggest that measurement of natriuretic peptides may be useful in asymptomatic patients to determine the optimal timing of AVR (2) .

Our group is interested in the role of angiotensin-converting enzyme 2 (ACE2) as a circulating biomarker of cardiovascular disease (CVD) (7) (8) (9) (10) . ACE2 is a member of the counter-regulatory axis of the reninangiotensin system (RAS), and its main role is to degrade the pro-hypertrophic and profibrotic peptide, angiotensin II, and act to limit the adverse effects of angiotensin II.

ACE2 is an integral membrane protein expressed in the heart and vascular system (11, 12) and exists in both a membrane bound and a soluble form; the latter results from proteolytic cleavage of the ectodomain by the proteinase ADAM17 (a disintegrin and metalloproteinase) (13) .

The precise relationship between tissue and circulating levels of ACE2 is not yet understood. In experimental models, deletion or loss of ACE2 from the myocardium is associated with increased levels of tissue angiotensin II, which leads to cardiac fibrosis and dysfunction (14) , as well as increased levels of circulating ACE2 activity (15) . In healthy individuals without apparent CVD, circulating ACE2 activity is low (16) . Circulating ACE2 levels are increased and predict adverse events in the presence of CVD, including coronary artery disease (8, 9) , atrial fibrillation (10) . and heart failure (7) . To our knowledge, there are no studies of both circulating and myocardial levels of ACE2 in humans, and there are no studies of ACE2 in common valvular heart diseases such as AS.

We hypothesized that plasma ACE2 activity levels would reflect AS severity and/or maladaptive myocardial structural changes and have incremental prognostic usefulness to predict long-term mortality.

We also examined the relationship between plasma ACE2 activity, myocardial ACE2 gene expression, and myocardial fibrosis in a subgroup of patients who underwent AVR.

The study protocol was approved by the Human

Research Ethics Committee at Austin Health,

Helsinki. Patients gave informed written consent.

Consecutive patients ages older than 18 years who attended a follow-up in a cardiology valve clinic and who had mild, moderate, or severe AS were recruited (June 2008 to May 2010) as part of a prospective study that evaluated the development, progression, and outcomes of AS (5) . Patients with another valvular lesion of greater than moderate severity were excluded. Valvular calcification and AS severity were classified using echocardiography according to current guidelines (17) . Dobutamine stress echocardiography and/or valvular calcium score by multislice computed tomography were used to determine AS severity in those with discordant findings on baseline echocardiography (17) . An abnormal LV ejection fraction was defined using sex-specific cutoff points (<52% for men and <54% for women) (18) .

Baseline demographic, clinical, and biochemical data were obtained, and blood collected for the measurement of ACE2 in 127 patients. Of the total cohort, 58 patients underwent AVR, with 22 patients having myocardial tissue collected at the time of AVR.

BLOOD SAMPLING AND ANALYSIS. At recruitment, blood was collected into cold lithium heparin tubes and spun at 3,000 rpm at 4 C for 10 min. Plasma was stored at -80 C until measurement of plasma ACE2 activity, which was performed using a validated, sensitive quenched fluorescent substrate-based assay as previously described (16) . Briefly, plasma (0.25 ml) was diluted into low-ionic strength buffer (20 mmol/l Tris-HCl, pH 6.5) and added to 200 ml ANXSepharose 4

Fast-Flow resin (Amersham Biosciences, GE Healthcare, Uppsala, Sweden) that removed a previously characterized endogenous inhibitor of ACE2 activity (16) . After binding and washing, the resulting eluate was assayed for ACE2 catalytic activity. Duplicate Park, Illinois). Normal values of BNP specific to age and sex were derived based on available data from Abbott Laboratories from a cohort of 890 individuals without a diagnosis of heart failure (19) . Patients with values above the maximal limit (95th percentile) for age and sex were considered to have elevated BNP;

these patients were classified as having BNP clinical activation as previously described (20) .

MYOCARDIAL TISSUE COLLECTION. In patients who underwent AVR (n ¼ 22), right atrial appendage (RAA) tissue was obtained at the site of cannulation for cardiopulmonary bypass. The sample was snap frozen in isopentane and stored at À80 C for mRNA extraction, with remaining tissue fixed in 4% paraformaldehyde and embedded in paraffin for determination of interstitial collagen.

REAL-TIME POLYMERASE CHAIN REACTION. Total RNA was isolated from frozen RAA using the RNeasy kit method (Qiagen, Hilden, Germany). cDNA was synthesized with a reverse transcriptase reaction using Superscript III (ThermoFischer Scientific, Victoria, Australia), as described previously (11) . Cardiac ACE2 and tumor necrosis factor-a converting enzyme (TACE) (also known as ADAM17) gene expression was determined using pre-designed human TaqMan assays (ThermoFischer Scientific, Victoria, Australia). 

FRACTION. Myocardial fibrosis was determined as previously described (21) . Briefly, RAA paraffin sections 4-mm thick were deparaffinized, rehydrated, and stained with 0.1% Sirius Red (Polysciences, Warrington, Pennsylvania) in saturated picric acid (picrosirius red) for 1 h, differentiated in 0.01% hydrogen chloride for 30 s, and rapidly dehydrated.

Staining was quantified using computerized image analysis (Imaging Research, Ontario, Canada) . Interstitial collagen volume fraction (CVF) was determined by measuring the area of stained tissue within a given field, excluding epicardium, vessels, artefacts, minor scars, or incomplete tissue fields; 10 to 20 fields were analyzed per sample by a blinded reviewer. As per previous classification of fibrosis (22) , CVF #6% was classified as nonsevere fibrosis and CVF >6% as severe fibrosis.

STATISTICAL ANALYSIS. Statistical analysis was performed using STATA version 15 Cox proportional hazard modeling was used to estimate the adjusted hazard ratio (HR) and 95%

confidence interval (CI) for all-cause mortality.

Multivariable forward stepwise regression was performed using significant variables from univariate analysis and those with clinical relevance to identify independent predictors of all-cause mortality. Plasma ACE2 was entered in the model categorically, dichotomized according to an optimal discriminatory value determined from receiver-operating characteristic (ROC) curve analysis, which was selected to detect the primary outcome of all-cause mortality with a combined sensitivity and specificity closest to 100% and 100%, respectively (Supplemental Figure 1 ) (7, 23) . A p < 0.05 was required for a variable to enter the multivariate Cox model, and a p > 0. 10 methods (24) . The IDI summarizes a new model's ability to improve integrated (average) sensitivity without sacrificing integrated (average) specificity.

For ACE2 gene expression analysis, patients were divided according to median plasma ACE2 activity.

ACE2 mRNA expression for the group with plasma ACE2 activity less than or equal to the median was arbitrarily standardized to 1 by taking the average of the results in this group. Gene expression in the group with plasma ACE2 activity more than the median was expressed relative to this group. Two-tailed p values <0.05 were considered significant.

The cohort consisted of 127 patients with mild (25%), moderate (24%), or severe AS (51%). The baseline clinical, biochemical, and echocardiographic characteristics are presented in Table 1 (63% men; mean age 75 AE 10 years). There was a high prevalence of cardiovascular risk factors and/or disease, including hyperlipidemia (75%), diabetes (26%), hypertension (81%), ischemic heart disease (IHD) (37%), atrial fibrillation (28%), and heart failure (32%). With regard to baseline medical therapy, 75% of subjects were on ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), 71% were on statins, and 39% were on beta-blockers. (34) (35) (36) (37) (38) (39) (40) (41) (42) (43) (44) (45) (46) (47) 38 (32) (33) (34) (35) (36) (37) (38) (39) (40) (41) (42) (43) (44) (45) (46) 40 (35) (36) (37) (38) (39) (40) (41) (42) (43) (44) (45) (46) (47) 0.420 with above-median plasma ACE2 activity were more likely to be men (p ¼ 0.02) with a history of IHD and higher body mass index (p < 0.05). There were no significant differences in baseline pharmacological therapy. On multivariable regression analysis, male sex was the only independent clinical predictor of higher plasma ACE2 activity (p ¼ 0.001). The proportion of patients with BNP clinical activation was also significantly higher in those with abovemedian plasma ACE2 activity (57% vs. 37%; p ¼ 0.027) ( Figure 1 ). There was no difference in hemoglobin concentration and creatinine levels between the 2 groups (p > 0.05).

PLASMA ACE2 ACTIVITY AND ALL-CAUSE MORTALITY.

The median duration of follow-up was 5 years (IQR: 0.19 to 5 years). Over this period, 58 patients underwent AVR, and 31 patients (24%) died. There was a higher incidence of all-cause mortality in those with above-median plasma ACE2 activity compared with below-median plasma ACE2 (38% vs. 11%; log-rank p < 0.001). ROC analysis was used to determine the plasma ACE2 value with the best combination of sensitivity and specificity for all-cause mortality. The ROC area under the curve was 0.73 (95% CI: 62% to 82%) and a plasma ACE2 cutoff value of 41.2 pmol/ml/min had a sensitivity of 65% and a specificity of 75% for detecting all-cause mortality (Supplemental Figure 1 ).

Patients with plasma ACE2 activity above this threshold had a significantly increased likelihood of all-cause mortality compared with those without activity (HR: 3.86; 95% CI: 1.85 to 8.06; p < 0.001) ( Figure 2A) ; therefore, this ROC-derived value was used for subsequent analysis. When analyzed according to sex, elevated plasma ACE2 activity >41.2 pmol/ml/min was associated with a higher incidence of all-cause mortality in both male (log rank test; p ¼ 0.01) and female patients (log-rank test:

p < 0.001) respectively. Patients with BNP activation had a significantly increased likelihood of death (HR: 4.64; 95% CI: 2.06 to 10.42; p < 0.001) ( Figure 2B ). Allcause mortality was highest in those with the combination of elevated plasma ACE2 activity and BNP clinical activation (HR: 13.78; 95% CI: 3.97 to 47.8;

p < 0.001) ( Figure 2C ).

Other univariate predictors of mortality included age, heart failure, IHD, beta-blocker use, LV mass, abnormal LV ejection fraction (sex-specific), BNP clinical activation, and log serum creatinine level ( Figure 4) . LV remodeling and myocardial fibrosis (25) . RAS inhibition has a positive impact on regressing hypertrophy, improving myocardial physiology, and slowing the rate of progression of valvular stenosis (26) . In 2000, our understanding of the RAS was significantly broadened with the discovery of the ACE2 gene (27) , which changed the simplistic vertical view of the RAS and led to the concept of a counterregulatory arm with opposing effects in cardiovascular biology (28) .

The key findings of this study in patients with AS were that increased plasma ACE2 levels were associated with myocardial structural abnormalities and provided added incremental prognostic information to predict long-term mortality over and above conventional risk markers, including BNP activation (Central Illustration). Plasma ACE2 levels correlated with the extent of valvular calcification but not AS severity. The median ACE2 level in the AS cohort was 34 pmol/ml/min, which was similar to levels we reported in a high-risk cohort with coronary artery disease (9) (median: 29 pmol/ml/min) and higher than levels in patients with atrial fibrillation (10) or in young healthy volunteers (mean: 4 pmol/ml/min) (16) . Consistent with previous reports, there was no correlation between ACE2 activity and treatment with ACE inhibitors, and male sex was an independent predictor of increased plasma ACE2 activity (9, 10) .

These results add to the growing body of evidence that plasma ACE2 activity levels may serve as a marker of myocardial abnormalities and/or adverse outcomes in cardiovascular disease, including coronary artery disease, atrial fibrillation, and heart failure (7) (8) (9) (10) . We recently reported that elevated plasma ACE2 activity was an independent predictor of major adverse cardiovascular events (cardiovascular mortality, heart failure, myocardial infarction) over a median follow-up of 10.5 years in patients with angiographically proven obstructive coronary artery disease (9) . Plasma ACE2 levels also reflect cardiac structural alterations. For example, in human atrial fibrillation, increased plasma ACE2 activity was associated with more advanced left atrial structural remodeling assessed by electroanatomic mapping (10) . In patients with heart failure, elevated circulating ACE2 levels independently predicted cardiovascular events (death, cardiac transplantation, or heart failure hospitalization) after 34 months of follow-up and were positively correlated with imaging indexes of ventricular remodeling and dysfunction (7) . Similarly, following ST-segment elevation myocardial infarction, circulating ACE2 activity increased in relation to the infarct size and correlated with more severe LV remodeling on cardiac magnetic resonance (8) .

The present study extended knowledge in this regard. We found a positive correlation between plasma ACE2 activity and LV mass, although the relationship BNP ¼ brain natriuretic peptide; CI ¼ confidence interval; HR ¼ hazard ratio; IHD¼ ischemic heart disease; LVEF ¼ left ventricular ejection fraction; LVMI ¼ left ventricular mass index; other abbreviation as in Table 1 . 

Relative myocardial ACE2 mRNA in patients according to median plasma ACE2 activity (19.5 pmol/ml/min in cohort of 24 patients). Gene expression for the group with plasma ACE2 activity less than or equal to the median was arbitrarily standardized to 1. Gene expression in the group with plasma ACE2 activity above the median was expressed relative to this group. Data are expressed as mean AE SEM. Abbreviation as in Figure 1. in this patient population with AS was likely influenced by the presence of hypertension and/or antihypertensive therapies. Furthermore, we found that increased plasma ACE2 activity was associated with increased LV diastolic volume but not LV ejection fraction or GLS. These data suggested a potential role for measurement of plasma ACE2 activity levels as a marker of early myocardial decompensation in AS.

Guidelines for risk stratification in AS emphasize the importance of recognizing early myocardial decompensation and suggest that natriuretic peptide levels may be useful in asymptomatic patients to determine the optimal timing of AVR (Class IIa, Level of Evidence: C) (2) . Plasma BNP activation was shown to independently predict long-term mortality in a prospective study of 1,953 patients with at least moderate AS who were followed up over 4.3 years (20) . More recently, plasma BNP measurement enhanced the prediction of all-cause mortality in patients with low-flow, low-gradient AS (29) .

In the present study, patients with BNP activation and elevated plasma ACE2 activity had increased mortality compared with those without elevation of either ACE2 or BNP or with elevation of only 1 biomarker. Because plasma ACE2 measurement had prognostic value not captured by BNP alone, the combination of the 2 biomarkers might enhance clinical decision-making in AS. Importantly, >40% of patients with above-median ACE2 activity had normal BNP levels suggesting different pathophysiological mechanisms and/or stimuli for the release of the 2 markers. BNP is a 32-amino acid peptide secreted from the heart in response to myocardial stretch from cardiac volume or pressure overload (29) and has a well-established role in risk stratification in valvular heart disease (2) . ACE2 is highly expressed in the heart and undergoes cleavage or "shedding" to release the catalytically active ectodomain into the extracellular milieu (13) , a process that involves the proteinase ADAM17, also known as TACE (13, 30) .

Release of ACE2 from the heart is regulated by various stimuli, including angiotensin II and the loss of ACE2 from the tissue leads to unopposed proinflammatory and pro-fibrotic effects of angiotensin II in the myocardium (31) . In an experimental mouse model of targeted ACE2 disruption (14) , loss of myocardial ACE2 led to increased cardiac angiotensin II levels, cardiac hypertrophy and fibrosis, and impaired cardiac function. In human tissue, ACE was upregulated (32) and ACE2 downregulated in stenotic aortic valves (33) . This is the first report in patients with AS to describe that myocardial ACE2 gene expression was reduced, that reduced tissue levels were associated with elevated plasma ACE2 activity, and that those with the highest plasma ACE2 activity had more severe myocardial fibrosis, an important predictor of death in AS (34) . STUDY LIMITATIONS. The strengths of this study includes the detailed cardiac phenotyping and longterm follow-up, as well as the assessment of circulating and myocardial ACE2, and cardiac fibrosis.

Some important limitations should be acknowledged.

First, the finding of elevated plasma ACE2 activity and the association with abnormal myocardial function and increased mortality suggests a possible relationship but does not determine a causal relationship. Second, the LV is the first extra-valvular cardiac structure to be affected in the earliest stages In patients with aortic stenosis (AS), elevated plasma angiotensin-converting enzyme 2 (ACE2) activity was associated with reduced myocardial ACE2 gene expression, myocardial structural abnormalities, and more severe myocardial fibrosis, and independently predicted mortality. to myocardial damage and fibrosis (8, 9) . The precise relationship between tissue and circulating ACE2 activity is not yet completely understood; however, it seems that loss of tissue ACE2 is associated with an increase in circulating ACE2 activity. Furthermore, loss of tissue ACE2 is associated with myocardial fibrosis (2) . This association between tissue ACE2 activity and myocardial fibrosis does not provide a cause and effect relationship. Previous studies have shown that high circulating ACE2 levels predict cardiovascular events in patients with coronary atherosclerosis, atrial fibrillation, and heart failure (2, 9) . The Recently, myocardial native T 1 was used to explore changes in myocardial blood volume during vasodilator stress (11) (12) (13) (14) , which suggested that native T 1 has the potential to detect myocardial ischemia. STUDY PROTOCOL. Figure 1A shows the healthy subject protocol. After image localization, subjects underwent rest cine CMR, native T 1 and T 2 mapping, and maximal supine bicycle ergometer exercise followed by 3 successive native T 1 and T 2 mapping scans. To assess reproducibility, healthy subjects also partook in a second exercise followed by 2 successive native T 1 and T 2 mapping scans during the same session. Peak stress was targeted based on achieving a heart rate of at least 0.85 Â (220 À age), with age in years. Figure 1B shows the CAD patient protocol. Patients with CAD underwent rest cine CMR, native T 1 and T 2 mapping, and maximal exercise followed by 3 suc- Table 3 . Figure 2 illustrates representative native T 1 and T 2 map images at rest and post-exercise. Figure 3 shows the mean AE SD of T 1 and T 2 changes in the whole myocardium. Statistically significant differences between baseline and each of the time points were obtained using the linear mixed-effects model estimate of fixed effects. Native T 1 was elevated in all healthy subjects immediately after exercise and tended to decrease by the second scan (2.5 to 3.0min after exercise completion), and returned to baseline by the third scan (4.5 to 5.5 min after exercise completion). There were no differences in T 1 reactivity between basal, mid-ventricular, and apical slices (6.6 AE 2.0% vs. 6.2 AE 1.9% vs. 5.9 AE 2.3%;

Similarly, there were no statistical differences between intersegmental T 1 reactivity values (p ¼ 0.79). This trend was also observed after the second exercise, which indicated that T 1 could be a surrogate marker for detecting myocardial blood flow.

In contrast, T 2 gradually increased and was more pronounced after the second scan. Figure 4 shows the relationship between native T 1 reactivity and MRPP during exercise. Figure 7 shows the analysis using the linear mixed-effects model of R e s t 1 s t S c a n A f t e r 1 s t e x 1 s t S c a n A f t e r 2 n d e x 2 n d S c a n 2 n d S c a n 3 r d S c a n (A) Healthy subject septal native T 1 was significantly elevated immediately after the first (approximately 30 s after exercise completion) and second exercises (approximately 30 s after exercise completion). (B) The increase in T 2 was significantly more pronounced after the second scan. previous inferior myocardial infarction and inferior fixed defects on SPECT. Rest and/or stress native T 1 map shows higher native T 1 time in the basal inferior wall, and the T 1 reactivity map demonstrates severely reduced T 1 reactivity in the right coronary artery (RCA) territory. LAD ¼ left anterior descending; LCx ¼ left circumflex; other abbreviation as in Figure 5 . Exercise-Stress T 1 Mapping for Functional CAD detecting abnormal myocardial blood flow after exercise. We demonstrated that: 1) changes in native T 1 , but not T 2 , could be a surrogate marker for detecting myocardial blood flow during exercise; and 2) T 1 reactivity was associated with severity of myocardial perfusion abnormality on SPECT/MPI. More importantly, combined assessment of resting native T 1 and T 1 reactivity had the potential to differentiate ischemic myocardium from infarcted myocardium.

The results from our study were consistent with recent reports by Liu et al. (13, 14) who showed preand/or post-native T 1 increases in myocardial blood flow during vasodilator adenosine stress and predicted myocardial ischemia in patients with CAD.

Because exercise stress provided additional information that was unobtainable from pharmacological stress, such as hemodynamic response and symptoms during exercise, exercise stress was preferable for cardiac stress testing in patients unwilling or unable to tolerate pharmacological stress. Despite the importance of exercise stress cardiac testing, the clinical usefulness of exercise-stress CMR was limited by difficult image acquisition during high heart rates and rapid and/or deep breathing. The introduction of free-breathing native T 1 mapping enabled T 1 measurements of the whole heart within 90 s. Pharmacological or exercise stress could lead to differences in the cutoff T 1 reactivity value for detecting flowlimiting coronary artery stenosis.

Currently, SPECT/MPI is a commonly used stress test that is well validated. A negative result provides reassuring prognostic information (19) . We found that segments with myocardial perfusion abnormality on SPECT/MPI had lower T 1 reactivity, and more importantly, integration of native T 1 at rest allowed differentiation between reversible and fixed perfusion defects. In addition, in this pilot study, exercise stress and/or rest T 1 mapping seemed to be similar to SPECT/MPI in its ability to detect significant CAD. Exercise stress and/or rest T 1 mapping could overcome the limitations of soft tissue attenuation and low spatial resolution of SPECT/MPI (20) . A multicenter perfusion CMR study showed a sensitivity of 85% and a specificity of 67% with an AUC of 0.86 for detecting significant CAD on coronary x-ray angiography (1) . Similarly, the large CE-MARC CMR study demonstrated that the AUC of comprehensive CMR (left ventricular function, myocardial perfusion, late gadolinium enhancement, coronary artery imaging) was 0.84 (2) . These AUC values were slightly higher than that of our exercise stress and/or rest native T 1 mapping. The present study demonstrated that exercise stress and/or rest native T 1 mapping could be an effective alternative to radionuclide MPI for detection of flow-limiting coronary stenosis without GBCA or ionizing radiation. Considering the pathological and prognostic aspects of myocardial tissue characterization such as myocardial scar and/or diffuse fibrosis and edema (21) (22) (23) in the rest native T 1 mapping, exercise stress and/or rest T 1 mapping might have the potential to improve patient outcomes.

There was a substantial difference in the regression analysis of T 1 reactivity in relation to MRPP between normal myocardium in healthy young subjects and remote myocardium in patients with CAD. The difference might be partly explained by impaired microvascular dilatation during exercise in the remote myocardium. The MRPP was the index that best correlated with myocardial oxygen consumption (17) . Alternatively, a reduction in oxygen supply might decrease contractility in patients with CAD, and, in turn, further reduce oxygen cost and exercise tolerance (24) . The difference in the T 1 reactivity versus MRPP relationship was not due to a difference in blood catecholamine levels, because this factor would have resulted in changes in the opposite direction.

Myocardial T 2 is theoretically more sensitive to changes in myocardial water content secondary to increased myocardial blood flow during stress. (A) A 66-year-old female with angina on effort and single-vessel disease. T 1 reactivity map demonstrates a lower T 1 reactivity in the mid-anteroseptal and apex walls. The mid-LAD reveals severe stenosis by coronary angiography (arrow). Stress SPECT/MPI shows moderate to severe perfusion defects in the LAD territory, confirming flow-limiting stenosis. T 1 reactivity in the LAD territory was severely reduced to 1.39% in this case. (B) A 53-year-old male with angina on effort, ventricular arrhythmia, and single-vessel disease. Coronary angiography reveals single-vessel disease with RCA total occlusion (arrow) with rich collaterals from left coronary artery. Stress SPECT/MPI shows mild to moderate perfusion defects, suggesting flow-limiting lesions. T 1 reactivity map demonstrates lower T 1 reactivity in the corresponding myocardial segments, and T 1 reactivity in the RCA territory moderately decreased to 2.35%. Figures 5 and 6 . However, the current T 2 mapping technique might not have the necessary sensitivity needed to detect changes in myocardial T 2 associated with a change in blood flow during stress. The serial changes of T 2 time after exercise might also be explained by T 2 mapping detection of subclinical myocardial edema after intense exercise. We observed an approximate 10% variation in myocardial T 2 among healthy volunteers.

Another potential source for this variation could be attributed to the imaging and physiological confounders of myocardial T 2 mapping, including sensitivity to field inhomogeneities. T 1 might have some advantages related to T 2 and/or blood oxygen levelÀdependent sensitivities and magnetization transfer effects (25) . Further studies are warranted to assess this rigorously. STUDY LIMITATIONS. First, the present study was a single-center and small proof-of-concept study with a small sample size. Neither myocardial blood flow nor perfusion was directly measured. However, it was known that MRPP was well correlated with myocardial blood flow and myocardial oxygen consumption during exercise. It would be ideal for healthy subjects to partake in a second exercise followed by native T 1 and T 2 mapping scans on 2 separate days to assess reproducibility of T 1 reactivity. We assessed 3 middle slices covering the left ventricle to report the degree of T 1 reactivity heterogeneity in healthy control subjects. However, T 1 reactivity might not be as homogeneous across the left ventricle as in the middle 3 slices when the true basal, mid-ventricular, and apical slices were analyzed. Exercise stress and/or rest native T 1 mapping was not validated against perfusion CMR and late gadolinium enhancement CMR.

Reliable measurement of native T 1 in a thin-wall area might be challenging. However, the present study demonstrated that it might be applicable to infarcted myocardium characterized by a thin myocardial wall.

The study was too small to assess diagnostic accuracy of the proposed exercise stress and/or rest T 1 mapping protocol.

Anatomical CAD >50% (6) .

The use of GBCAs and pharmacological stressor agents is undesirable, prohibitive, or suboptimal in specific patient groups. GBCAs are contraindicated in patients with severe renal dysfunction, and there is an ongoing concern in the field regarding whether the detection of gadolinium deposition in the brain has any clinical relevance (7) .

Attempts have been made to develop methods that eliminate GBCAs from the CMR approach to assessing myocardial perfusion in ischemia testing. Dobutamine stress CMR does not require a GBCA to evaluate contractile reserve or inducible wall motion abnormalities and has shown both diagnostic accuracy and prognostic strength (8) . However, although dobutamine stress CMR has an established and justified role in the cardiac imaging diagnostic arsenal, it has not seen as widespread a clinical adoption as the use of perfusion assessment using vasodilator stress. Native T 1 mapping during vasodilator stress has emerged as a non-ÀGBCA-based perfusion assessment approach that has shown initial promise as a tool for assessing myocardial ischemia (9) . However, like blood oxygenation level-dependent or arterial spin labeling approaches, native T 1 mapping has challenges, including imaging artifacts and an imaging contrast between normal and ischemic myocardium that has a small magnitude of difference, and relatively high variability. All these noncontrast techniques have yet to show data in the form of convincing images with low noise and a visually conspicuous difference between normal and ischemic myocardium in routine clinical patients.

Regarding the limitations of pharmacological stressors, adenosine requires a continuous intravenous infusion and is contraindicated in selected conditions, in particular, severe asthma. Although regadenoson offers the ease of a bolus injection and is not contraindicated in asthma, it does not match adenosine in its ability to provide the added benefit of being able to detect inadequate stress using the splenic switch-off sign (10) . Furthermore, both adenosine and regadenoson are both hampered by the fact that caffeine is a powerful antagonist to their vasodilatory effects (11) . This is further complicated by data that show that between 8% and 19% of patients undergoing vasodilator stress have residual levels of caffeine in their blood, and this is likely due to delayed caffeine metabolism rather than noncompliance regarding avoiding caffeine consumption (12) .

Physiological stress in the evaluation of ischemic heart disease using exercise has several advantages over approaches using pharmacological stress. The impetus for stress testing is often symptoms that the patient experiences during exertion. Myocardial ischemia as the cause of these symptoms would preferentially be assessed under similar circumstances, for the psychological benefit of giving the patient confidence that their symptoms have been assessed under circumstances similar to their daily lives. Exercise stress also has the added benefit of providing important prognostic information regarding the duration of exercise, as well as heart rate and blood pressure dynamics during and after exercise (13) .

Imaging with CMR requires the patient to be lying inside the bore of the scanner at the time of imaging.

Thus, exercise must either be performed inside the scanner, for example, using contrast-enhanced, firstpass perfusion on a supine bicycle (14) , or outside the scanner. Approaches to perform exercise on a treadmill and then immediately transition into the scanner to perform CMR perfusion using GBCAs have shown excellent multicenter diagnostic performance (15) .

NO PROBLEM? Early developments in the field showed the ability to detect metabolic changes associated with myocardial ischemia using CMR spectroscopy during hand-grip exercise performed inside the scanner (16) . This was arguably the first example of "no gad, no drugs" CMR testing of myocardial ischemia. In this issue of iJACC, Nakamori et al. (17) add to the body of literature on cardiac imaging techniques and the "no gad, no drugs" CMR approach to evaluating myocardial ischemia by combining in-scanner supine bicycle exercise stress with native T 1 mapping. This pilot study in 28 patients showed that T 1 reactivity during exercise stress could detect a physiological signal related to exerciseinduced myocardial ischemia, and that this was associated with the severity of myocardial perfusion defect by single-photon emission computed tomography. For the first time, the investigators present rest and stress native T 1 mapping images using a color scale with which it is possible to visually evaluate the magnitude and variability of the differences between remote and ischemic myocardium. These T 1 maps and the manually defined regions of interest for measuring T 1 illustrate that although this novel work should be applauded for showing that the approach can detect a signal, there are a number of hurdles remaining before such a technique can provide convincing images for robust clinical adoption.

Taken together, the innovation race that is the quadrimodal tug of war among cardiac imaging modalities vying for a position as the test of choice in the evaluation of stress-induced myocardial ischemia has born a new kid on the block. Hinchliffe's Rule tells us that if a research paper's title is in the form of a yesno question, the answer to that question will be "no."

Indeed, the proposed technique is not free from problems, but the ongoing research in the field will continue to innovate and improve on our mouse trap, and inform our continued evolution in the field of cardiac imaging. C ardiac magnetic resonance (CMR) enables full coverage of the heart using high spatial and temporal resolution, without the constraints of limited acquisition windows or use of ionizing radiation, as with echocardiography or computed-tomography (1) . Cine CMR has become the gold standard for non-invasive quantification of cardiac volumes and ejection fraction (EF) (1). However, cine CMR images hold significantly more detailed information that allow for quantification of advanced markers of cardiac function such as ventricular shape (2) , ejection and filling rates (3), myocardial wall motion, and myocardial strain (ε) (4, 5) .

These parameters have shown to be valuable biomarkers for earlier detection and monitoring of disease (2) (3) (4) (5) . However, obtaining them is time and 

Step 1

Step 2

Step 3

Step 4

Short axis, 4-and 2-chamber and ejection parameters as well as ε circ , ε long , and ε rad stratified by sex are shown in Tables 3 and 4 . Supplemental Table 4 shows the regression analysis of changes in cardiac function in men and women with age.

In this study, we presented and validated a pipeline for automated analysis of ventricular function from cine CMR. Our pipeline is not solely a DL image analysis algorithm, but a framework that includes extensive QC steps to allow fully automatic processing of large numbers of CMR datasets without direct clinician oversight. We show that, using our proposed technique, we were able to obtain a detailed description of cardiac function in >2,000 healthy individuals.

To the authors' best knowledge, this is the first comprehensive framework for automated cine CMR analysis that approaches clinical standards of QC.

AUTOMATED QC. QC is essential in developing DL algorithms for automated processing of clinical data, but has so far been mostly overlooked (12) . In our framework, we implemented QC in 2 separate steps, a pre-analysis control of image quality, QC1, and a postanalysis control of the quality of the output parameters, QC2. Table 2 ) and sensitivity of error detection in validation2 ( Sensitivity, specificity and balanced accuracy (BACC) of the pipeline in detecting inaccurate or unusual output versus correct output with respect to manual assessment are shown. Ruijsink et al. Abbreviations as in Table 3 . Within the field of machine learning, the lowhanging fruit is often thought to be the automation of tasks that are "easy but tedious." Without a doubt, quantitative analysis of CMR images is tedious, but is it easy? The answer to that question lies in the nature of the images themselves. If signal-to-noise and spatial resolution are high, motion artifacts are absent, and the heart itself is physiologically normal, quantitative analysis is typically easy. The difficulty rises exponentially, however, when image quality is poor or images are acquired in patients with aspects of cardiac structure and function that differ markedly from those of normal volunteers. The trained model was then used to automatically analyze a second group of 700 patients, and the results of automated analyses were then classified as "right" or "wrong/unusual" by a human CMR expert.

These "right/wrong" classifications were used to define the "sensitivity" and "specificity" reported in Table 1 in Ruijsink et al. (5) . High sensitivity means that automated QC correctly rejected solutions that the human CMR expert judged were "wrong," and was typically over 90% ( Table 1 in Ruijsink et al. [5] ).

High specificity means that QC correctly accepted solutions that the human CMR expert judged as "right," and was typically lower, in the range of 75% to 85% ( Table 1 in Ruijsink et al. [5] ). The trained model was then used to determine normal ranges for cardiac functional parameters in 2,029 healthy subjects from the UK Biobank dataset ( Table 3 in Ruijsink et al. [5] for QC2 for strain). This means that roughly onequarter of all automated attempts fail to provide a meaningful solution, even in healthy subjects.

Moreover, the images used in this study were acquired at a single magnetic field strength (1.5-T), and appear to have come primarily from a single medical center, which suggests that the trained model may not perform as well in diverse clinical environments.

As pointed out by the authors, however, the principles and training methods they present could be repeated using a larger and more diverse set of training images, which itself is greatly facilitated by the authors' publication of their open source software.

Quantitative analysis of CMR images is "tedious and time consuming," while machine learning works well for tasks which are "easy but tedious." Rapid progress is being made in removing the "tedious" nature of quantitative CMR image analysis, but the pitfall will likely be exposed when the task isn't "easy." Is it realistic to expect that full automation can be achieved in the next decade for use in routine clinical settings, in which sick patients are imaged on MRI scanners with differing field strengths, manufacturers, pulse sequences, and protocols? Perhaps a more realistic goal for machine learning in CMR would be "fast and semi-automatic."

Physician time was not reported in the paper by . Myocardial fibrosis has been documented according to histopathological studies in patients with AS and is associated with increased morbidity and mortality (8, 9) .

Cardiac magnetic resonance (CMR) imaging offers a noninvasive, accurate, and reproducible assessment of LV architecture and function. CMR imaging detects the presence of replacement myocardial fibrosis by using late gadolinium enhancement (LGE) and diffuse reactive myocardial fibrosis using extracellular volume (ECV) fraction calculated from T1 mapping (10) (11) (12) (13) (14) . Both LGE and ECV correlate strongly with collagen content as measured by histological investigation, suggesting that they are both surrogate markers of myocardial fibrosis (9, 12, 15, 16) . Recent studies have reported an association between LGE and ECV with worse outcomes in patients with AS (10, 11, (17) (18) (19) . Several factors, and in particular age and sex, may also have an effect on the expansion of diffuse myocardial fibrosis, a key marker of LV decompensation in AS (18, 20) . The objectives of the current study were therefore to assess the determinants of diffuse (ECV) and focal (LGE) myocardial fibrosis in patients with AS, and in particular, to assess the effect of sex on these 2 types of fibrosis. Institute; and NCT01755936, Edinburgh Heart Centre) (18, 21) . The inclusion and exclusion criteria have been described previously (18, 21) . Patients enrolled in these prospective studies who underwent both echocardiography and CMR examinations were included in this analysis (Supplemental Figure 1) . The studies were approved by local ethics committees, and all patients provided written informed consent. was considered statistically significant. (Figure 2A) , the prevalence of LV hypertrophy did not differ between sexes (27% vs. 36%; p ¼ 0.17). However, there was a trend toward more LV concentric remodeling and concentric hypertrophy in men compared with women.

The systolic function as measured according to LV ejection fraction did not differ between sexes (p ¼ 0.16).

LGE. In the study population, LGE was present in 95 (38%) patients, and noninfarct LGE was present in 85 (34%) patients ( Table 1) . There was a trend toward a higher proportion of patients with detectable LGE in Figure 3C ).

However, there were significant differences between sexes according to tertiles of LV mass index (p ¼ 0.03) ( Figure 3D ).

Univariable linear regression analysis in the whole study population showed that V peak and LV mass index were associated with higher LGE (both, p < 0.0001), whereas there was only a trend toward an association between coronary artery disease and LGE (p ¼ 0.07) ( Figure 2) . 

4.6% (2.5 -7.6) P between-group = 0.08 Figure 4A ).

However, the slope of the correlation line between V peak and ECV fraction was steeper (p ANCOVA < 0.0001) in men than in women, suggesting a more pronounced impact of the AS-related pressure overload on LV fibrosis in men but not in women. Figure 4B ).

There was also an effect of sex on the relationship between LV mass index and ECV (p ANCOVA < 0.0001), Table 1 ).

The analyses of ECV fraction according to sex within each center yielded similar results (Supplemental Figure 3 ).

FRACTION. In the whole cohort, age (p ¼ 0.03), female sex (p < 0.0001), and hematocrit (p < 0.0001) were significantly associated with ECV fraction ( filling pressure (E/e 0 ratio), which may be related to reduced LV compliance and more advanced LV diastolic dysfunction in women (28, 39 and degree of LV hypertrophy/remodeling. In this study, we found an association between AS severity, LV mass index, and ECV in men but not in women ( Figure 4 , Supplemental Figure 4 ). Moreover, women had higher ECV than men, regardless of the degree of AS severity. Altogether, these results suggest that in men, the expansion of ECV is mainly driven by AS severity and extent of LV hypertrophy, whereas in women, the LV response to AS-related pressure overload in terms of remodeling, hypertrophy, and fibrosis is more heterogeneous and multifactorial.

The susceptibility to fibrosis has been mostly attributed to sex hormones such as estrogen, which could exert a cardioprotective effect in female hearts (44) (45) (46) . However, most patients with AS are >60 years of age, and the effect of sex hormones on the profibrotic process in postmenopausal women remains unknown. Conversely, chronic activation of the renin-angiotensin-aldosterone system is believed to play a key role in the cardiac remodeling process as well as in the profibrotic process (32) . Some evidence suggests that these processes may predominantly affect female hearts (32, 47) . Further studies are needed to determine the underlying mechanisms for the sex differences in the magnitude of myocardial fibrosis in patients with AS.

To the best of our knowledge, the current study is the first to perform separate analyses of explanatory variables for increased diffuse and replacement fibrosis in women and men. In women, there were no variables associated with higher ECV fraction, but interestingly older age, presence of coronary artery disease, and LV mass index were associated with higher LGE. The latter findings could reflect the presence of impaired coronary microcirculation related to the LV hypertrophic response and increased LV transmural pressures associated with AS (1) . Some studies reported that among patients with AS, the coronary microcirculation is more frequently impaired in women (48) . In men, older age and higher LV mass index were associated with higher ECV fraction; LV mass index was the strongest variable Tastet et al.

associated with higher LGE. Therefore, in men, the LV hypertrophic response due to chronic pressure overload seems to be the main factor for the adverse LV remodeling and subsequent fibrosis (Supplemental Figure 4 ). This outcome is consistent with a previous study that reported maladaptive LV remodeling associated with the activation of profibrotic markers predominantly in men with AS (49) . The association of older age with higher ECV fraction in men has been previously reported (31) . This finding is also supported by histological evidence suggesting that the aging process associated with myocyte cell loss affects the myocardium of men but not women (50) . ECV fraction is not specific to fibrosis, and thus it is possible that the larger ECV fraction in women could be related to many other factors, including the intravascular compartment rather than interstitial expansion due to diffuse myocardial fibrosis (55).

However, multiple histological studies (9, 12, 17) (2).

Sex difference in the LV response to AS has been investigated for several decades (3) (4) (5) . The "conventional" findings using echocardiography are that women have an exaggerated response to pressure overload, with more marked concentric LV hypertrophy with supernormal LV ejection fraction, and men have higher LV mass index and lower normal LV ejection fraction (3) (4) (5) . As a result of LV hypertrophy induced by high afterload in AS, myocardial ischemia as well as myocyte apoptosis and fibrosis occur (6) . 

However, findings by Tastet et al. (7) are not all consistent with previous reports, as summarized in Table 1 and Figure 1 . Previous studies showed similar or larger late gadolinium enhancement and ECV in men (11) (12) (13) . This is probably related to different study populations because most other studies evaluated symptomatic patients with severe AS, whereas the current report evaluated patients with mild to severe AS. The fact that the inclusion of less severe AS in the study led to the finding of a higher ECV fraction in women indicates that there is significant background myocardial fibrosis related to age and female sex, not related to AS. Concentric LV hypertrophy was more frequent in women when echocardiography was used and in men when cardiac magnetic resonance imaging was used. Our echocardiography data in 621 patients with severe AS show that concentric hypertrophy was more common in women than men (51% vs. 39%) when AS was severe ( Figure 1 ). In (4) Larger (3,5,7) Smaller (7,11-13) Larger (7, (11) (12) (13) LV hypertrophy Concentric LVH (3) (4) (5) LV remodeling patterns are similar to those of men (7) More dilated LV (3, 5) LV mass/volume is smaller (7,13) Normal geometry and concentric remodeling are more common (12) LV mass/volume is similar between sexes (11) Concentric LVH (7,12) Eccentric LVH (12)

Higher (3, 4) No different between sexes (5) Higher (12, 13) Similar between sexes (7,11) E/eʹ Much higher (7, 13) No different between sexes (12) Strain, LV contractility LV contractility more commonly declined (4) Longitudinal strain similar between sexes (13) ECV --Larger (7) Smaller (12) Smaller (7) Larger (12) LGE --Larger (7) Smaller (12) Similar between sexes (11) Outcomes Women with concentric LVH had worse prognosis (16) Sex does not affect early mortality rate (5) Men and women equally symptomatic (3) Symptom is more common (5) Symptomatic status is similar between sexes (7,11,12) Symptom onset is much higher (13) CMR ¼ cardiac magnetic resonance; ECV ¼ extracellular volume fraction; LGE ¼ late gadolinium enhancement; LV ¼ left ventricle; LVEF ¼ left ventricular ejection fraction; LVH ¼ left ventricular hypertrophy. Editorial Comment classification in cardiac magnetic resonance imaging (3) (4) (5) (11) (12) (13) .

Despite the discordant results, it is clear is that sex difference in LV reaction to AS exists. However, what is not clear is the mechanism driving the differences.

Sex differences are probably the result of the interaction of the molecular pathway directed by the sex chromosomes and hormones (14) . Although differences and changes in sex steroids across the life course may contribute to the differences in cellular remodeling, the contribution of the sex chromosomes has not been investigated systematically in preclinical models of ventricular disease.

Although data continue to accumulate that identify sex differences in phenotypic characteristics for AS, the question that follows is how these data could be Nonculprit lesions are present in approximately 50% of patients with STEMI and, if left unattended, carry a poor prognosis (11, 12) . In these patients, CMR is of special interest as it allows for simultaneous assessment of left ventricular function, infarction size, and perfusion. CMR thus not only provides valuable prognostic information, but also identifies patients with ischemia in nonculprit vascular territories who may benefit from revascularization.

The aim of the present study was to determine the agreement between CMR and invasive mea- were not subjected to physiological interrogation and were also regarded as hemodynamically obstructive.

In a subset of vessels, thermodilution derived coronary flow reserve (CFR thermo ) and index of microcirculatory resistance (IMR) were determined as described previously (22, 23 Table 1 . Timing of follow-up CMR and ICA Time between pPCI and CMR (days) 30 [28] [29] [30] [31] [32] [33] Time between pPCI and follow-up ICA (days) 31 [29] [30] [31] [32] [33] [34] Table 2 ).

Splenic switch-off was present in 72 (94%) patients. were randomly assigned to revascularization or optimal medical therapy (38) . Revascularization was associated with a 56% reduction in cardiac events. Everaars et al. Wong has reported that she has no relationships relevant to the contents of this paper to disclose. at an infusion rate of 6.2 ml/s followed by 50 ml of saline solution. The scan window was based on HR.

A body mass index-adapted scanning protocol was used, as previously described (14) . (14) and is given in Supplemental Figure 1 .

Vasodilatation was induced with an intravenous adenosine injection (0.14 mg/kg/min over 4 min). and an impaired signal/image-to-noise ratio (4 cases). Table 1 (segment-based analysis) and in Table 3 (territoryand patient-based analyses). Among the 417 stents classified as evaluable, coronary CTA correctly territory-, and patient-based analyses.

Supplemental Table 1 (stent-based analysis) and Abbreviations as in Table 1 . Abbreviations as in Tables 1 and 3 .

Andreini et al. Andreini et al. BACKGROUND Next to lesion severity, plaque vulnerability as assessed using coronary CT angiography affects fractional flow reserve (FFR), which is associated with imminent acute coronary syndromes. Instantaneous wave-free ratio (iFR) has recently emerged as an alternative for FFR to interrogate coronary lesions for ischemia. It is, however, unknown whether vasodilator-free assessment with iFR is associated with plaque stability similarly as FFR. ). CT-derived plaque characteristics were related to these invasive pressure measurements.

RESULTS Atherosclerotic plaques were present in 170 (66%) coronary arteries. On a per-vessel basis, luminal stenosis severity was significantly associated with impaired FFR, iFR, Pd/Pa, and iFRa. Multivariable analysis revealed that FFR and iFR were independently related to $70% stenosis (À0.10, p < 0.001 and À0.09, p ¼ 0.003, respectively) and plaque volume (-0.02, p ¼ 0.020 and -0.02, p ¼ 0.030, respectively). Additionally, PR and SC were also independent predictors of an impaired FFR (À0.10, p < 0.001 and À0.07, p ¼ 0.021, respectively), but adverse plaque characteristics were not independently related to the vasodilator-free iFR. (6).

From an anatomic point of view, there is a growing body of literature recognizing that a major share of acute coronary events originate from non-obstructive and so-called 'vulnerable plaques', which are prone to rupture (7) (8) (9) . Such atherosclerotic plaque morphology can now be assessed non-invasively using coronary computed tomography (CT) angiography, and has been described as a strong predictor of adverse events (10, 11) . Recently, these high-risk plaques have been linked to hyperemic myocardial blood flow and FFR, independent of luminal stenosis severity (12) (13) (14) . Hypothetically, this might in part explain the relationship between a low FFR and the risk of cardiac events beyond angiographic stenosis significance (15) .

Whereas FFR measurements require a hyperemic state, instantaneous wave-free ratio (iFR) has recently emerged as a novel invasive physiological measure obviating the need for hyperemia, notwithstanding a seemingly comparable relation with flow as well as short-term outcome (16) (17) (18) . Yet, studies describing an association between iFR and high-risk plaque morphology are lacking, which could provide insights regarding the currently debated differences and equalities of FFR and iFR (19) .

Accordingly, the aim of the present study was to investigate differences between FFR and the non-hyperemic iFR in relationship with CT-derived high-risk plaque features. PET. The PET scanning protocol has been described in detail previously (20) . In summary, a dynamic PET software. Among the various high-risk plaque features derived from CT, LAP (11%) and PR (9%) were most frequently found next to the less prevalent SC (5%) and NRS (2%). The quantitative association between plaque (18) Calcium-channel blocker 34 (28) Long-acting nitrate 9 (8)

Typical angina 42 (35) Atypical angina 50 (41) Nonspecific chest discomfort 28 (23) Values are mean AE SD or n (%).

ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin II receptor blocker; CAD ¼ coronary artery disease. Values are n (%) or mean AE SD.

CAC ¼ coronary artery calcium; CT ¼ computed tomography; FFR ¼ fractional flow reserve; iFR ¼ instantaneous wave-free ratio; iFRa ¼ instantaneous wave-free ratio during adenosine; Pd/Pa ¼ distal coronary artery pressure/aortic pressure. Tables 3 and 4 . In a univariable analysis, obstructive stenosis, coronary artery calcium score, plaque volume, and nearly all high-risk plaque features were inversely related to detrimental flow parameters, both hyperemic and non-hyperemic ( Table 3) .

Although coefficients values could not be normalized, a systematic numerical trend is shown from non- According to established cut-off values, dichotomized FFR and iFR showed discordant results in 5.5% of the cases. Discordancy most often occurred in the LAD (50%), and to a lesser extent in the RCA (14%) and LCX (36%). In total, 7 (2.7%) vessels showed normal FFR but abnormal iFR measures, whereas the opposite results were found in a similar number of 7 (2.7%) vessels. Figure 2A shows that mean stenosis severity in vessels with concordant negative FFR and iFR was significantly lower than the stenosis when either one or both FFR or iFR were positive. In coronary arteries with dissimilar FFR-iFR test results, however, mean stenosis severity was not different. Accordingly, Figure 2B Table 2 . Abbreviations as in Tables 2 and 3 . 

The present subanalysis of the prospective PACIFIC trial aimed to explore the relationship between CTderived high-risk atherosclerotic plaque morphology and FFR in comparison with the vasodilator-free iFR.

Multivariable models, including luminal stenosis severity, plaque volume, and adverse plaque features, showed that PR and SC were, next to stenosis severity, independent predictors of an abnormal FFR and iFRa, but not of resting indices Pd/Pa and iFR.

Furthermore, vessels with an abnormal FFR despite a preserved iFR showed significantly more high-risk plaque features than the opposite group with an abnormal iFR.

PHYSIOLOGICAL MEASURES TO PREDICT OUTCOME.

The current study may provide new insights in previously reported, but not fully elucidated findings.

Our data ( iFR ¼ instantaneous wave-free ratio; iFRa ¼ pressure ratio during adenosine within the wave-free period; Pd/Pa ¼ distal coronary artery pressure/aortic pressure;

ROC ¼ receiver-operating characteristic. Figure 2B indicates that have shown its incremental predictive value (36) .

Also, the plaque assessment itself remains variable to some extent, with inter-observer reproducibility between 0.66 and 0.81, as previously reported (14) .

Finally, although current findings provide some new insights, the relationship between physiological parameters, plaque morphology, and clinical events is highly complex and remains not yet fully understood.

The present subanalysis of the prospective PA- (1). Studies also strongly suggest that actively progressing atheroma is associated with worse outcome than stable disease (2) . Treatment that halts the progression of atherosclerosis (e.g., lipid-lowering therapy), and medications altering the probability of vascular thrombosis in response to plaque disruptions (e.g., antiplatelet therapy), are known to reduce risk of myocardial infarction or death in patients with coronary heart disease.

Conversely, treating individual plaques with coronary stents, even though most targeted lesions exhibit so called "vulnerable characteristics" (3), has not been shown to reduce the risk of myocardial infarction or death in many randomized controlled trials of patients with stable coronary heart disease (4). This is not surprising when considering that individual plaques are associated with low risk of catastrophic events (5 (48) Values are mean AE SD or n (%).

CAD ¼ coronary artery disease; cCTA ¼ coronary computed tomography angiography; CT-FFR ¼ coronary computed tomography angiography-derived fractional flow reserve FFR ¼ fractional flow reserve. Abbreviations as in Figure 1 .

Tesche et al. (12, 20, 21) . Baseline characteristics of the study cohort are presented in Table 1 . (Figures 2A and 2B) . Tables 2 to 4 .

showed superior diagnostic performance over cCTA Figure 3) . A representative example of cCTA, CT-FFR, and ICA with FFR is shown in Figure 4 . Key findings are shown in the Central

Additional case examples are provided in the Supplemental Appendix. Imaging times were 4 to 6 min for both scanners (13).

One-day rest-stress, stress-rest, stress-only, or 2-day stress-rest protocols were performed according to site-specific protocols. Patients underwent symptomlimited standard exercise treadmill testing or pharmacologic stress (16) . Rates of events were calculated using a Kaplan-Meier analysis for both stratification by visual assessment and TPD in the overall population and in Otaki et al. subgroups of suspected CAD. The log-rank test was used to assess any differences in event risks with worsening of visual perfusion or quantitative perfusion assessment among the classified groups. Integer values were considered for TPD analysis. Stress TPD category $5% has been previously established as the threshold for diagnostic abnormality (18, 19) . An SSS of $4 was considered equivalent to TPD $5% as it is used as an abnormal threshold during clinical reading (10) . The visual score SSS <1 (or SSS ¼ 0) was considered an approximate equivalent to TPD <1%. Table 1 . Overall population.

Patient characteristics of overall populations with and without MACE are shown in Table 3 . Compared with the group of patients without MACE, the MACE group was older and consisted of more males. Pharmacological stress testing was more commonly used for patients with MACE, and the incidence of ischemic ECG changes was higher in patients who had MACE than in Table 4 ) and among patients with suspected CAD (Supplemental Table 2 ). Similarly, in both unadjusted and adjusted Cox proportional analyses, higher rates of MACE were associated with increases in stress TPD in the overall population ( Table 4 ) and among patients with suspected CAD (Supplemental Table 2 ). stress TPD $5% (18, 19) . SSS ¼ summed stress score; other abbreviations as in Figures 1 and 2 .

Otaki et al. In the present study, 12,066 patients were visually scored as normal. MACE rates also increased progressively with increasing intervals of stress TPD cardiologists in real practice and observed significant MACE risk increases for "probably normal" and "equivocal" categories compared with risks in the "normal" category. However, "probably normal" is often avoided, and "equivocal" is reserved for For visual analysis, the authors applied commonly accepted categories of normal, probably normal, equivocal, and abnormal. In a subset of 13,533 patients, in whom the images were scored on-site using the 17-segment model (9) , images were also categorized using the stress image summed stress score (SSS) of 0 ¼ normal, (3) (4) (5) (6) . Despite much progress, prospective identification of rupture-prone plaques, which would be crucial to stratify risk and improve patient management, remains elusive (7-10). Current OCT and OFDI modalities rely on subjective interpretation and fall short of providing an objective and quantitative assessment of plaque morphology and composition (11) (12) (13) (14) .

Recently, we have introduced intravascular polarimetry by using polarization-sensitive (PS) OFDI in combination with standard intravascular OFDI catheters (15) (16) (17) . Intravascular polarimetry complements the high-resolution imaging of subsurface microstructures known from OCT and OFDI with polarimetric measurements of tissue birefringence and depolarization (15, 16) . Tissue with fibrillar architecture, such as interstitial collagen or layered arrays of arterial smooth muscle cells, exhibits birefringence, which can serve to assess collagen and smooth muscle cell content (16, 18) . Depolarization corresponds to the randomization of the detected polarization states Table 1 . Coregistration between conventional OFDI and polarimetric signals is intrinsic, because they are In addition to the lumen, we segmented the internal elastic lamina, whenever visible, using the birefringence map to leverage from the improved visibility of the media in the birefringence map (16) .

In areas in which the internal elastic lamina segmentation was unattainable, typically in lipid-rich areas of advanced lesions, an automatic outer border corresponding to a tissue depth of 1 mm from within the fibrous caps, which has been shown to correlate with macrophage infiltration (3, 12) . NSD was computed by first evaluating the SD of the linearscale backscatter intensity data within elliptical Figure 3B ). Figures S1A and S1B ).

Calcifications located in fibrous tissue exhibited lower birefringence and depolarization than those in lipid-rich lesions (p < 0.001 for both), as shown in Supplemental Figures S1C and S1D. Thrombus (white thrombus) presented very low birefringence and depolarization (Supplemental Figures S2A and S2B ).

CULPRIT LESIONS. The lipid arc and minimum fibrous cap thickness differed with statistical significance between the ACS and/or PR and the SAP groups, as shown in Table 2 . When comparing the polarimetric signals of the fibrous caps in the culprit lesions, we found lower birefringence in the ACS and/or PR group than in patients with SAP (p ¼ 0.002), but comparable depolarization (p ¼ 0.772) ( Figures 4A and 4B) . Table 3 shows generalized estimating equation The relationships between polarization properties and clinical and optical frequency domain imaging parameters were determined by unadjusted generalized linear model using a generalized estimating equation to take into consideration the intrasubject correlations among multiple cross-sectional images from individual patients. Beta values and 95% CIs for birefringence are given in units of Â10 À3 .

Abbreviations as in Tables 1 to 3 . In a less advanced stage of atherogenesis, birefringence and depolarization increase along with the proliferation of thick collagen, smooth muscle cells, and lipid content (atherogenesis and progression). Birefringence of the plaques declines in hand with the reduction of interstitial collagen, and the development of the lipid/necrotic core, which in turn leads to a significant increase in depolarization, corresponding to the transition of pathological intimal thickening (fibrous plaque [FP] and fibrofatty plaque [FF]) to a fibroatheroma (progression and destabilization). ACS ¼ acute coronary syndrome; FC ¼ fibrocalcified plaque; PR ¼ plaque rupture;

Otsuka et al. (20) . Histopathologic studies showed that ruptured fibrous caps lack layered smooth muscle cells and feature different collagen phenotypes than intact caps (20) , which offers an explanation for the low birefringence observed in the fibrous caps of patients with ACS and/or PR. In addition to cap birefringence, minimum fibrous cap thickness and lipid arc angle also featured statistically significant differences between these 2 patient groups. Yet fibrous cap thickness alone is insufficient to identify caps that are prone to rupture (4, 5, 8, 9) . The polarization metrics available to intravascular polarimetry complement these structural features and may advance our understanding of the pathogenesis of ACS with or without fibrous cap rupture (10, 21) . Second, our plaque classification corresponds well to the current understanding of plaque subtypes in OFDI (6) and could be readily performed on the conventional OFDI signal, yet conventional OFDI has limited ability to classify lesion types, especially in advanced lesions (11, 14) . Although lipid-rich plaques offer some prognostic implication From a prediction perspective, plaque composition assessed in patients with stable and unstable CAD is associated with the development of future clinical events (4, 9) . Optical coherence tomography (OCT) is a high-resolution intravascular imaging technique that can assay coronary wall structure on a histopathological scale (w10 to 20 mm), and has been used for detecting high-risk plaques (10) . However, the predictive ability of OCT and other intracoronary imaging modalities remains modest, and the quest for new prognostic developments in the intracoronary imaging arena is ongoing (11) . Finite element modeling (FEM) is a widely accepted computational tool for biomechanical profiling of coronary plaques. In FEM, plaque contours are determined using idealized models (8, 9) , histology cross sections (10, 11) , or imaging tools such as virtual histology, IVUS, or computed tomography (CT) (12) (13) (14) .

The contours are discretized into meshes, and tensile stress is mathematically derived in response to physiological pressure and information on the material properties of the constituent tissues (8, 12) . Several FEM studies have underscored the importance of local maximum (peak) tensile stress in the fibrous cap and indicated that peak stress is profoundly related to the propensity of plaque rupture and ensuing risk of acute coronary events (12) (13) (14) . Various morphological factors, including fibrous cap thickness (8, 11) , NC size (11, 12, 14) , plaque burden (13), stenosis severity (8) , and presence of calcifications (13) , have been shown to influence peak stress. Clinical studies suggest that the measurement of peak stress may improve the prediction of future major adverse cardiovascular events, thus highlighting the clinical need for prospectively quantifying biomechanical stress in coronary plaques (13, 15) . Table 1 Table 2 ).

Mesh generation and modal solution. The segmented plaque geometries were meshed with 2-dimensional, 6-node triangular and 8-node quadrilateral isoparametric elements. Appropriate boundary conditions and wall thickness of 300 mm were used to suppress the rigid body motion and radial overstretching of the artery, respectively. Static intraluminal pressure of 13.33 kPa was applied as the loading condition to mimic physiological pressure.

The distribution of tensile stress was computed within each element, and the average stress of neighboring elements was calculated to obtain the tensile stress at each node. The tensile stress distribution was similarly calculated for all nodes within the coronary cross section, and the location of the maximum tensile stress (peak stress) was noted ( Figure 2D ). (Figures 3D3 to 3D5) . Furthermore, thicker NCs with large NC arc elicited high peak stress.

We also observed that the presence, location, and thickness of calcium modulated peak stress. observed between FEM-derived peak stress and FC thick , and the best fit was obtained using power law (8, 11, 12) .

We used stepwise multivariate regression analysis to identify the most influential plaque parameters and exclude redundant variables ( Figures 6C1 to 6C3 ).

The tensile stress distribution in NCFAs, particularly peak stress in the fibrous cap, is a crucial predictor of plaque rupture and major adverse cardiovascular events in patients (12) (13) (14) . The traditional FEM modeling approach used to compute the peak stress is mathematically complex, requires specialist operators, and takes hours to report results. In this study, A key finding of our study is that peak stress in the fibrous cap can be directly estimated by using a closed-form equation (Equation 1 ). Similar to other studies (8, 11, 12) , we demonstrated a nonlinear relationship ( Figure 4A ) between peak stress and FC thick .

Although the critical FC thick of <65 mm has been extensively reported in published reports as a major determinant of plaque vulnerability (1, 18) , our study demonstrated that under certain conditions, NCFAs with thicker FC thick similarly exhibited elevated peak stress. We further observed that in plaques with thicker caps (>200 mm), the peak stress is only minimally influenced by FC thick , where NC thick was the major determinant of PSM, whereas when FC thick is reduced to <200 mm, peak stress is exponentially Doradla et al. that peak stress was considerably elevated when a thin calcific nodule (Cal thick <200 mm) was located in the vicinity of the lumen (CalLu dist <200 mm).

Other biomechanical studies using FEM indicate a large variability in peak stress values (100 to 900 kPa) measured in ruptured and intact coronary plaques in patients (21) (22) (23) . In this study, we observed peak stress values ranging from w100 to 1,000 kPa even in Table 3 ).

In our study, FEM was used purely for the purpose NCFAs (Figure 6) , through straightforward MSE measurements, we observed that peak stress was significantly elevated in the vicinity of the rupture site.

Although further validation through prospective clinical testing is warranted, this initial result is significant because it indicates that just 6 morphometric measurements of plaque geometry may accurately localize rupture-prone sites.

STUDY LIMITATIONS. In the patient cohort investigated in this study, ruptured plaques were observed in only 3 patients; therefore, the MSE was applied to identify rupture sites in only these patients. In 3 patients with plaque ruptures we observed that the maximum PSM was elevated close to the site of plaque rupture ( Figure 6) . which may be used as a risk measure for a plaque to destabilize or rupture (8, 9) .

The current study by Doradla et al. (15) valve morphology (8, 9) , and later studies using 3DE revealed that the primary mechanism of this MR is attributable to tethering of the mitral valve caused by the dilated LV and displaced papillary muscle rather than mitral annular dilatation (10) (11) (12) (13) Anatomically, the mitral leaflets are able to cover the mitral annulus, which is the narrowest portion connecting the LA to LV, with a 1.5 to 2.0 times larger leaflet area than that found in healthy individuals (22, 23, 25, 28, 29) . (21, 24, 32, 33) . Table 1) ; thus, the generality of this mechanism in patients with atrial functional MR is somewhat uncertain, although such cases with posterior leaflet tethering have been encountered in clinical practice.

According to our clinical impressions, posterior leaflet tethering is a relatively rare subtype in patients with atrial functional MR and tends to be observed in patients with extremely advanced LA remodeling. In fact, in these studies reporting atriogenic tethering as the main mechanism of atrial functional MR, LA size was notably larger than in other studies ( Table 1) .

IMPORTANT CO-SUBSTRATES. The mitral annulus is primarily composed of fibrous and adipose tissue. It does not actively contract by itself, but moves passively with contraction of the LA and the more muscular LV. The normal mitral annulus is known to be saddle shaped. In early systole, the area of the mitral annulus decreases 20% to 25% compared with that in diastole (36, 37) , and the saddle shape increases in depth (24, 37) . AF rhythm immediately blunts the motion of the mitral annulus (38) and

gradually increases the size and flatness of the mitral annulus (24, 27) . The reduced annular contraction results in a larger systolic mitral annulus area, further boosting the annulus area to leaflet area imbalance.

The flattening of the annulus, which results in a loss of the deep saddle shape, causes increased stress on the mitral leaflets and a greater tethering distance (20, 39, 40) . With regard to the saddle shape, 2 studies demonstrated a significantly higher nonplanar angle (more flattened annulus) in patients with atrial functional MR (23, 24) . Other studies also reported a similar annulus height between those with and without atrial functional MR despite the larger annulus in atrial functional MR, suggesting a more flattened annulus is present in patients with atrial functional MR (20, 22, 23, 25) . Thus, flattened annulus seems to be pervasive as well. In total, 9 studies referring to the prevalence of atrial functional MR in patients with AF and preserved LV function ( (Figure 8 ). Multivariate analysis also showed that MR was a significant predictor of worse outcomes (hazard ratio: 4.0; 95% confidence interval: therefore, comprehensive multiparametric grading is recommended (6, 57) . Novel 3D methods including vena contracta area and 3D proximal isovelocity surface area have the potential to overcome these limitations regarding orifice shape (58, 59) . Transesophageal echocardiography has superior image quality and enables a more detailed morphological assessment of mitral valve apparatus; however, mild anesthesia is often required because of discomfort, which may modify the severity of functional MR (60, 61) .

Another challenge in the quantification of atrial functional MR is the beat-to-beat variation of cycle lengths, along with variable severity of MR. Although guidelines recommend quantification using the average of 5 or more heart beats for chamber quantification, it is not always easy to implement this recommendation in clinical practice (62) . The use of an index beat, whose preceding and pre-preceding beat have the same RR intervals, may be an effective alternative (63) . control therapy for AF, particularly for paroxysmal AF (64) , and lately the scope/application of catheter ablation has expanded to treat permanent AF (65) .

Several studies have shown that catheter ablation is superior to drug therapy to maintain sinus rhythm.

Maze procedures, which have better free-from-AF Surgical treatment may currently be the most reliable treatment option for MR in atrial functional AF. A few small-sized studies showed that atrial functional MR can be controlled by surgical annuloplasty in most cases (16, 33) ; however, an annuloplasty alone may not always be effective. Figure 6 shows 2 cases with different anatomical characteristics of the mitral valve. In case A, MR was primarily attributable to insufficient leaflet remodeling with a very small mitral leaflet-to-annulus ratio of repair or replacement annually (15) . Tricuspid regurgitation is known to be associated with significant mortality (16) . Therefore, there may be many patients who may benefit from repair/replacement who are not offered surgery (up to 25% significant morbidity or mortality), but for whom a less invasive, percutaneous approach could be highly beneficial (17) . ventricle, all of which potentially complicate access and device deployment/fixation (Central Illustration) (17, 22) . Given all these extremely important anatomic variables that require detailed measurements for a specific percutaneous therapy, CTA is critical in patient assessment and therefore, image quality is of the utmost importance.

One of the developing challenges will be the need to anatomically screen a single patient for multiple devices for a given valve using CTA, without knowing which device will be used before protocoling the scan.

Given that each device has specific anatomic considerations and interactions, a broad protocol needs to be developed at each institution to cover their potential devices. Although the current document covers considerations for cardiac CTA acquisition for planning of currently available and studied devices, adjustments need to be made to protocols as devices and access pathways evolve.

TMVR. Optimal left-sided opacification is necessary in all cases. If device and access path are unknown, Scan trigger value 150 HU (though for Toshiba Aquilion One family voice trigger should be 30 HU below scan trigger value). *For patients with BMI #25 kg/m 2 and of younger age, for which radiation exposure reduction is desired, can consider adjusting kV to 70-80. †Optimize mA when possible recommend using automatic mA or manual selection by experienced operator. ‡Recommend using upper end of range of contrast dose for earlier generation scanners.

BMI ¼ body mass index; CTA ¼ computed tomography angiography; HU, Hounsfield units; other abbreviations as in Table 1 . If using the Toshiba Aquilion One family, trigger values for voice 30 HU below scan trigger value. *When possible recommend using automatic mA selection. Alternatively, optimization of mA may be selected manually by an experienced operator. †For patients with BMI #25 kg/m 2 and of younger age that radiation exposure reduction desired, can consider adjusting tube potential to 70 or 80 kV (depending on scanner; 70 kV using Siemens Force with maximum tube current selection up to 1,300 mA). ‡Use 70 ml protocol for earlier generation scanner that requires longer cardiac scan to cover up to 16 cm craniocaudal coverage.

Abbreviations as in Tables 1 and 2 . is set to allow for ideal homogenous mixing of right-sided contrast. In these 2 images, significant streak artifact is seen in the right heart (arrow). RA ¼ right atrium;

RV ¼ right ventricle; other abbreviation as in Figure 2 . for each patient during which contrast enhancement of common femoral vein remained within 90% of peak value attained. At 120 s from CT pulmonary angiogram, 85% of patients were within 90% of their peak enhancement. CT ¼ computed tomography. The protocol adjustment would require either reducing the injection rate to 3 to 3.5 ml/s of 100% iodinated contrast, or changing to a mixed contrast/ saline approach of 75%/25% for 10 to 12 s and reducing the added delay to 2 rather than 5 s ( Table 2) .

Tricuspid protocol. In TTVR, bolus tracking in the middle of the right ventricular cavity is used. To avoid the higher chance of streak artifact, to decrease possible premature scanning, and to limit total contrast media used, a triphasic injection is recommended, using a mixed contrast/saline approach ( (Figures 4 and 5) . We use 180 HU as our standard trigger threshold value, Dilute contrast especially for ideal right-sided opacification (see Table 3 )

Not diluting contrast for imaging focusing on right-sided cardiac structures Arrhythmia/tachycardia If tachycardic consistently above 100 beats/min, generally give lowdose metoprolol or diltiazem (depending on institutional approach and individual patient safety) to control heart rate If significant fluctuating R-R intervals (although not tachycardic) in setting of atrial fibrillation or other atrial or ventricular arrhythmia, we prolong the scan exposure so that a full R-R can be reconstructed Scanners that use arrhythmia editing should be used Ignore heart rate without consideration of rate control Not considering adjusting scan exposure Not using arrhythmia editing if scanner has capability CT ¼ computed tomography; FOV ¼ field of view; PVC ¼ premature ventricular contraction; other abbreviations as in Tables 1 and 2. although it should be set at least 100 HU above precontrast baseline Hounsfield value. For TTVR scans, because right-sided cardiac structures are being scanned, a monitoring delay of no more than 2 to 3 s should be used before the initiation of bolus tracking.

A venogram is needed as part of the tricuspid protocol, because vascular access possibilities include internal jugular, subclavian, and femoral veins. We perform a nongated (medium-to-high pitch) helical scan of neck, chest, abdomen, and pelvis (from external auditory canal to lesser trochanter). For the venogram scan, an 80-s delay after the cardiac scan is used to allow adequate contrast opacification of the required venous structures (34) . In our experience, peak femoral venous opacification can be quite variable and an 80-s delay from the cardiac scan has been selected with goal of obtaining within 90% peak venous opacification (as measured in HU). (Figures 6A and 6B) . In situations of renal impairment or a desire to limit contrast volume, a total of 30 to 40 ml contrast at 4 ml/s ( Table 3 ) could be used, by slightly adjusting the recommended protocol (eliminating the second 25/75% contrast/saline injection). For annuloplasty devices that will be implanted with proximity to the right coronary artery, the CT protocol should trigger off of the thoracic aorta with reduced scan delay to 2 s, using a faster 4.5 to 5 ml/s flow rate, so as to ensure adequate right coronary and right heart opacification ( Figures 7A and 7B) . For this modification, the delay for the venogram scan should be adjusted to 65 s after cardiac scan. Poor renal function Risk of contrast-induced nephropathy Lower total iodine administered, generally by decreasing total contrast volume Consider performing cardiac and vascular scans on different days (although necessary in rare situations) in concert with individual injection day contrast volume reduction Perform noncontrast assessment and/or consider alternative imaging modalities Frequently encountered patient variables (i.e., low cardiac output, severe valvular heart disease, arrhythmias, severe renal impairment), potential problem, and recommendations/tips to maximize image quality while limiting patient risk. *Increasing tube current results in a linear increase in radiation exposure. Increasing peak tube potential results in a more-than-linear increase in radiation exposure. Adapted with permission from Khalique et al. (23) . Tables 1 and 2 .

Several challenges can arise when performing these specialized scans. Recommended approaches to avoid suboptimal scanning are offered in Table 4 in a "Do and Don't" format.

Several patient-specific factors need to be taken into consideration that may modify the particulars of scan protocol specification. These include patient size, heart size, cardiac output, renal function, and heart rate and rhythm. 

Clinical trials have begun of numerous transcatheter mitral valve and tricuspid valve repair and replacement devices.

Cardiac and vascular assessment before transcatheter intervention requires highquality, anatomy-specific CT angiography protocols.

The many possible clinical challenges affecting CT angiography are reviewed and specific tips and trouble-shooting approaches provided.

As this field rapidly advances, so too will the requirement for high-quality CT angiography protocols. Furthermore, the recent addition of high-resolution LGE imaging to the CMR protocol has significantly This finding indicates that a holistic "anatomic and electroanatomic" approach is the key because it allows a complete identification of the arrhythmogenic substrate, an improved selection of the ventricular area to focus mapping, and finally better localization of the target ablation site (i.e., the conducting channel entrances).

Although CRT has been used for more than 2 decades, Bimodal distribution of pixel intensities of the left atrial (LA) wall. "Normal tissue" is defined as the first mode of lower pixel intensities and "injured tissue" at n SD above the mean pixel intensity of normal tissue, and histogram of pixel intensities: "normal" tissue is defined as the lower region of the pixel intensity histogram, between 2% and 40% of the maximum intensity within the LA wall. The fibrotic threshold was then calculated as 2 to 4 SDs above the mean of "normal" tissue.

Comparative analysis of pre-existing fibrosis assessment methods in a healthy subject. The magnetic resonance image was processed with the addition of 2, 3, or 4 SDs above the mean of the normal myocardium (14) and also with the image intensity ratio (IIR) techniques using the validated cutoffs (0.97 to 1.61). Modified with permission from Pontecorboli et al. (20) . Imaging in Electrophysiology and Device Implantation (35) (36) (37) . The use of novel strategies that combine electric and mechanical (strain) assessment may be particularly suitable for an endocardial pacing approach, with the ability to target any region on the LV endocardial wall without the constraint of the coronary venous anatomy (38) . The recent development of a wireless intracardiac LV endocardial electrode for CRT delivery represents a unique opportunity to use integrated multimodality image guidance for optimal LV site selection (35) . Electrophysiologists increasingly rely upon cardiac imaging for diagnosis, treatment, and management of patients with various arrhythmic disorders.

Integration of diagnostic and interventional cardiac imaging will further increase the effectiveness of cardiac electrophysiological procedures.

More extensive use of cardiac imaging will help in delivering patient-specific therapies with ablation and cardiac implantable electronic devices.

imaging will serve the ultimate goal of increasing effectiveness and efficiency of electrophysiological procedures and interventions as well as to deliver patient-specific therapies in cardiac electrophysiology and device indication and implantation. Lung ultrasound performed at peak stress shows the development of B-lines in interrogated lung zones. B-lines are vertical hyperechoic reverberation artifacts that originate from the pleural line (yellow arrow). These stress-induced B-lines indicate thickening of the lung interstitium correlating with the accumulation of extravascular lung water. Thus, the mitral valve disease can be clearly classified as hemodynamically severe since with exercise there was marked increase in the left atrial pressure that lead to the development of acute pulmonary edema from increased pulmonary capillary hydrostatic pressure. The echocardiographic findings of a high transvalvular mitral gradient and marked exercise-induced elevation of right ventricular systolic pressure confirm the diagnosis. Ultimately, the patient underwent mitral valve replacement following the stress test. See Video 2.

Wiley et al. 

Patient B achieved 75W in 6 min on the supine bike. Peak heart rate was 141 BPM (90% of age-predicted max). The peak transvalvular mitral gradient was 25 mm Hg and the regurgitation increased from moderate to severe (qualitative assessment). The tricuspid regurgitation Doppler envelope was incomplete but was estimated to be at least 4 m/s (70 mm Hg). The left ventricular ejection fraction increased mildly to 65%. shortening (i.e., MCF and strain) (8, (13) (14) (15) (16) In both disorders, stroke volume is markedly reduced; however, because the LVEDV is also reduced, the calculated ratio of stroke volume to LVEDV (i.e., the LVEF) typically falls into the normal or near-normal range, A similar discordance between LVEF and myocardial shortening is seen in patients who have heart failure and a preserved ejection fraction (HFpEF) in the context of a chronic systemic inflammatory or metabolic disorder (e.g., obesity, diabetes). In these patients, inflammatory changes in the endothelium of coronary microvasculature causes microcirculatory dysfunction and fibrosis of the myocardium, impairing the ability of the left ventricle to accommodate increases in chamber volume (17) (18) (19) (20) . However, central blood volume is often elevated in these patients as a result of sodium retention or a decrease in systemic venous capacitance (17) . Consequently, stroke volumes are normal or mildly increased and the LVEDV is also normal or mildly increased (20, 21) .

Because the LVEF is a ratio of stroke volume to LVEDV, the measured LVEF resides in the normal range; yet, myocardial contraction is meaningfully impaired. The inflammatory and fibrotic processes in the myocardium serve to both increase myocardial 

Systolic performance should be assessed by quantifying the degree of myocardial shortening, which can best be carried out by measurement of myocardial strain or by normalizing the observed systolic ejection to the capacity for myocardial contraction (i.e., calculating a ratio of stroke volume to myocardial volume), as in the measurement of the MCF (4, 9) However, currently, the most widely used metric of systolic performance normalizes stroke volume for LVEDV and not myocardial volume. As a result, if the LVEDV is not markedly enlarged (as is true for hearts that have microcirculatory dysfunction or fibrosis or an infiltrative or hypertrophic process rather than ventricular remodeling and enlargement), the calculation of LVEF will indicate that systolic function is normal, when it is (in fact) meaningfully (and often markedly) impaired (22) (23) (24) (25) (26) .

Under these circumstances, a measure of myocar- ing given similarities in histopathologic features between the 2 diseases and to our knowledge has not been previously described (2) . Fabry disease is an X-linked lysosomal storage disorder caused by the deficiency of a-galactosidase A activity, characterized by progressive accumulation of lysosomal glycosphingolipids in multiple organs, including the heart.

The mechanism of AM toxicity is likely related to Some agents may be helpful in the prevention or early treatment of cancer therapeutics-related cardiac dysfunction (1); therefore, timely prediction of cardiotoxicity could be significant. A previous systematic review described echocardiographic myocardial deformation parameters during or after cancer chemotherapy (2) . In comparison, we included only prospective studies, focused on the predictive accuracy, and pooled the estimates. To the best of our knowledge, our study is the first meta-analysis of the (Figure 1) .

EAT BMI appears to be an independent predictor of MACE at 30 days in patients undergoing elective noncardiac surgery and appears to be incremental to RCRI and coronary CTA. CACS between patients with and those without gout Gout was also associated with higher serum uric acid (7.0 mg/dl [IQI: 5.7 to 8.6 mg/dl] vs. 5.8 mg/dl [IQI: 4.9 to 6.9 mg/dl]; p < 0.001).

MACE occurred in 18 patients with gout (19%) and 83 gout-free patients (9%) ( Figure 1A) . When patients were stratified by CACS, gout was associated with increased annualized MACE at high CACS, though median CACS was significantly increased for gout in that category ( Figure 1B) To the best of our knowledge, this is the first study to systematically report alterations in cardiac Please note: Drs. Petersen, Neubauer, and Piechnik acknowledge the British Heart Foundation for funding the manual analysis to create a cardiovascular magnetic resonance imaging reference standard for the UK Biobank imaging resource in 5000 cardiovascular magnetic resonance scans (www.bhf.org.uk; PG/14/89/31194). Dr. Aung is supported by a Wellcome Trust Research Training Fellowship (wellcome.ac.uk; 203553/Z/Z). Dr. Fung is supported by the Medical College of Saint Bartholomew's Hospital Trust, an independent registered charity that promotes and advances medical and dental education and research at Barts and the London School of Medicine and Dentistry. Dr. Piechnik has received support from the National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Centre at Barts. Drs. Piechnik and Lee have received support from and from the "SmartHeart" Engineering and Physical Sciences Research Council (EPSRC) programme grant (www.nihr.ac.uk; EP/P001009/1). Dr. Jensen is supported by The Danish Heart Foundation (16-R107-A6791) and the Danish Society of Cardiology. Drs. Neubauer and Piechnik have received support from the Oxford National Institute for Health Research Biomedical Research Centre and the Oxford British Heart Foundation Centre of Research Excellence. This project was enabled through access to the Medical Research Council (MRC) eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council. The funders provided support in the form of salaries for authors as detailed but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr. Petersen provides consultancy to Circle Cardiovascular Imaging Inc., Calgary, Canada, and Servier. Dr. Jensen has served as consultant, on advisory boards, or as invited speaker for AstraZeneca, Novo Nordisk, Novartis, and GE. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Assuming the observed overall complication rate of 7.3% and the sample size of the study, differences in complication rates of 8% (i.e., 3.3% vs. 11.3%) or larger could have been detected (power 80%, type I error ¼ 0.05; 2-sided).

Procedural complications occurred less often in women in the CT group compared with the ICA group (CT: 1.1% vs. ICA: 11.5%). Procedural complications were similar in men in both groups (CT: 7.6% vs. ICA: 9.5%). Major procedural complications were uncommon in the CT and ICA group in both sexes ( Table 1) .

Minor procedural complications occurred less often in women in the CT group compared with the ICA group ( Table 1 ). The interaction sex study arm regarding procedural complication was p ¼ 0.072.

The number of any events at long-term follow-up at 3.3 years was similar in women and men in both groups ( Table 1) . This study is limited by its single-center design and the small total number of adverse events. Although earlier studies revealed differences between women and men regarding the prevalence and symptoms of CAD, ours is the first study analyzing sex differences in terms of outcomes of diagnostic procedures (CT and ICA). This study shows that women with atypical chest pain and a clinical indication for coronary evaluation may benefit from a strategy based on CT instead of ICA, specifically due to a reduction in minor procedural complications.

Possible reasons for these results are:

1. Having a lower pretest probability of disease than men and a lower rate of complex diseases women are expected to benefit less from initial ICA.

2. Women with obstructive CAD have more comorbidities, present with atypical symptoms, and tend Letters to the Editor Values are n (%). *Significant after Bonferroni correction with factor 2 for testing of 2 subgroups.

CT ¼ computed tomography; ICA ¼ invasive coronary angiography. Although the investigators mentioned non-LBBB, separate data on the population with non-LBBB

were not reported in their study, which is important because of the controversy on CRT benefit in non-LBBB and/or right bundle branch block. Also, as a receiver-operating characteristic analysis was not reported (absence of non-CRT control group) and

because CRT response is probably continuously related to SSI, clinicians may speculate on the added value of SSI or any SSI threshold to be used in cardiology practice. A low SSI value may not preclude patients from being treated with CRT.

Finally, a common observation in both studies was that CRT response was associated with echodyssynchrony measures, irrespective of the presence of LBBB. Does this mean that echocardiography is taking back control over the selection of CRT candidates, after it was discredited a decade ago (7) imaging and subsequently in CT (4) and CMR (5) . CMR studies also show that quantitation might also allow differentiation of epicardial CAD from microvascular disease (6) . Quantitation of perfusion has also found a role in prognostication in multiple modalities other than SPECT and PET but with evidence both for (4, 7) and against (8) that was lacking contemporary data on risk stratification. This is incredibly important given the evidence of declining risk in our symptomatic patient cohorts, manifesting in reduced rates of ischemia and obstructive coronary artery disease (4, 5) . The high predictive accuracy of the presented SPECT findings provide for novel evidence that this modality continues to be highly predictive of cardiac risk.

All of these statements are important, but the vital message from this registry is that not only was the quantitation complementary, but further refined the risk estimates in this large patient cohort. In fact, for the 1,062 patients with a normal visual read, annualized event rates ranged considerably from 1.6% to 3.4% for stress total perfusion deficits quantified automatically from 0% to $5% of the myocardium. A similar stratification was also reported for those patients with a summed stress score of 0. These data support an important further stratification of risk, which to date has not been appreciated in nuclear interpretation.

These findings are significant, as recent trial evidence reports that patients with lower risk findings As we see new and emerging evidence supporting the utility of nuclear cardiology, especially in the exciting age of big data and machine learning (14), let us also hope that there are unfolding data from randomized trials that compare its effectiveness with that of cardiac magnetic resonance or coronary computed tomographic angiography. We are also seeing growth in the use of cardiac PET, and it would be fundamental to optimal patient care that trial evidence support the superiority of accuracy and improvement in clinical outcomes when compared with other competitive modalities, including SPECT.

This, by far, is the challenge for the nuclear community to raise the bar to a new level!

Etiology of valvular heart disease in the 21st century

Plasma ACE2 activity predicts mortality in aortic stenosis and is associated with severe myocardial fibrosis

The aortic stenosis complex

The aortic stenosis complex: aortic valve, atherosclerosis, aortopathy

Flow vortices in the aortic root: in vivo 4D-MRI confirms linium contrast agents

Gadolinium-free cardiac MR stress T1-mapping to distinguish epicardial from microvascular coronary disease

Exercise electrocardiogram testing: beyond the ST segment

MRcompatible treadmill for exercise stress cardiac magnetic resonance imaging

The rate-pressure product as an index of myocardial oxygen consumption during exercise in patients with angina pectoris

Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on

Prognostic value of gated myocardial perfusion SPECT

Phantom study of breast tissue attenuation in myocardial imaging

Myocardial edema as detected by pre-contrast T1 and T2 CMR

First-pass nuclear magnetic resonance imaging studies using gadolinium-DTPA in patients with coronary artery disease

Assessment of myocardial perfusion in coronary artery disease by magnetic resonance: a comparison with positron emission tomography and coronary angiography

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International Society for Magnetic Resonance in Medicine. Gadolinium deposition in the brain: summary of evidence and recommendations

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Adenosine stress and rest T1 mapping can differentiate between ischemic, infarcted, remote, and normal myocardium without the need for gadolinium contrast agents

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3T MRI investigation of cardiac left ventricular structure and function in a UK population: the Tayside Screening for the Prevention of Cardiac Events (TASCFORCE) study

A survey on deep learning in medical image analysis

Fully-automated left ventricular mass and volume MRI analysis in the UK Biobank population cohort: evaluation of initial results

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Fully automated segmentation-based respiratory motion correction of multiplanar cardiac magnetic resonance images for large-scale datasets

Calcific aortic stenosis

Calcific aortic stenosis: a disease of the valve and the myocardium

The symptoms of aortic stenosis

Progression from compensated hypertrophy to failure in the pressure-overloaded human heart

Myofibroblast-mediated mechanisms of pathological remodelling of the heart

Pathological ventricular remodeling: mechanism

Prognostic value of normal exercise and adenosine

Tc-tetrofosmin SPECT imaging: results from the multicenter registry of 4,728 patients

Prognostic study of risk stratification among Japanese patients with ischemic heart disease using gated myocardial perfusion SPECT: J-ACCESS study

A novel high-sensitivity rapid-acquisition single-photon cardiac imaging camera

Nuclear myocardial perfusion imaging with a cadmiumzinc-telluride detector technique: optimized protocol for scan time reduction

Single photon emission computed tomography (SPECT) myocardial perfusion imaging guidelines: instrumentation, acquisition, processing, and interpretation

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Automated quantification of myocardial perfusion SPECT using simplified normal limits

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Comparative definitions for moderate-severe ischemia in stress nuclear, echocardiography, and cardiac magnetic resonance

Comparing the areas under 2 or more correlated receiver-operating characteristic curves: a nonparametric approach

Fully automated analysis of attenuation-corrected SPECT for the long-term prediction of acute myocardial infarction

Prognostic value of quantitative high-speed myocardial perfusion imaging

Prognostic value of combined clinical and myocardial perfusion imaging data using machine learning

The prognostic value of regadenoson myocardial perfusion imaging

The prognostic value of normal exercise myocardial perfusion imaging and exercise echocardiography: a meta-analysis

Corridor4DM: the Michigan method for quantitative nuclear cardiology

Effects of age, gender, obesity, and diabetes on the efficacy and safety of the selective A2A agonist regadenoson versus adenosine in myocardial perfusion imaging: integrated ADVANCE-MPI trial results

Regadenoson induces comparable left ventricular perfusion defects as adenosine: a quantitative analysis from the ADVANCE MPI 2 trial

Quantitative assessment of myocardial perfusion abnormality on SPECT myocardial perfusion imaging is more reproducible than expert visual analysis

Automated assessment of serial SPECT myocardial perfusion images

Automatic and visual reproducibility of perfusion and function measures for myocardial perfusion SPECT

Comparison of fully automated computer analysis and visual scoring for detection of coronary artery disease from myocardial perfusion SPECT in a large population

5-Year prognostic value of quantitative versus visual MPI in subtle perfusion defects: results from REFINE SPECT

Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association

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Prognostic value of gated myocardial perfusion SPECT

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A normal stress SPECT scan is an effective gatekeeper for coronary angiography

Pathology of the vulnerable plaque

Quantification of macrophage content in atherosclerotic plaques by optical coherence tomography

New ST-elevation myocardial infarction

Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation

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Imaging plaques to predict and better manage patients with acute coronary events

Sources of error and interpretation of plaque morphology by optical coherence tomography

Macrophages and intravascular OCT bright spots: a quantitative study

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NIRS and IVUS for characterization of atherosclerosis in patients undergoing coronary angiography

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Histopathology of postpercutaneous transluminal coronary angioplasty remodeling in human coronary arteries

Biomechanical stress in coronary atherosclerosis: emerging insights from computational modelling

Initial stress in biomechanical models of atherosclerotic plaques

Necrotic core thickness and positive arterial remodeling index: emergent biomechanical factors for evaluating the risk of plaque rupture

Plaque structural stress estimations improve prediction of future major adverse cardiovascular events after intracoronary imaging

Plaque rupture in coronary atherosclerosis is associated with increased plaque structural stress

A three-dimensional finite element analysis of stress distribution in a coronary atherosclerotic plaque: in-vivo prediction of plaque rupture location

Repeatability assessment of intravascular polarimetry in patients

Biomechanical interaction between cap thickness, lipid core composition and blood pressure in vulnerable coronary plaque: impact on stability or instability

Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries

Computational approaches for analyzing the mechanics of atherosclerotic plaques: a review

Peak cap stress calculations in coronary atherosclerotic plaques with an incomplete necrotic core geometry

Distribution of circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation

Novel combined miniature optical coherence tomography ultrasound probe for in vivo intravascular imaging

Novasight Hybrid System Recives FDA 510(k) Clearance

A prospective natural-history study of coronary atherosclerosis

Near-infrared spectroscopy predicts cardiovascular outcome in patients with coronary artery disease

Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VH-IVUS in Vulnerable Atherosclerosis) Study

Natural history of experimental coronary atherosclerosis and vascular remodeling in relation to endothelial shear stress: a serial, in vivo intravascular ultrasound study

The dynamic nature of coronary artery lesion morphology assessed by serial virtual histology intravascular ultrasound tissue characterization

Arterial remodeling and endothelial shear stress exhibit significant longitudinal heterogeneity along the length of coronary plaques

Role of low endothelial shear stress and plaque characteristics in the prediction of nonculprit major adverse cardiac events: the PROSPECT Study

High coronary shear stress in patients with coronary artery disease predicts myocardial infarction

Role of biomechanical forces in the natural history of coronary atherosclerosis

Plaque rupture in coronary atherosclerosis is associated with increased plaque structural stress

Anatomically correct three-dimensional with intravascular ultrasound for endothelial shear stress assessment in humans

A novel semiautomated atherosclerotic plaque characterization method using grayscale intravascular ultrasound images: comparison with virtual histology

Prediction of atherosclerotic disease progression using LDL transport modelling: a serial computed tomographic coronary angiographic study

Biomechanical stress profiling of coronary atherosclerosis: identifying a multifactorial metric to evaluate plaque rupture risk

Impact of longitudinal lesion geometry on location of plaque rupture and clinical presentations

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The natural history of lone atrial fibrillation. A population-based study over three decades

Left atrial diameter in nonvalvular atrial fibrillation: an echocardiographic study. Stroke Prevention in Atrial Fibrillation Investigators

Structural and functional remodeling of the left atrium: clinical and therapeutic implications for atrial fibrillation

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Integrated mechanism for functional mitral regurgitation: leaflet restriction versus coapting force: in vitro studies

Mechanistic insights into functional mitral regurgitation

Impact of atrial fibrillation on tricuspid and mitral annular dilatation and valvular regurgitation

Mitral regurgitation associated with mitral annular dilation in patients with lone atrial fibrillation: an echocardiographic study

Evidence of atrial functional mitral regurgitation due to atrial fibrillation: reversal with arrhythmia control

Severe functional mitral regurgitation arising from isolated annular dilatation

The impact of mitral regurgitation on patients undergoing catheter ablation of atrial fibrillation

Mitral valve repair for atrial functional mitral regurgitation in patients with chronic atrial fibrillation

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The CIBA Collection of Medical Illustrations

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Effect of atrial fibrillation on the dynamics of mitral annular area

Anatomy of the mitral valve apparatus: role of 2D and 3D echocardiography

Distant position of chordae from coaptation causes mitral regurgitation in patients with atrial fibrillation

Left atrial strain: a useful index in atrial fibrillation

Left atrial mechanical function and stiffness in patients with paroxysmal atrial fibrillation

Left atrial speckle tracking analysis in patients with mitral insufficiency and history of paroxysmal atrial fibrillation

Usefulness of atrial deformation analysis to predict left atrial fibrosis and endocardial thickness in patients undergoing mitral valve operations for severe mitral regurgitation secondary to mitral valve prolapse

Left ventricular volumes during ventricular tachycardia, first post-tachycardia beat, and subsequent beats in normal rhythm

Hemodynamic consequences of atrial and ventricular arrhythmias in man

Mitral incompetence in experimental auricular fibrillation

Effect of atrial systole on ventricular pressure and closure of the A-V valves

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Clinically unrecognized mitral regurgitation is prevalent in lone atrial fibrillation

Prevalence, clinical characteristics, and outcome of atrial functional mitral regurgitation in hospitalized heart failure patients with atrial fibrillation

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Effect of general anesthesia on the severity of mitral regurgitation by transesophageal echocardiography

The effect of depth of anesthesia on the severity of mitral regurgitation as measured by transesophageal echocardiography

Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

Indexbeat assessment of left ventricular systolic and diastolic function during atrial fibrillation using myocardial strain and strain rate

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Comparison of the efficancy and complication rates of the hybrid Maze, complete Cox-Maze and catheter ablation in the treatment of atrial fibrillation

Trials and travails of electrogram-guided ablation of chronic atrial fibrillation

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Echocardiographic left atrial reverse remodeling after catheter ablation of atrial fibrillation is predicted by preablation delayed enhancement of left atrium by magnetic resonance imaging

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Losartan inhibits endothelial-to-mesenchymal

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Global, regional, and national burden of rheumatic heart disease

Europe: the Euro Heart Survey on Valvular Heart Disease

Transannular calcification: results from the First Multicenter Global Registry

Percutaneous transvenous transseptal transcatheter valve implantation in failed bioprosthetic mitral valves, ring annuloplasty, and severe mitral annular calcification

First-in-human case of transfemoral CardiAQ mitral valve implantation

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Prevalence and spectrum of conditions associated with severe tricuspid regurgitation

Practical considerations for optimizing cardiac computed tomography protocols for comprehensive acquisition prior to transcatheter aortic valve replacement

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CT in transcatheter aortic valve replacement

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Three-dimensional geometry of the tricuspid annulus in healthy subjects and in patients with functional tricuspid regurgitation

CT angiography of the cardiac valves: normal, diseased, and postoperative appearances

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Right heart: split-bolus injection of diluted contrast medium for visualization at coronary CT angiography

Optimization of combined CT pulmonary angiography with lower extremity CT venography

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After reading this article the reader should be able to discuss how cardiac imaging can be helpful

Medtronic, and Microport CRM; has intellectual property with Biosense Webster, Boston Scientific, and Microport CRM; and has received speaker fees from Boston Scientific, Medtronic, Microport CRM, and Philips. Dr. Faletra has received speaker fees from Philips

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Declining risk of sudden death in heart failure

ischemic and nonischemic LV dysfunction: a meta-analysis

Defibrillator implantation in patients with nonischemic systolic heart failure

Outcomes of cardiac resynchronization therapy with or without defibrillation in patients with nonischemic cardiomyopathy

therapy: the GAUDI-CRT Study

Prevalence and clinical outcome of mitral-valve prolapse

Mitral valve prolapse and sudden cardiac arrest in the community

Mitral valve prolapse: cardiac arrest with long-term survival

Sudden cardiac death, mitral valve prolapse, and long QT syndrome

Papillary muscle traction in mitral valve prolapse: quantitation by two-dimensional echocardiography

Cardiovascular magnetic resonance characterization of mitral valve prolapse

Arrhythmic mitral valve prolapse and sudden cardiac death

Morphofunctional abnormalities of Mitral annulus and arrhythmic mitral valve prolapse

Association of atrial tissue fibrosis identified by delayed enhancement MRI and atrial fibrillation catheter ablation: the DECAAF study

Low incidence of left atrial delayed enhancement with MRI in patients with AF: a single-centre experience

Left atrial LGE and arrhythmia recurrence following pulmonary vein isolation for paroxysmal and persistent AF

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Drugs vs ablation for the treatment of atrial fibrillation: the evidence supporting catheter ablation

Left atrial strain predicts recurrence of atrial arrhythmias after catheter ablation of persistent atrial fibrillation

Cardiac imaging in patients with ventricular tachycardia

3D delayed-enhanced magnetic resonance sequences improve conducting channel delineation prior to ventricular tachycardia ablation

Advancement in cardiac imaging for treatment of ventricular arrhythmias in structural heart disease

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resynchronization therapy: a combined magnetic resonance imaging, electroanatomic contact mapping, and hemodynamic study to target endocardial lead placement

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Utility of dual-source computed tomography in cardiac resynchronization therapy-DIRECT study

for the Collaborative Study Group. Feasibility, safety, and short-term outcome of leadless ultrasound-based endocardial left ventricular resynchronization in heart failure patients: results of the Wireless Stimulation Endocardially for CRT (WiSE-CRT) study

Department of Cardiovascular Medicine

Ultrasound comet-tail images

Myocardial contraction fraction: a volumetric in

Myocardial contraction fraction: a volumetric measure of myocardial shortening analogous to strain

Noncompressibility of myocardium during systole with freehand three-dimensional echocardiography

Geometry as a confounder when assessing ventricular systolic function: comparison between ejection fraction and strain

Novel wall motion score-based

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Myocardial contraction fraction predicts cardiovascular events in patients with hypertrophic cardiomyopathy and normal ejection fraction

Echo parameters for differential diagnosis in cardiac amyloidosis: a head-to-head comparison of deformation and nondeformation parameters

Myocardial contraction fraction by Mmode echocardiography is superior to ejection fraction in predicting mortality in transthyretin amyloidosis

Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction

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Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction

The epicardial adipose inflammatory triad: coronary atherosclerosis, atrial fibrillation, and heart failure with a preserved ejection fraction

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Impaired systolic function by strain imaging in heart failure with preserved ejection fraction

Impaired left ventricular global longitudinal strain in patients with heart failure with preserved ejection fraction: insights from the RELAX trial

Left ventricular systolic dysfunction potentially contributes to the symptoms in heart failure with preserved ejection fraction

Predictive value of left ventricular myocardial strain by fourdimensional speckle tracking echocardiography combined with red cell distribution width in heart failure with preserved ejection fraction

Speckle tracking echocardiographydetermined measures of global and regional left ventricular function correlate with functional capacity in patients with and without preserved ejection fraction

Indeimmunoglobulin light chain amyloidosis

Prognostic value of novel imaging parameters derived from standard cardiovascular magnetic resonance in high risk patients with systemic light chain amyloidosis

The myocardial contraction fraction is superior to ejection fraction in predicting survival in patients with AL cardiac amyloidosis

Relation of the myocardial contraction fraction, as calculated from M-mode echocardiography, with incident heart failure, atherosclerotic cardiovascular disease and mortality (results from the Cardiovascular Health Study)

Association between reduced myocardial contraction fraction and cardiovascular disease outcomes: the Multi-Ethnic Study of Atherosclerosis

Usefulness of the left ventricular myocardial contraction fraction in healthy men and women to predict cardiovascular morbidity and mortality

Left atrial strain performance and its application in clinical practice

Please note: Dr. Hanneman has received funding from the Radiological Society of North America Research Scholar Grant (RSCH1608). Dr. Thavendiranathan is supported by a Canadian Institutes of Heath Research New Investigator Award (147814)

Antimalarial-induced cardiomyopathy: a systematic review of the literature

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Inhibition of cardiomyocyte lysosomal activity in hydroxychloroquine cardiomyopathy

Use of myocardial T1 mapping at

T to differentiate Anderson-Fabry disease from hypertrophic cardiomyopathy

Native T1 and T2 mapping by CMR in lupus myocarditis: disease recognition and response to treatment

E-mail: gykpanda@163

Key Research and Development Project Fund of Department of Science and Technology of Sichuan Province (2019YFS0430), Program for Young Scholars and Innovative Research Team of Department of Science and Technology of Sichuan Province (2017TD0005), and 1$3$5 Project for Disciplines of Excellence

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Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy

Prognostic capabilities of coronary computed tomographic angiography before non-cardiac surgery: prospective cohort study

Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery

Epicardial adipose tissue volume but not density is an independent predictor for myocardial ischemia

of the American College of Cardiology Foundation. Please note: yDrs. Christensen and Yu are joint first authors

Choudhary) from the National Heart, Lung, and Blood Institute; Institutional Development Award P20GM103652 (to Dr. Morrison) from the National Institute of General Medical Sciences; grant T35HL094308 (to Dr. Chu) from the National Heart, Lung, and Blood Institute; Career Development Award 7IK2BX002527 (to Dr. Morrison) from the U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Program; Veterans Affairs Merit Award I01CX001892 (to Dr. Choudhary); and Agency for Healthcare Research and Quality Award 5K12HS022998 (to Dr. Shah). The authors have

Impact of comorbidities on gout and hyperuricaemia

Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement

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ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults

Hospital Barts Health NHS Trust Glen Road London E13 8SL United Kingdom E-mail: m.khanji@qmul

FIGURE 1 Cardiac Chamber and Function Changes With Regular Versus Rare/Never Recreational Cannabis Use (N ¼ 3,407) 1. United Nations Office on Drugs and Crime (UNODC). Statistics and Data

World Health Organization. The Health and Social Effects of Nonmedical Cannabis Use

Lifestyle advice and interventions for cardiovascular risk reduction: a systematic review of guidelines

Cardiovascular risk assessment: a systematic review of guidelines

vessels (5), and thus, benefit more from risk factor modification than from coronary revascularization. In addition, CT allows more detailed risk stratification, which may improve outcomes

Kofoed has received research grants from AP Møller og hustru Chastine McKinney Møllers Fond, The John and Birthe Meyer Foundation, Research Council of Rigshopitalet, The University of Copenhagen, The Danish Heart Foundation, The Lundbeck Foundation, and The Danish Agency for Science, Technology and Innovation by The Danish Council for Strategic Research; has served as principle investigator of the investigator initiated CATCH-2 trial, CSub320 trial, and at the steering committee of the CORE320 trial-supported in part by Toshiba Medical Corporation

Heart disease and stroke statistics-2019 update: a report from the American Heart Association

Evaluation of computed tomography in patients with atypical angina or chest pain clinically referred for invasive coronary angiography: randomised controlled trial

Emergence of nonobstructive coronary artery disease: a woman's problem and need for change in definition on angiography

Cardiovascular disease in women: clinical perspectives

Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes

Papillary muscle dyssynchronymediated functional mitral regurgitation: mechanistic insights and modulation by cardiac resynchronization

Systolic stretch characterizes the electromechanical substrate responsive to cardiac resynchronization therapy

Mechanism of improvement in mitral regurgitation after cardiac resynchronization therapy

Effectiveness of cardiac resynchronization therapy by QRS morphology in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT)

Effect of QRS duration and morphology on cardiac resynchronization therapy outcomes in mild heart failure: results from the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) study

Septal flash: at the heart of cardiac dyssynchrony

Papillary muscle dyssynchronymediated functional mitral regurgitation: mechanistic insights and modulation by cardiac resynchronization

Refining the prognostic impact of functional mitral regurgitation in chronic heart failure

A unifying concept for the quantitative assessment of secondary mitral regurgitation

CRT improves LV filling dynamics: insights from echocardiographic particle imaging velocimetry

Mechanism of decrease in mitral regurgitation after cardiac resynchronization therapy: optimization of the force-balance relationship

E-mail: shekh003@ umn.edu OR Dr. Leslee J. Shaw, Dalio Institute for Cardiovascular Imaging

5-year prognostic value of quantitative versus visual MPI in subtle perfusion defects: results from REFINE SPECT

Incremental prognostic value of myocardial blood flow quantified with stress dynamic computed tomography perfusion imaging

Diagnostic performance of fully automated pixel-wise quantitative myocardial perfusion imaging by cardiovascular magnetic resonance

Automated Pixel-Wise Quantitative Myocardial Perfusion Mapping by CMR to Detect Obstructive Coronary Artery Disease and Coronary Microvascular Dysfunction

Prognostic Value of Quantitative Stress Perfusion Cardiac Magnetic Resonance

A comparison of cardiovascular magnetic resonance and single photon emission computed tomography (SPECT) perfusion imaging in left main stem or equivalent coronary artery disease: a CE-MARC substudy

chest pain: insights from the PROMISE trial

Prognostic value of noninvasive cardiovascular testing in patients with stable chest pain: insights from the PROMISE Trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain)

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

Prognostic Value of Combined Clinical and Myocardial Perfusion Imaging Data Using Machine Learning

Additional studies, such as using dual-sensor OFDI-IVUS, are needed to investigate the use of biomechanical stress profiling for the prognostic evaluation of patients with atherosclerosis. Otsuji et al., 2002 (14) None Global longitudinal strain (%) w-20 to -24 w-10 to -16 w-12 to -18 w-6 to -12 w-6 to -12HFpEF ¼ heart failure with preserved ejection fraction; LV ¼ left ventricular. Values are drawn from the original research papers (1, 8, 15, 28, 29) .

An Regular cannabis use was independently associated with adverse changes in left ventricle size and subclinical dysfunction compared with rare/never cannabis use.*Changes remain significant after multivariable adjustment. #Changes remain significant after adjustment for age and sex. Please note: This work was supported by a KLIF of the Austrian Science Fund (KLI 818-B). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.