Ultrasound contrast agents have unique acoustic properties that enable them to enhance the cardiac blood flow and thus are used broadly in modern echocardiography laboratories for salvage of nondiagnostic studies, improving accuracy and reducing variability even in the presence of adequate image quality. Contrast echocardiography is also used as an adjunctive technique when unenhanced echocardiography falls short in the differentiation of cardiac structural abnormalities such as cardiac masses. Ultrasound contrast agents are pure intravascular tracers. Development of innovative ultrasound imaging techniques has led to myocardial perfusion imaging with contrast echocardiography. Although currently an off-label indication, it has been shown that perfusion imaging with contrast echocardiography adds incremental value to stress echocardiography in the detection of coronary artery disease. Moreover, it can be used for assessment of myocardial viability. In this paper we briefly discuss the basics of contrast echocardiography and its use in daily clinical practice. Despite technological advances in echocardiography, such as harmonic imaging, a significant number of rest or stress echocardiography studies are labeled as nondiagnostic. Even in the presence of adequate image quality, some cardiac structural abnormalities pose a diagnostic challenge. Ultrasound contrast agents (UCAs) have been shown to improve the diagnostic accuracy of echocardiography. Furthermore, assessment of myocardial perfusion by means of contrast echocardiography has been extensively studied with proven independent diagnostic and prognostic benefits. This paper (a) briefly highlights some technical aspects of UCAs and the relevant imaging techniques and (b) summarizes the use of contrast echocardiography in daily clinical practice.Use of UCAs in echocardiography is not new. In 1968, Gramiac and Shah noted a cloud of echo at the tip of cardiac catheters while doing M‑mode studies on the aortic root in the cardiac catheterization laboratory . Thus, iThe acoustic behavior of UCAs in response to the different range in ultrasound mechanical index (MI) is an important part of contrast echocardiography. MI is directly proportional to an ultrasound beam’s peak negative pressure and inversely proportional to the frequency of the beam and is considered as the ultrasound acoustic power. In an MI > 0.1, contrast microbubbles contract and expand unequally, which means they will produce ultrasound backscatter with a lower amplitude than the transmitted fundamental frequency, the so-called nonlinear response. In lower MI myocardial tissue backscatter, however, typically shows a linear response, i. e., producing backscatter signals at the same amplitude. Modern scanners will be able to cancel out the tissue backscatter and image only reflected signals from the UCA. An MI of more than 0.9 will cause destruction of the UCA resulting in brief but strong nonlinear backscatter signals that also can be used in contrast echocardiography. In summary, the two techniques are called low-MI and high-MI imaging, respectively. The real-time low-MI <0.3) techniques are those that are more routinely used in clinical practice [ techniquContrast echocardiography is used for a variety of diagnostic and prognostic reasons. Table Assessment of global and regional left ventricular function has both diagnostic and prognostic value in a range of cardiac conditions such as coronary artery disease, heart failure, and cardio-oncology. It is well reported that up to 15% of echocardiography studies are uninterpretable owing to poor image quality. This is even more prominent in critically ill patients and has been reported to be as high as 30% . Both AmConventional 2D echocardiography uses high MI that results in destruction of contrast microbubbles. When performing an LVO study, this will result in contrast swirling, especially in the apical area that is closer to the ultrasound beam source. Furthermore, at high MI, tissue will also produce harmonic backscatters (nonlinear response) that make delineation of the endocardial border more difficult. For these reasons, LVO studies should be performed with low MI (<0.3), which is usually available on modern echocardiography machines, to reduce microbubble destruction and tissue signals. The focal zone should be at the level of the mitral valve annulus and a minimum frame rate of 25 MHz is required. Adjusting time gain compensation helps to achieve a homogeneous opacification of the left ventricle from the apex to the base. Bolus injections are usually used for LVO studies and should be of such volume that adequate opacification of the left ventricle is reached. In high volumes of contrast, however, microbubbles can act as a barrier to the ultrasound beam and cause attenuation resulting in the far field view being attenuated. This can be resolved by using the “flash” or “burst” function that sends high-MI ultrasound beams over 4–5 frames and destroys the contrast allowing for a better differentiation of the endocardial border Fig. .Fig. 1aTransthoracic echocardiography has a sensitivity as high as 93% for diagnosing cardiac masses . Left veapical hypertrophic cardiomyopathy on transthoracic echocardiography can be confirmed by an LVO study demonstrating the spade-shape apex with the thick apical cap and apical systolic cavity obliteration. Contrast LVO can also help differentiate prominent trabecula from noncompaction morphology.Diagnosis of suspected LVO can also be used in the detection of acute myocardial infarction complications such as pseudo-aneurysm. It has also been used with transesophageal echocardiography to facilitate the diagnosis of left atrial appendage closure particularly before direct-current cardioversion .The aforementioned limitations of transthoracic echocardiography in visualization of the endocardial border can pose an even more significant challenge in stress echocardiography, when definition of the endocardial border for detection of regional wall motion abnormalities is crucial. Even in cases with adequate image quality, the respiratory effort in the case of an exercise test or tachycardia resulting from use of inotropic agents and the narrow window in acquiring images could all lead to difficulty in interpreting the studies. Suboptimal studies have been reported as high as 30% in routine stress echocardiography with an inter-institutional agreement as low as 43% in those with poor image quality. LVO has been shown to reduce the nondiagnostic stress echo studies to less than 10%, to improve test accuracy and reader confidence, and to reduce variability in several studies –21.Again, real-time low-MI imaging is the preferred method. While bolus injections are easier to adopt for exercise stress echocardiography and should be administered about 30 s before acquiring images, an infusion can be used in pharmacologic stress echocardiography. Given that the infusion of the contrast takes longer to reach the adequate concentration, it is best started at least 45 s before image acquisition is performed. As discussed, a higher concentration of microbubbles can act as a barrier to the ultrasound beam causing attenuation. Thus stress echo imaging should be started with apical views since attenuation from the higher concentration of the microbubbles in the right ventricle can affect the image quality of the parasternal left ventricular views.LVO for improvement of endocardial border definition both at rest and stress along with its role in defining cardiac structural abnormalities are the licensed applications for the use of UCAs and should be an integral part of any echocardiography laboratory. Contrast echocardiography can also be used for enhancement of Doppler signals. This can be achieved even after fragmentation of contrast microbubbles, in the absence of visible opacification of the cardiac cavities, owing to remaining microbubble shells in the circulation. More advanced use of UCAs includes myocardial contrast echocardiography (MCE), which is technically challenging and requires significant experience. The adoption of this technique, despite several favorable clinical studies, has been slow and is limited to expert centers.Coronary blood flow is equally distributed between the arteries and arterioles, capillary network, and venules. Myocardial blood volume represents a third of total coronary flow, of which more than 90% resides in the capillary network . MCE relThere are essentially two main MCE imaging techniques.Destructive (high MI) imaging techniques use an MI > 1 that will cause microbubble destruction, resulting in a nonlinear response and generation of strong harmonic signals in multiples of the transmitted fundamental frequency. However, after the destruction phase, the myocardium will require some time to be refilled with contrast. Therefore, it is not possible to perform real-time MCE and imaging should be done by triggering ultrasound every few frames . This means that assessment of wall motion abnormality with triggered imaging is not possible, which is considered an important disadvantage. Moreover, it is difficult to maintain the same imaging window in-between triggered frames. For these reasons, high-MI MCE is not the preferred modality in daily practice. harmonic power Doppler and pulse inversion Doppler. In harmonic power Doppler, two consecutive pulses are transmitted in the same scan line. The reflected backscatter from the first pulse will be from both tissue and myocardial capillaries, while the signals from the second pulse will be solely from myocardial tissue (because of microbubble destruction by the first pulse). If the myocardial capillaries are not filled with contrast because of a perfusion defect, then there will not be a shift in frequency, whereas a normally perfused myocardium will result in backscatter signals from both tissue and microbubbles from the first pulse and only the tissue from the second pulse. In pulse inversion Doppler, two pulses are sent down shortly after each other that are 180° out of phase. Since the response of the myocardial tissue to the transmitted signal will be linear, they will cancel each other out. However, microbubbles will respond in a nonlinear fashion and therefore the backscattered signal intensity will be a reflection of the contrast microbubbles in the myocardial capillaries. At high MI, myocardial tissue will also produce harmonics that will be filtered out using modern narrow-band transducers.The two main destructive techniques areNondestructive or real-time low-MI imaging techniques allow for simultaneous assessment of the left ventricular regional wall motion with perfusion imaging. This means a minimum frame rate of 25 MHz is required and thus a lower MI  is used to avoid microbubble destruction, but this is at the cost of a weaker backscatter from the microbubbles. The nondestructive techniques are essentially the same as destructive ones but use a lower amplitude of transmitted waves. In power modulation technique , multiple pulses are transmitted in each scan line with each alternate phase only in 50% amplitude pulses. The ultrasound scanner doubles the received signals from the 50% amplitude pulses and then subtracts that from the received signal from the 100% amplitude pulses. Therefore, backscattered signals from the myocardial tissue, which produces a linear response, will be cancelled out. Power modulation is considered a highly sensitive technique but has lower resolution and image quality [Pulse inversion Doppler, as was explained in high-MI imaging, can also be used in the real-time low-MI MCE. In this technique, essentially, nonlinear scatters from the microbubbles will be detected while linear response from myocardial tissue will be canceled resulting in high-resolution images. However, because it can only receive even harmonics, there will be attenuation artifact, particularly in the basal myocardial segments. The contrast pulse sequencing  is another multiphase technique that uses both alternate amplitude and polarity resulting in high image quality and sensitivity but is still subject to attenuation  and thus myocardial blood flow can be measured . Use of A prerequisite for MCE is that the relationship between the contrast concentration and the scatter intensity is linear. With a contrast bolus injection, at a certain level, when the maximum UCA concentration is achieved, the linear relationship is lost. At this point, even a hypoperfused region may appear falsely normal. It is only during the contrast decay that the myocardial contrast intensity and hence the myocardial blood volume can be assessed. Thus, with the bolus injection, maintaining a window where the UCA can be detected and yet not saturated is crucial. Whereas with the contrast infusion, an optimal level of microbubble concentration within the myocardium can be easily achieved. Moreover, since the mean transit time of the microbubbles during contrast injection cannot be calculated, it is impossible to measure myocardial blood flow. For these reasons a contrast infusion is preferred for performing MCE.Exercise, vasodilators, or inotropes can be used for stress MCE. The incorporation of MCE into an exercise stress test is challenging but has been shown to be feasible with improvement of both left ventricular wall assessment and perfusion , 24. It MCE can be used for the assessment of myocardial tissue viability since an intact tissue will be replenished with contrast because the capillaries and microvasculature will still be intact, whereas an ischemic or fully infarcted territory will show patchy or absent contrast density. In fact, the contrast density has an inverse relationship with myocardial collagen. MCE has been used for evaluation of the myocardial viability in both acute and chronic settings. Ito in 1992 demonstrated that despite a patent artery related to an infarcted zone, up to 25% of patients did not show myocardial opacification in an infarcted area and thus no myocardial viability, a phenomenon that is called “no flow” and was first described by Kolner in 1974. Other studies have shown the independent prognostic impact of assessment of the infarct-related myocardial region (treated with either thrombolysis or percutaneous intervention) on left ventricular remodeling and death . PerfusiA study by Gaibazzi et al. showed that a positive stress MCE predicted a 1-year incidence of acute coronary syndrome in those who presented to the emergency department with chest pain and unremarkable ECG changes and negative troponin findings. This suggests a possible role for bedside stress MCE in risk stratification of these patients .Despite the initial concern about the safety of UCAs, there is a universal consensus that contrast echocardiography is safe. Although extremely rare, anaphylactic reaction remains a true side effect that has been reported in approximately 1 in 10,000 patients. Use of UCAs in pulmonary hypertension, right-to-left shunt through a patent foramen ovale, and in critically ill patients that were of initial concern have been proved in several studies to be safe .Contrast echocardiography should be an integral part of a modern echocardiography laboratory and is considered as a quality control marker. LVO has an established role in a wide range of clinical scenarios in rest echocardiography and improves the accuracy of stress echocardiography. Perfusion imaging with MCE, although supported by a large body of evidence, has not passed the regulatory processes in the EU and USA and thus remains an off-label indication and currently limited to expert centers. Beyond daily clinical use, UCAs are currently being tested in trials for molecular imaging and targeted drug delivery and thrombolysis.


This study aimed to investigate the feasibility of SSTR–PET/CT for detecting cardiac sarcoidosis in comparison to CMR.Diagnosis of cardiac sarcoidosis is often challenging. Whereas cardiac magnetic resonance imaging (CMR) and positron emission tomography/computed tomography (PET/CT) with mean) and maximum standardized uptake values (SUVmax) of affected myocardium were calculated and compared with both remote myocardium and left ventricular (LV) cavity.15 patients  with sarcoidosis and suspicion on cardiac involvement underwent SSTR-PET/CT imaging and CMR. Images were visually scored. The AHA 17-segment model of the left myocardium was used for localization and comparison of inflamed myocardium for both imaging modalities. In semi-quantitative analysis, mean  was missed by PET. The remaining two CMR+/PET− patients displayed no adverse cardiac events during follow-up.SSTR-PET was positive in 7/15, CMR in 10/15 patients. Of the 3 CMRmean and SUVmax in inflamed areas were 2.0±1.2 and 2.6±1.2, respectively. The lesion-to-remote myocardium and lesion-to-LV cavity ratios were 1.8±0.2 and 1.9±0.2 for SUVmean and 2.0±0.3 and 1.7±0.3 for SUVmax, respectively.In the 17-segment model, PET/CT yielded 27 and CMR 29 positive segments. Overall concordance of the 2 modalities was 96.1% . SUVDetection of cardiac sarcoidosis by SSTR-PET/CT is feasible. Our data warrant further analysis in larger prospective series. For quantification of increased tracer uptake, a visual score using the terms “mild”, “moderate” and “intense” was used. Areas of increased rt model .max) and mean standardized uptake values (SUVmean). SUVmax and SUVmean were also derived in normal reference regions defined by two distinct methods: (1) a second ROI (diameter of 15 mm) in a remote region of the left ventricular wall (not supplied by the culprit vessel) without late-gadolinium-enhancement (LGE) in the corresponding MRI data (if applicable) and (2) another ROI with a diameter of 25 mm in the left ventricular cavity. Signal-to-background ratios were calculated for each method.For semi-quantitative analysis, the axial PET image slice with maximum cardiac uptake was selected. A standardized 15mm circular region was placed over the area with the peak activity. This first ROI was used to derive maximum  and 3.0T  scanner using dedicated phased array coil for radiofrequency reception. Sequences were gated to the heart cycle via a four lead vector cardiogram. The protocol included a morphologic study based on balanced turbo field echo sequences for documentation of standard cine long and short axis views . A T2-weighted multi echo gradient echo sequence was used for imaging myocardial edema in both long and short axis  3). Late enhancement imaging was performed 9 to 12 min after antecubital intravenous administration of 0.15 mmol/kg of a gadolinium based contrast agent . An inversion recovery T1 turbo field echo sequence was used, and the inversion time was adjusted to completely null the myocardial signal.Image analysis was performed using the Extended Workspace software . In analogy to PET, all LGE and T2-weighted scans were segmentally analyzed with regards to scar and edema distribution within the myocardium according to the 17-segment model. Concordant signal enhancement in both LGE and T2-weighted sequences was considered as CMR positive for active cardiac involvement. LGE positivity in parallel with T2 negativity was rated as consistent with fibrotic changes.Most data presented in here are descriptive. Quantitative data are presented as median, range, and mean ± SD.


Left ventricular (LV) remodeling is closely linked to the progression of heart failure. There are limited data on the epidemiology of new onset LV remodeling among elderly women, which requires further investigation.We examined data from a community-based cohort of women aged > 65 years, who had received > 2 echocardiography scans from 2009 to 2014. Exclusion criteria for patients included prior echocardiographic evidence of left ventricular enlargement (LVE) or hypertrophy (LVH). LVE was defined as the index of left ventricular internal diameter at end-diastole to height, and LVH was defined as the left ventricular mass and thickness index which indicate hypertrophy.2), B-type natriuretic peptide (BNP) ≥ 100 (pg/mL)  and brachial-ankle pulse wave velocity (baPWV) ≥16 m/s . Predictors of LVE were CBP (per 10 mmHg) , BMI˃25(kg/m 2), Low-density lipoprotein cholesterol (LDL-C)  and E/e’ ratio .Of the 474 subjects (age 71.85 ± 6.47 years), 49 (10.3%) developed LVH, while 55 (11.6%) developed LVE during the mean follow-up period of 5 years. Independent predictors of LVH included: central blood pressure  , BMI˃25(kg/m CBP and BMI were demonstrated to be independent and robust predictors of left ventricular remodeling among elderly women, including both LVE and LVH. BNP and baPWV were specifically related to the development of LVH, whereas LDL-C and E/e’ ratio were related to LVE. Left ventricular (LV) remodeling is considered as a precursor for worsening cardiac function and is often associated with a high mortality rate in affected patients . StudiesNumerous studies support the notion that males are significantly more at risk in the development of cardiovascular events. A potential underlying mechanism may be closely related to the protective effect of estrogen expression in women . In the There are limited studies which examine the relationship between various bio-markers and central hemodynamic indexes with the specific type of LV remodeling. Our previous study demonstrated that women have double the incidence rate of LV remodeling compared to men . TherefoThe baseline examination was carried out in 2009. All the participants underwent physical examination, structured interview, blood sampling, and pulse wave analysis at the research center, as well as an echocardiography scan . A totalEchocardiography examination with trans-thoracic two-dimensional (2D) scanning was performed using a color Doppler ultrasonic device equipped with a 1.0–5.0 MHz transducer . Cardiac parameters including left atrium diameter (LAD), left ventricular internal diameter at end-diastole (LVIDd), left ventricular ejection fraction (LVEF), inter ventricular sepal thickness (IVST) and posterior left ventricular wall thickness (PVWT) were collected based on echocardiographic examination. E/A ratio was calculated based on peak early diastolic flow velocity (E velocity)/peak velocity of atrial contraction (A velocity). E/e’ ratio was determined by the E velocity/velocity of mitral annulus early diastolic motion (e’).2.71. LVM was calculated based on the guidelines from the American Society of Echocardiography: LVM (g) = 0.8 × {1.04 × [(LVIDd + PVWT + IVST) 3− (LVIDd) 3]} + 0.6 (g) [2.71 for women and LVE was determined by indexing LVIDd to height, as previously demonstrated [We have previously reported the methodology for defining LVH and LVE in a cross-sectional study . Thus, w 0.6 (g) . LVH wasnstrated . LVE wasnstrated .All blood samples were obtained during the morning fasting state. Plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and Fasting plasma glucose (FPG) were measured enzymatically. Brain natriuretic peptide  was measured using electro chemiluminescence immunoassay. Glaciated hemoglobin (HbA1C) was measured using ion-exchange high performance liquid chromatography. Serum high-sensitivity C reactive protein (hsCRP) was measured using immunonephelometry . Homocysteine (HCY) was measured using fluorescence polarization immunoassay . Diabetes was defined as fasting plasma glucose (FPG) levels ≥7.0mmol/L, or self-reported diagnosis of diabetes. Dyslipidemia was defined as total cholesterol (TC) >5.7 mmol/L or low-density lipoprotein cholesterol (LDL-C) >3.6 mmol/L.Non-invasive pulse wave analysis was performed with an automated oscillometric device . Subjects were examined in a sitting posture. Radial augmentation index (AI), Systolic blood pressure(SBP), diastolic blood pressure (DBP), and estimate of central blood pressure (CBP) were obtained after resting for 5–10 min. Hypertension was defined as either systolic blood pressure (SBP) ≥140 mmHg, diastolic blood pressure (DBP) ≥90 mmHg, or usage of antihypertensive medication. The detailed methodology was validated in our previous report .baPWV was measured using a volume-plethysmographic device , which simultaneously recorded brachial and posterior tibial arterial wave forms with automated oscillometric method . Echocarp<0.05 was considered statistically significant.SPSS 19.0  was used for statistical analysis. Categorical variables were presented as frequency percentages and the comparison between groups were based on the chi-squared test. Continuous variables were presented as means and standard deviation (SD) for normal distribution. Two samples T-test was used to compare differences between groups. We described skewed distribution variables as median (inter-quartile range). Accordingly, these variables were compared by nonparametric Mann-Whitney U-test. Multivariate cox proportional hazards regression models were developed to assess independent predictive value of LVE or LVH. A value of The baseline characteristics of the study population and patients with LVH or LVE are summarized in Tables P <0.05 for all). A similar result was observed in patients with or without LVE. Of note, increased BNP level was only found in subjects with LVH. Patients with LVE had higher age and were prone to have increased levels of LDL-C. Cardiac ultrasonography parameters between these groups are displayed in Table Comparison between patients with or without LVH at baseline indicated that the level of BMI, CBP, baPWV and hsCRP in patients with LVH was significantly higher than that in those without LVH (2) , BNP ≥ 100 (pg/mL)  and baPWV ≥16 (m/s)  were associated with the development of LVH. Independent predictors of LVE included CBP , BMI˃25(kg/m 2) , LDL-C  and E/e’ ratio , as demonstrated in Table The multivariate models were developed to predict the first events of LVH and LVE. We selected variables that demonstrated significant statistical differences between groups  and those variables were entered into multivariate Cox regression models for the assessment of independent risk factors of LVH or LVE. As shown in Table In this longitudinal cohort study among elderly women, there was a high incidence of new-onset LVE (11.6%) and LVH (10.3%) occurrence. The increase in the levels of CBP and BMI were predictive for both LVE and LVH, after accounting for various potential confounding factors. BaPWV index using detailed noninvasive evaluation and BNP were specifically correlated with the development of LVH, but not LVE. In addition, the E/e’ ratio using Doppler echocardiogram and LDL-C were predictive for the development of LVE.The effect of gender during cardiac remodeling is still unclear. Data from Framingham Heart Study revealed that women have a greater age-related increase in LV wall thickness . It has Increased BMI and BP are commonly recognized as predictors of cardiovascular disease. Our study further strengthened the notion that BMI and CBP were the important predictors of LV remodeling, and were strongly related to the development of both LVH and LVE. These findings suggest that effective control of body weight and BP are crucial in the early prevention of LV remodeling. We had previously reported that BNP was a risk factor for both LVH and LVE in the general population . HoweverDyslipidemia is the metabolic abnormalities observed frequently in patients with heart diseases. Francesco et al reported that unsatisfactory control of LDL cholesterol after myocardial infarction independently predicts LV remodeling . For theThe ratio of early trans-mitral flow velocity (E) to early diastolic septal mitral annulus velocity (E/e’) has been shown to be the most accurate noninvasive predictor of elevated LV filling pressure . AccordiCardiac abnormalities in adults often develop in concert with atherosclerosis . BaPWV iThis study has several limitations that need to be addressed. Firstly, the prevalence of LVH and LVE might be overstated since the use of echocardiography as a routine screening strategy for cardiac remodeling in population-based investigation remains controversial. LV mass calculated according to the measurements of echocardiography may be overestimated when compared with the gold standard of MRI . EchocarThis study shows the incidence rates of new onset LV remodeling in a community-based nested case-control cohort. Risk profiles at baseline for LVH and LVE were determined. We determined that increased LV remodeling may be associated with higher incidence of HF with preserved ejection fraction (HFpEF) in elderly women. Therefore, better understanding of LV remodeling in women is critical in improving the prevention of HF.


Congenital heart malformations are the most common type of defects found at birth. About 1% of infants are born with one or more heart defect on a yearly basis. Congenital Heart Disease (CHD) causes more deaths in the first year of life than any other congenital abnormality, and each year, nearly twice as many children die in the United States from CHD as from all forms of childhood cancers combined. Atrioventricular septal defects (AVSD) are congenital heart malformations affecting approximately 1 in 2000 live births. Babies born with an AVSD often require surgical intervention shortly after birth. However, even after successful surgery, these individuals typically have to deal with lifelong complications with the most common being a leaky mitral valve. In recent years the understanding of the molecular etiology and morphological mechanisms associated with the pathogenesis of AVSDs has significantly changed. Specifically, these studies have linked abnormal development of the Dorsal Mesenchymal Protrusion (DMP), a Second Heart Field-derived structure, to the development of this congenital defect. In this review we will be discuss some of the latest insights into the role of the DMP in the normal formation of the atrioventricular septal complex and in the pathogenesis of AVSDs. Atrioventricular septal defects (AVSDs) form a class of congenital heart malformations found in 1 in 2000 live births . When AVIn the fully septated heart, the oxygenated blood in the left part of the heart is separated from the oxygen depleted blood in the right part of the heart by an atrial and a ventricular septum A. In theThe pathogenesis of AVSDs has been the topic of research and discussion for many years. For a very long time, the accepted paradigm was that perturbation of the development or fusion of the endocardial AV cushions, the precursor tissues for the AV valve leaflets see  was respTo fully understand the role of the DMP in the pathogenesis of AVSDs it is important to describe all the components that participate in the formation of the atrioventricular mesenchymal complex and to discuss how these components relate to other tissues involved in atrioventricular septation.The development of the heart starts with the generation of the precardiac mesoderm forming two bilateral primary heart fields. These heart fields eventually fuse thereby creating the linear primary heart tube ,28. ThisThe formation of the atrial septal complex involves the development of a myocardial primary and secondary atrial septum . Together with the mesenchymal tissues described in this section they are responsible for the formation of the atrial septal complex dividing the lumens of the left and right atria see also . The proThe third major component of the atrioventricular mesenchymal complex is the Dorsal Mesenchymal Protrusion (DMP) , sometimThe development of the atrial septal complex involves a complicated series of events. This includes the formation of the respective components of the atrioventricular mesenchymal complex (see above) and the development of a number of myocardial structures, in particular the myocardial component of the primary atrial septum (pAS) and the secondary atrial septum (sAS). To make matters more complex, it also involves the myocardial differentiation of the mesenchyme of the SHF-derived DMP during the formation of the muscular inferior rim. Given the complexity of all the events involved, it is virtually impossible to describe atrial septation as a simple series of consecutive events. As a result, the following description significantly simplifies the process see also .Atrial septation “starts” when the myocardial primary atrial septum  starts to grow from the atrial roof into the common atrium. As the pAS develops it is in continuity with the left mesocardial reflection of the dorsal mesocardium . It is tWhile the mesenchyme found in the cap and the mesenchyme of the DMP has different origins , the two mesenchymal tissues are contiguous. The development of the pAS and that of the DMP are therefore closely related . During The secondary atrial septum (sAS) develops later than the pAS C and is Insights into molecular mechanisms that govern the cellular events in the (posterior) SHF that allow proper DMP development and its maturation are slowly emerging. In fl/fl mutants at E10-10.5 revealed decreased proliferative index of SHF cells and, consequently, a reduced number of pSHF cells at the cardiac venous pole . Pr. Prfl/− n et al.   and their receptors (Pdgfrs) are important for cardiac development. For instance, Pdgf-B ligand knockout mice have multiple cardiac defects, including VSDs, double outlet right ventricle (DORV), aortic arch abnormalities, and sporadic AVSD . Pdgfrα  embryos , albeit  embryos .Holt-Oram Syndrome (HOS) is a serious condition caused by haploinsufficiency of the transcription factor Tbx5 ,76. Patiavc1/Ift172avc1) showed AVSDs in 100% of the mutants analyzed [Primary cilia are solitary organelles protruding from the cell surface of most mammalian cell types. The core structure of primary cilia is the ciliary axoneme, which consists of nine doublet microtubules that extends, via a transition zone, from a microtubule-based basal body. Intraflagellar transport (IFT) isoforms are proteins that play crucial roles in the formation, maintenance, and function of cilia and allow the trafficking of particles up and down along the axoneme. Two IFT complexes can be distinguished; the IFT-A complex and the IFT-B complex. The proteins in the IFT-A complex are involved in controlling retrograde ciliary trafficking, whereas the proteins found in the IFT-B complex are required for anterograde trafficking from the base to the tip of the cilium. Ciliary “dysfunction” has been associated with a spectrum of human congenital malformations, including defects found in the cardiovasculary system, such as AVSDs. A comprehensive study of a mouse model carrying a hypomorphic mutation of the IFT protein Ift172 , in heterotaxy this left/right laterality of the internal organs is disturbed (a condition referred to as situs ambiguous). Heterotaxy is a severe condition and has a reported incidence of one in ten thousand and at least 3% of individuals with congenital heart defects are patients suffering from heterotaxy . The twoStudies described in this review show that failure of proper development of the SHF-derived DMP leads to a primary atrial septal defect (pASD), the common septal defect seen in complete and incomplete AVSDs. This new insight has led to a paradigm shift in the understanding of AVSDs as the prevailing paradigm for many years was that failure of proper development of the AV cushions was the sole defect responsible for AVSDs . Further


Diffuse myocardial fibrosis is an important pathophysiological process involved into essential hypertension which may increase myocardium stiffness, cause ventricular remodeling and increase adverse cardiovascular risk eventually. It is strongly evident that optimal antihypertensive therapy will reduce the risk induced by hypertension, however, very few proportion of patients with hypertension can reach the recommended target of blood pressure (BP) control. So far little knowledge has been illuminated for effect of blood pressure control status on the myocardial fibrosis in hypertension. T1 mapping and extracellular volume (ECV) quantified by CMR has been adopted as a good method in examination of diffuse fibrosis. Besides, variation of serum fibrosis biomarkers may also reflect the degree of myocardial fibrosis. Based on the above we hypothesised that there was a correlation between ECV, serum fibrotic biomarkers and long-term BP control status in patients with essential hypertension.T1 mapping by using modified Lock-Locker inversion recovery(MOLLI) sequence on a 3.0 Tesla scanner was performed on 40 hypertension patients (20 patients with documented well BP control and 20 with uncontrolled BP) and 20 healthy controls. Myocardial native, post T1 and average ECV of left ventricle were measured based on pre contrast and post contrast T1 mapping(15 minutes after intravenous injection with gadopentetate dimeglumine (0.15 mmol/kg). Serum PICP and ICTP level were detected with ELISA kits.β = 0.37, p = 0.02, PICP/ICTP: β = 0.30, p = 0.03) (Table Uncontrolled hypertensive patients had a higher interventricular septum thickness(IVS) or left ventricular mass index(LVMI) than well controlled hypertensive patients, whereas there was no difference in left ventricular functional parameters between two groups. Hypertensive patients had higher mean ECV of left ventricular myocardium than normal controls, furthermore, mean ECV of LV in hypertensive patients with uncontrolled BP was higher than in patients with ECV well- controlled,whereas the differences of native or post-contrast T1 time of LV myocardium between the two groups was not statistically significant (Table ECV of LV myocardium was higher in hypertensive patients which was associated with BP control status. ECV could be associated with the LV hypertrophy in patients with uncontrolled hypertension and could also reflect the changes of myocardial fibrosis in hypertension.


Over 26 million people worldwide suffer from heart failure annually. When the cause of heart failure cannot be identified, endomyocardial biopsy (EMB) represents the gold-standard for the evaluation of disease. However, manual EMB interpretation has high inter-rater variability. Deep convolutional neural networks (CNNs) have been successfully applied to detect cancer, diabetic retinopathy, and dermatologic lesions from images. In this study, we develop a CNN classifier to detect clinical heart failure from H&E stained whole-slide images from a total of 209 patients, 104 patients were used for training and the remaining 105 patients for independent testing. The CNN was able to identify patients with heart failure or severe pathology with a 99% sensitivity and 94% specificity on the test set, outperforming conventional feature-engineering approaches. Importantly, the CNN outperformed two expert pathologists by nearly 20%. Our results suggest that deep learning analytics of EMB can be used to predict cardiac outcome. Cardiovascular diseases are the leading cause of death globally and the leading cause of hospital admissions in the United States and Europe . More thWith the advent of digital pathology, a number of groups have been applying computer vision and machine learning to these datasets to improve disease characterization and detection –11. ReceRecently, many approaches for image analysis have applied deep convolutional neural networks (CNNs) or “deep learning” instead of engineered image features. Deep learning is an example of representation learning, a class of machine learning approaches where discriminative features are not pre-specified but rather learned directly from raw data . In a CNDeep learning has already been successfully applied to detect cancer in biopsies , 28, diaThe dataset consisted of left ventricular tissue from 209 patients, collected at the University of Pennsylvania between 2008 and 2013. There were two cohorts of patients: those with end-stage heart failure  and a comparison group without heart failure . The failing cohort tissue was collected from patients with clinically diagnosed ischemic cardiomyopathy  or idiopathic dilated cardiomyopathy  who received heart transplants or left-ventricular assist devices during the collection period and consented to the study. The patients in the non-failing cohort were organ donors without a history of heart failure, but where the heart tissue was ultimately not used for transplant. All patients with tissue sectioned, stained, and scanned during the collection phase were included for analysis.2) at random from within the Otsu-thresholded [We randomly split the patients into two datasets: 104 patients were designated for training, and a separate cohort of 105 patients was held out as an independent test set. Patient demographics for the training and held-out test dataset are shown in esholded  and manuThe training images were used to build two independent models to classify patients with or without heart failure from cardiac histopathology. The primary classifier used a CNN with a network architecture modified from Janowczyk and Madabhushi  S1 Tabl to transFor each image, both classifiers calculated the probability of whether that image came from a patient with heart failure. Images with probabilities greater than 50% were considered as a prediction of the “failing” class at the image-level. The image-level predictions were grouped by patient and the fraction of images predicted as ‘failing’ for each patient gave the patient-level probabilities. We evaluated the performance of the CNN on the training set using three-fold cross validation. In addition, we applied each of the trained models to the held-out test dataset as an independent test for model generalization. Next, we compared the classification accuracy of the CNN to the WND-CHRM + RF model . AlthougIn the clinical setting, pathologists do not routinely assess whether a patient has clinical heart failure using only images of cardiac tissue. Nor do they limit their assessment to small ROIs randomly sampled from the tissue. However, in order to determine how a human might perform at the task our algorithms are performing; we trained two pathologists on the training dataset of 104 patients. The pathologists were given the training images, grouped by patient, and the ground truth diagnosis. After review of the training dataset, our pathologists independently reviewed the 105 patients in the held-out test set with no time constraints.During the evaluation phase, the pathologists were blinded to the patients’ clinical history, and they were only shown the same 11 images per patient that were used in evaluating the algorithms. For each set of patient images, they gave a binary prediction of whether the set of 11 images were from a patient with clinical heart failure or not. The pathologists both had an individual accuracy of 75% at the patient-level  with a CRepresentative images that were correctly classified by both algorithms are shown in Review of the errors unique to the WND-CHARM + RF model reveals some false negative errors, such as classifying an image with extensive fibrosis as “Non-Failing”, when it is actually from a patient with heart failure , but what these intermediate features represent and how they are combined to make a diagnosis will require interpretation by pathologists. However, a benefit of representation learning approaches is that they may reveal novel image features, learned by the CNN, that are relevant to myocardial disease. The performance difference between the CNN and WND-CHRM + RF pipeline likely reflects the contribution of the features learned by the CNN, which are not present in the set of engineered features.The highly accurate and reproducible performance by the CNN shows that cardiac histopathology contains robust image features sufficient for classification and diagnosis. However, a somewhat surprising finding of this study was that the CNN outperformed pathologists at detecting clinical heart failure by a significant margin, up to 20% in terms of sensitivity and specificity. Unlike cancer, where the definitive diagnosis is based on tissue pathology and genetic or molecular markers, heart failure is a clinical syndrome. In the clinical setting, pathologists are not called upon to determine whether a patient is in heart failure given cardiac histopathology. Rather, when no cause of heart failure can be identified, pathologists interpret the tissue to identify potential etiologies . However, it is interesting to note that the Cohen’s kappa inter-rater agreement of 0.40 in our task is similar to the value of 0.39 reported for Fleiss’s kappa inter-rater agreement for grading heart rejection using the ISHLT 2005 guidelines . TogetheA review of the misclassified non-failing patients where the CNN gave a high likelihood of heart failure led to the discovery of severe tissue pathology in two patients. Unsupervised clustering reproducibly grouped these patients away from the non-failing class and into the failing class or a third, intermediate cluster. Thus, the CNN identified tissue pathology in patients without pre-existing heart failure, suggesting these patients may represent cases of occult cardiomyopathy. An important area of research moving forward is whether CNNs or other models can use EMBs to predict the future onset of heart failure or the rate of decline in patients with mild or moderate heart failure.Our study did have its limitations. We assessed our classifier on the extremes of heart disease: patients with severe heart failure requiring advanced therapies  versus patients without a history of clinical heart failure. One may argue that comparing extremes exaggerates classifier performance. However, the identification of tissue pathology in a small subset of patients without a definitive clinical diagnosis suggests these algorithms are very sensitive to pathological features of myocardial disease. Future research will need to evaluate the ability of CNNs to detect pre-clinical disease.In summary, we develop a CNN classifier to detect heart failure and show that cardiac histopathology is sufficient to identify patients with clinical heart failure accurately. We also find that these algorithms are sensitive to detect tissue pathology, and may aid in the detection of disease prior to definitive clinical diagnosis. These data lend support for the incorporation of computer-assisted diagnostic workflows in cardiology and adds to the burgeoning literature that digital pathology adds diagnostic and prognostic utility. Future work will focus on predictive modeling in heart failure and post-transplant surveillance for rejection, etiologic discrimination of cardiomyopathy etiologies, and risk stratification studies which correlate digital histopathology with disease progression, survival and treatment responses.Human heart tissue was procured from two separate groups of subjects: heart transplant or LVAD recipients with severe heart failure , and brain dead, organ donors with no history of heart failure . Tissue from patients with ischemic cardiomyopathy sampled infarct-free regions. No organs or tissue were procured from prisoners. Prospective informed consent for research use of heart tissue was obtained from all transplant or LVAD recipients and next-of-kin in the case of organ donors. All patient data and images were de-identified, and all protocols were performed in accordance with relevant guidelines for research involving tissue from human subjects. Tissue used in this study was collected and processed at the Cardiovascular Research Institute and the Department of Pathology and Laboratory Medicine at the University of Pennsylvania between 2008 and 2013. All patients were from the same institutional cohort. All study procedures were approved or waived by the University of Pennsylvania Institutional Review Board.Both failing and non-failing hearts received in situ cold cardioplegia in the operating room and were immediately placed on wet ice in 4°C Krebs-Henseleit buffer. Within 4 hours of cardiectomy, transmural tissue from the left ventricular free wall were fixed in 4% paraformaldehyde and later processed, embedded in paraffin, sectioned and stained with hematoxylin and eosin (H&E) for morphologic analysis. Whole-slide images were acquired at 20x magnification using an Aperio ScanScope slide scanner. Images were down-sampled to 5x magnification for image analysis, a magnification sufficient for expert assessment of gross tissue pathology. The allocation to the training and held-out test cohort was random and performed prior to image analysis.The primary neural network used in this study was adapted from Janowczyk and Madabhushi (32). This fully-convolutional architecture is composed of alternating convolutional, batch normalization , and RecAdditional networks used in this study include : AlexNetThe comparative approach used WND-CHARM  to extraThe performance of the heart failure classifiers was evaluated using traditional metrics derived from a confusion matrix including accuracy, sensitivity, specificity, and the positive predictive value . The areThe human-level detection of heart failure was performed independently by two pathologists experienced in cardiac histopathology. In order to train the pathologists for the task, they were given access to the 104 patients in the training dataset, grouped by patient, with their images and ground truth labels. To evaluate their performance on the test set, each pathologist was blinded to all patient information in the test set. For each patient in the test set, they were asked to provide a binary prediction of whether the set of images were from a patient with clinical heart failure or not. The pathologists were given unlimited time to complete the task. The inter-rater agreement was measured using Cohen’s kappa statistic .https://github.com/wnd-charm/wnd-charm. The deep learning procedure used here follows the method described in Janowczyk and Madabhushi 2016 [http://www.andrewjanowczyk.com/deep-learning. The image data that support the findings of this study have been uploaded to the Image Data Resource [https://idr.openmicroscopy.org/webclient/.WND-CHARM is open-source and hosted at shi 2016 ; a deep Resource  under acStatistical tests were performed in MATLAB R2016a or newer. An unpaired, two-sample t-test was used to compare two sample means. A one sample t-test was used to compare the CNN to the best human performance value for each evaluation metric. A two-sample Kolmogorov-Smirnov test was used to compare two distributions. Unsupervised clustering was performed using the package consensusClusterPlus in R .S1 Fig(a) Normal cardiac tissue shows regular, dense arrays of cardiomyocytes (green) with stroma limited to perivascular regions (orange). (b) Patients with heart failure have an expansion of the cellular and acellular stromal tissue (orange) that disrupts cardiomyocyte arrays (green). Other features seen in heart failure include large myocytes with enlarged, hyperchromatic, “boxcar” nuclei . Images are 5x magnification and the scale bar is 1mm.(PDF)Click here for additional data file.S2 FigThe probability of heart failure per image is shown in (A). Values close to one represent a high probability of heart failure and values close to zero represent a low probability of heart failure, or conversely a high probability the patient is clinically normal. The eleven ROIs per patient were averaged to generate the patient-level probability, shown in (B). In general, the random decision forest gives predictions closer to 0.5 than the CNN, at the image and patient-level, indicating that the random forest predictions are less confident than the CNN predictions.(PDF)Click here for additional data file.S3 FigThe original H&E stained image is shown on the left. One hidden layer ReLU activation after the Conv1a layer has been upsampled to match the original image size and is shown on the right in a rainbow colormap. This node appears to activate strongest on regions of myocyte tissue as opposed to nuclei or stroma/ fibrosis. Identifying the myocyte from the stroma is important in heart failure, as fibrosis is a common histologic finding in heart failure. Future work will investigate the other hidden-layer activation patterns in this and other networks in order to understand which features the network uses to make predictions.(PDF)Click here for additional data file.S1 TableThe primary network used in this study was adapted from Janowczyk and Madabhushi (32). This fully-convolutional architecture is composed of alternating convolutional, batch normalization , and Rec(PDF)Click here for additional data file.S2 TableTop 20 features in the training dataset identified by mRMR feature selection. A complete list of features computed by WND-CHARM can be found in Orlov et al. 2008.(PDF)Click here for additional data file.S3 TableWe assessed the image-level performance accuracy for neural network architectures including AlexNet , GoogLeN(PDF)Click here for additional data file.


All subjects received a CMR in a 1.5-T whole-body scanner. Patients were also screened with Holter monitoring, echocardiography, and a blood test of cardiac markers. Myocardial mass in ALS hearts was reduced compared to the control group, and ejection volumes in the left and right heart were severely decreased in ALS patients, as shown by echocardiography and CMR. The myocardium showed increased T1 enhancement in 77% of the patients compared to 27% of controls (p = 0.0001). A trend toward late gadolinium enhancement patterns consistent with myocardial fibrosis was observed in 23.5% of the patients (9.1% of controls). Holter monitoring was normal in all patients as well as troponin T. Cardiac involvement seems to be present in ALS patients without clinical cardiac symptoms and with a normal cardiac routine assessment. Structural myocardial defects in CMR may be due to sympathetic dysfunction and may account for reported cardiac deaths in late-stage ALS patients.The objective of this study was to investigate the potential involvement of cardiac structure and function by cardiac magnetic resonance (CMR) imaging in amyotrophic lateral sclerosis (ALS) patients. Our study included 35 patients with ALS without a history of cardiac disease and an age- and gender-matched healthy control group ( A common limiting factor for life expectancy of amyotrophic lateral sclerosis (ALS) patients is respiratory failure that is caused by paresis of respiratory muscles as well as aspiration and resulting pneumonia , 2. AnotCardiac magnetic resonance (CMR) imaging is a valuable tool in the diagnostic assessment of inflammatory myocarditis –16 and fAll patients included had possible, probable, or definite ALS according to the revised El Escorial criteria. Patients participating in the diagnostic assessment at the Department of Neurology, University of Ulm (Germany) and in the regional ALS registry (ALS Register Swabia REF) were prospectively screened and enrolled in the study. In total, 53 patients were screened and provided written informed consent. Eighteen of these patients had to be excluded due to claustrophobia or inability to lie supine because of respiratory dysfunction. The ALS Register Swabia and this CMR study were approved by the local Ethics Committee of the University of Ulm (protocols no. 11/10 and no. 05/11).Exclusion criteria were contraindications for CMR or gadolinium-based contrast agent or pregnancy.N-terminal pro brain natriuretic peptide (NT-pro BNP) were analyzed in each patient. For NT-pro BNP, normative age-related values were used , myocardial creatine kinase (CK-MB), and ere used .As controls, a cohort of age and gender matched patients was implemented. These patients exhibited no signs of cardiac insufficiency. Clinical characteristics of ALS patients and controls are presented in Table A 24-h Holter monitoring was performed using a Digi Trac XT recorder . Holter monitoring was considered abnormal in the presence of; atrioventricular block grade I–III, atrial fibrillation/flutter (AF/AFL), other supraventricular tachyarrhythmia (SVT) [>30 supraventricular premature contractions (SVPC) per hour or runs of ≥20 SVPC], frequent ventricular premature contractions (VPCs) (≥30/h), and non-sustained ventricular tachycardy (NSVT).Transthoracic echocardiography was performed using a CX 50 Ultrasound . Left ventricular (LV) cavity dimensions, mass and wall thickness and diastolic dysfunction were assessed in accordance with the recommendations of the European Association of Echocardiography .An abnormal echocardiography was defined by the following diameters of the left ventricle: a left ventricular end-diastolic diameter (LVEDD) >56 mm, an interventricular septum (IVS) >11 mm and a left ventricular end systolic diameter (LVESD) >40 mm. The ejection fraction was visually evaluated. In addition, echocardiography was used to assess valve disease and fractional shortening (FS).All patients were examined in a 1.5-T whole-body scanner  using a 32-channel phased-array cardiac surface coil. Steady-state free precession cine sequences were acquired in a contiguous short axis orientation covering the LV and right ventricle for volumetric and functional analysis of both ventricles  as previously reported .Ten minutes after an intravenous application of 0.2 mmol/kg body-weight gadolinium-based contrast agent , an inversion-recovery gradient-echo sequence for evaluation of late gadolinium enhancement (LGE) was acquired in a contiguous short axis orientation covering the entire left ventricle  .Cardiac magnetic resonance images (DICOM) were anonymized and transferred to a workstation. Two blinded and experienced readers  evaluated all images in consensus using commercially available software . End-diastolic and end-systolic endocardial contours of the LV and right ventricle were drawn manually for evaluation of end-diastolic and end-systolic volumes, and the ejection fractions were calculated. In addition, end-diastolic LV epicardial contours were drawn for the assessment of LV myocardial mass.For an early gadolinium enhancement compared to a thoracic skeletal muscle, early gadolinium enhancement ratio (EGEr)  or T1 raThe inversion-recovery gradient-echo sequence was evaluated for the presence of a hyper-enhancement consistent with myocardial fibrosis. LGE volume was quantified as a percentage of the LV myocardial mass using a cutoff signal intensity increase of more than five SDs of remote myocardium . An LGE t-test was used for the cohort comparison. A p-value ≤0.05 was regarded as statistically significant.All data are reported as a mean value ± SD in comparison to the control group. An unpaired Twelve patients had bulbar onset and spinal onset was seen in 23 cases. Mean disease duration at CMR was 2.6 ± 2.2 years and mean ALS functional rating scale (ALSFRS)-R score was 32.4 ± 8.5 points. None of the patients had any cardiac complaints. Patients were characterized with respect to cardiovascular risk factors, antihypertensive co-medication, and vital capacity as indicated in Table n = 26), with regard to atrial fibrillation/flutter, supraventricular tachycardia, atrioventricular block, and non-sustained ventricular tachycardia.In particular, we did not find any abnormality on Holter monitoring in patients with ALS . NT-pro BNP  was abnormal in 3/35 patients, indicating myocardial insufficiency. One of these patients showed a previous myocardial ischemia and the other two showed pericardial effusions.Creatine kinase was elevated in 14/35 patients  and CK-MB in 6/22 . Troponin T was normal in all patients tested (N = 27 ALS hearts had LVEF >60% of which n = 18 had increased T1 enhancement (67%) compared to N = 22 normal control hearts of which 6 had increased T1 enhancement (27%).Cardiac magnetic resonance was completed in 35 ALS patients and 34 controls. Mean left and right ventricular ejection fractions (LVEF and RVEF) were in the normal range  was observed in 6/33, and five of these patients also showed increased T1 enhancement. p = 0.0001).The mean LVEF in ALS patients was 64% (range 52–80) compared to controls . Early myocardial gadolinium enhancement in T1 could be observed in 24/31 (77%) of ALS patients  patients, but this abnormality did not reach significance, since three controls also had a pathological LGE. In four ALS patients, LGE was distributed in the basal inferolateral segments  for comparison with controls (Index = mass/BSA or volume/BSA) .Even after indexing these values to BSA, which may be lower in ALS patients, these differences remained. ALS hearts had lower myocardial mass than control hearts, and ejection volumes in the left and right heart were decreased in ALS patients. It is possible that reduced body weight or reduced physical activity may account for these abnormalities. There are studies implying that BMI is a strong predictor for heart mass , but ourThe function and the size of the heart show a regression in healthy inactive persons even without any structural heart disease . Therefop = 0.03), some of the reported abnormalities in ALS patients might be due to diabetic complications. With respect to CMR, a subclinical diastolic dysfunction but no significant fibrosis in LGE has been reported in diabetes  and hypertension , 31. Sindiabetes . With rediabetes , 34, butWith respect to the origin of the detected increased myocardial T1 values, typical patterns of myocardial infarction [subendocardial or transmural LGE pattern ] were noOne explanation for denervation would be increased sympathetic activity induced by respiratory weakness and, therefore, pulmonary hypertension, but no signs of pulmonary hypertension could be detected in our patient cohort. Primary involvement of the autonomic cardiac nerves may be an explanation for postulated sympathetic hyperactivity. Several groups have detected evidence of sympathetic hyperactivity even at the time of the initial ALS diagnosis , 39, 40.Studies of pTDP-43 pathology in the brain and the associated neuronal loss have revealed involvement of amygdala and the hypothalamus as central sympathetic structures , 45.Given that sympathetic hyperactivity can be associated with stress-induced cardiomyopathy and sudden cardiac death, this hypothesis may explain why sudden cardiac death is one of the main causes of death in ALS after respiratory insufficiency.Laboratory parameters have shown increased level of CK, as expected in ALS patients, whereas troponin T as an acute cardiac marker was not increased. Heart failure leading to increased NT-pro BNP was rarely detected and could be attributed to (preexisting) structural defects. Therefore, CMR seems to be more sensitive for the detection of cardiac involvement in ALS than cardiac parameters in blood tests.Limitations of this study are the inability to differentiate the gadolinium enhancement with regard to the underlying pathophysiology. Furthermore, our results probably underestimate cardiac changes due to relatively unaffected respiration of the ALS participants, since severely affected ALS patients could no longer lie flat in CMR.In summary, functional cardiac involvement with a tendency toward lower ejection volumes in ALS hearts and an increase in early myocardial T1 contrast enhancement appears to be a common finding in ALS. The late enhancement distribution did not correspond to typical ischemic patterns with subendocardial involvement. Hence, the changes are unlikely due to cardiac ischemia and do not correlate with the clinical severity of ALS. We suggest that the most likely mechanism is a primary dysfunction of sympathetic heart regulation. If sympathetic hyperactivity is the cause for these alterations, therapeutic beta- or alpha-blocking strategies should be considered and might be studied in future clinical trials.This study was carried out in accordance with the recommendations of the Ethics Committee of the University of Ulm with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of the University of Ulm (protocols no. 11/10 and no. 05/11).AR: acquisition of data, data analysis, writing of the manuscript draft, study supervision, and critical revision of manuscript. BS: acquisition of data, data analysis, interpretation of data, and writing of the manuscript draft. DB: acquisition of data, data analysis, writing of the manuscript draft, and critical revision of manuscript. JK: interpretation of data and critical revision of manuscript. WR: study concept and design, study supervision, and critical revision of manuscript. PB and AL: study concept and design, interpretation of data, study supervision, and critical revision of manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Myocarditis is a heterogeneous disease with a large spectrum of possible clinical courses ranging from complete healing to end stage heart failure. However, there is a lack of reliable prognostic factors to identify patients with an adverse outcome. T1 and T2 mapping are promising novel diagnostic cardiovascular magnetic resonance (CMR) tools for a quantitative assessment of the dynamic tissue changes such as edema, necrosis and fibrosis during the course of myocarditis. Thus, we evaluated T1 and T2 mapping CMR for the evaluation of disease activity in patients with myocarditis.This study included 26 patients with myocarditis, who underwent CMR at 1.5 Tesla acute at baseline (BL) and at 3 months follow-up (FU) after the initial presentation with myocarditis, respectively. T1 and T2 mapping CMR were performed in addition to a conventional CMR protocol in myocarditis. T1 quantification was performed on three short axis using the modified Look-Locker inversion-recovery (MOLLI) sequence before and 15 minutes after administration of 0.075 mmol/kg Gadolinium-BOPTA. T2 quantification was performed using a free-breathing, navigator-gated multi-echo sequence. Maps were generated using a dedicated plug-in for the OsiriX software to calculate global myocardial T2, native/post-contrast T1 and extracellular-volume-fraction (ECV).Left ventricular ejection fraction improved from 49 (29-62) % at BL to 54 (42-61) % at FU (p < 0.001). Global myocardial T2 significantly decreased from 60 (58-63) ms at BL to 58 (55-61) ms at FU (p < 0.05). Similarly, global myocardial native T1 decreased from 1119 (1097-1149) ms to 1075 (1037-1113) ms (p < 0.01). Furthermore, global myocardial ECV was significantly lower at FU with 26 (25-29) % compared to 28 (26-31) % at BL (p < 0.05). There were no significant differences between global myocardial T2, native T1 and ECV values of patients with myocarditis at FU and healthy controls.T1 and T2 mapping CMR techniques offer novel insights into the course of myocarditis. Our findings suggest that mapping techniques are useful for the assessment of disease activity and may serve as prognostic factors for patients with myocarditis.


Arterial blood pressure (BP) and ECG were recorded for power spectral analysis, ECG interval measurement and arrhythmia quantification. Left ventricular monophasic action potential duration (APD) and expression of L-type calcium (LTCC) and transient receptor potential (TRPC) channels were assessed in adjacent epicardial and endocardial sites. Chronic IH enhanced the incidence of ischemic arrhythmias, in particular ventricular fibrillation . IH also increased BP and plasma norepinephine levels along with increased low-frequency (LF), decreased high-frequency (HF) and increased LF/HF ratio of heart rate and BP variability. IH prolonged QTc and Tpeak-to-Tend intervals, increased the ventricular APD gradient and upregulated endocardial but not epicardial LTCC, TRPC1 and TRPC6 (p < 0.05). Chronic IH, is a major risk factor for sudden cardiac death upon myocardial ischemia through sympathoactivation and alterations in ventricular repolarization, transmural APD gradient and endocardial calcium channel expression.We investigated the effects of intermittent hypoxia (IH), such as that encountered in severe obstructive sleep apnea (OSA) patients, on the development and severity of myocardial ischemia-related ventricular arrhythmias. Rats were exposed to 14 days of IH (30 s at 5%O OSA is also causally related to excessive cardiovascular morbi-mortality2 including an increased risk of sudden cardiac death (SCD)3. The specific link between OSA and SCD is based on the observation that SCD occurs predominantly during sleep in apneic patients but not in the general population4. The severity of OSA  is also directly correlated with the risk of nocturnal SCD, independently of other well-established risk factors4.Obstructive sleep apnea (OSA) syndrome is a common sleep-related breathing disorder and represents a substantial public health problem as it affects at least 10% of the general population and is recognized as an important and independent risk factor for cardiovascular disease. In particular, accumulating evidence indicates that sleep apnea is associated with hypertension, left ventricular dysfunction, coronary artery disease and cardiac rhythm disorders5. In accordance with their increased rate of nocturnal SCD4, apneic patients exhibit a high prevalence of myocardial ischemia during the night6 and ventricular arrhythmias are prominent during sleeping hours7. Pro-arrhythmogenic mechanisms have been identified in OSA patients such as sympathoactivation and alterations in ventricular repolarization such as increased QTc and Tpeak-Tend intervals8.Myocardial ischemia (MI) is a leading cause of SCD, in particular through lethal ventricular arrhythmias such as sustained and irreversible ventricular tachycardia and/or fibrillation (VF)1. Accumulating evidence from animal models suggest that chronic IH, through sympathoactivation, oxidative stress and HIF-1-endothelin signaling, is the most important OSA-related consequence in terms of cardiovascular impact9. Indeed, IH alone induces systemic hypertension, vascular remodeling and dysfunction, atherosclerosis, cardiac remodeling and enhanced infarct size10. However, the relationship between IH exposure and the incidence of MI-related ventricular arrhythmias and SCD has been poorly investigated.OSA is characterized by repetitive upper airway collapses during sleep resulting in intermittent hypoxia (IH), sleep fragmentation and repetitive intrathoracic pressure changes due to increased respiratory efforts against occluded upper airwaysThus, the aims of the present study were to investigate the effects of chronic exposure to intermittent hypoxia on the incidence of MI-related ventricular arrhythmias and to identify the potential mechanisms involved with particular emphasis on sympathoactivation, alterations in ventricular electrophysiological properties and cardiac ion channel expression.Details are provided in the online supplement.The experiments were conducted in accordance with the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes  and were approved by the Université Grenoble Alpes Animal Research Ethics Committee (Cometh). Experiments were conducted on adult male Wistar rats (8 weeks) housed in controlled conditions and provided with standard rat chow.10. The animals were exposed in their housing cages during their daytime sleep period to 8 consecutive hours of 1-min IH cycles  for 14 consecutive days. FiO2 was monitored throughout the experiment with a gas analyzer . Control normoxic (N) animals were exposed to similar 1-min air-air cycles in order to reproduce the noise and air turbulences of the IH stimulus. At the end of N or IH exposure, arterial blood pressure and ECG lead II were recorded in anesthetized animals followed by blood and tissue sampling or by in vivo or ex vivo experiments.As previously described, intermittent hypoxia was performed using a specifically designed device programmed to induce arterial oxygen desaturation levels similar to those of severe OSA patientsBaseline 5-min segments of ECG and arterial pressure signals were processed using a rodent spectral analysis software . Frequency domain analysis of heart rate, systolic, diastolic, mean and pulse pressure variability was performed. Power and normalized units of the low frequency (LF) and high frequency (HF) components of the resulting power spectra, as well as the LF/HF ratio, considered as general marker of sympathovagal balance, were computed.Catecholamine content was measured by ELISA  in blood samples.11.Baseline ECG recordings were analyzed using a rodent ECG analysis software . QT and Tpeak-Tend intervals were measured and the QTc interval was computed using a modified Bazett’s formula for rats normalizing individual QT values to the mean RR values of the corresponding experimental group (QTc = QT/√RR/mean group RR)Left ventricular monophasic action potentials (MAP) were measured on isolated hearts paced at 300 beats/minute. After a 15-min stabilization period, MAP were recorded  on adjacent epicardial and endocardial sites. Action potential duration (in ms) was measured at 50% (APD50) and 90% (APD90) repolarization.1 subunits of Cav1.2 and Cav1.3 L-type calcium channels (LTCC) and of transient receptor potential channels (TRPC1 to TRPC6) were assessed by quantitative real-time PCR. Data were normalized to common reference housekeeping genes .Total mRNA was extracted from left ventricular epicardial and endocardial samples. mRNA levels of the αRegional myocardial ischemia was performed in anesthetized animal and in isolated hearts perfused in Langendorff mode. A 4/0 silk suture was placed around the left anterior descending coronary artery and a 30-min coronary occlusion was performed. Ischemic ventricular arrhythmias were analyzed in accordance with the Lambeth conventions. VF lasting more than 5 minutes was considered as lethal.post hoc Tukey tests. Arrhythmia incidence was analyzed using Fisher’s exact tests. A 2-sided p value < 0.05 was considered statistically significant.Data are expressed as mean ± SEM or median value. Measured data were analyzed (GraphPad Prism 6 software) using unpaired t-tests or nonparametric Mann-Whitney U tests, according to normality and variance, and by two-way ANOVA followed by The hemodynamic parameters measured in N and IH rats are summarized in Table In vivo, arterial blood pressure and ECG were recorded throughout the 30-min myocardial ischemia period. We observed a 2-fold increase in the incidence of lethal ischemia-induced arrhythmias in animals exposed to IH compared to those exposed to normoxia   Fig. .Sympathetic nervous system (SNS) activation was assessed indirectly through measurement of plasma catecholamine levels and spectral analysis of heart rate and arterial blood pressure variability. These data were obtained 12 to 16 hours after the end of normoxic or hypoxic exposure.As shown in Fig. Power spectral analysis of heart rate and arterial blood pressure variability revealed that, while total power was unchanged, rats exposed to IH had a significant increase in the low frequency (LF) component and a significant decrease in the high frequency (HF) component of heart rate , systolic and diastolic blood pressure spectra compared to normoxic rats Fig. . This reWhereas RR interval , P wave duration (21.7 ± 0.5 vs. 21.0 ± 0.8 ms), PR interval (48.4 ± 0.7 vs. 49.2 ± 1.3 ms) and QRS interval (21.5 ± 0.5 vs. 20.9 ± 0.5 ms) were unaffected by IH exposure, we observed a significant increase in QTc  and Tpeak-Tend  intervals, reflective of ventricular repolarization abnormalities and of increased arrhythmogenic risk, in animals submitted to IH Fig. .Figure 3We assessed transmural repolarization through measurement of MAP duration in adjacent ventricular epicardial and endocardial sites. Endocardial APD50 values were significantly longer than epicardial APD50 values in normoxic rats  as well as in those exposed to IH . However, while epicardial APD50 was not affected by IH exposure , we observed a significant increase in endocardial APD50 in IH-exposed rats compared to normoxic rats  Fig. . Consequv1.2 α1 subunit , TRPC1  and TRPC6  , IH exposure appeared to have little effect on ion channel expression in the left ventricular epicardium Fig. . In cont05) Fig. . TRPC2, The present study is the first to demonstrate, in a well-characterized rodent model, that chronic exposure to intermittent hypoxia, such as that occurring in severe OSA patients, is a major risk factor for SCD from MI-related ventricular arrhythmias. We also show that the pro-arrhythmogenic state promoted by intermittent hypoxia is characterized by SNS activation, altered ventricular repolarization and increased expression of left ventricular endocardial calcium channels.12. Moreover, this result confirms the causative role of IH in the high prevalence of myocardial infarction6 and associated SCD4 during sleeping hours in apneic patients. Indeed, the magnitude of SCD risk has been directly linked to multiple parameters characterizing the severity of OSA-related IH such as AHI greater than 20 and lowest nocturnal O2 saturation lower than 78%4.In the present study, we demonstrate for the first time that IH exposure, such as that encountered in severe OSA patients, greatly enhances the incidence of ventricular arrhythmias, in particular of lethal VF, during the early phase of MI. This is in accordance with the literature estimating that, in humans, approximately 50% of MI-related SCD occurs during the early phase13. Indeed, rodents exposed to chronic IH have increased basal resting plasma norepinephrine levels and SNS activity along with increased systemic blood pressure10. Similarly, healthy humans exposed to IH for 2 weeks develop enhanced muscle sympathetic activity and elevated blood pressure14. In accordance, apnea-induced IH is thought to be the main mechanism behind the chronic SNS activation characteristic of OSA and related systemic hypertension1. Indeed, although acute increases in SNS activity occur during apneas, a sustained activation is also seen during daytime in OSA patients characterized by enhanced daytime muscle sympathetic activity and plasma catecholamine levels15.The sympatho-adrenal activation induced by IH exposure is well characterized16. To our knowledge, our study is the first to perform power spectral analysis of both heart rate and blood pressure variability in IH-exposed rats. The resulting increase in LF component, decrease in HF component and increase in LF/HF ratio of heart rate, systolic and diastolic blood pressure are indicative of a cardiac and systemic sympathetic activation that is also corroborated by the increase in circulating catecholamines. In accordance with our data, various studies have reported a cardiac autonomic imbalance in moderate to severe OSA patients with an increase in LF and a decrease in HF components of heart rate variability along with an increase in LF/HF ratio18.Power spectral analysis of heart rate and blood pressure variability is widely used to assess autonomic modulation of the heart and blood vessels. It has proved to be a reliable and reproducible technique to demonstrate sympatho-vagal imbalance in various pathophysiological conditions such as essential hypertension12. In addition to the IH-induced sympathoactivation, efferent cardiac sympathetic fibers are reflexively activated by coronary occlusion in man19 and animal models20. Finally, local catecholamine release in ischemic myocardium through inversion of the reuptake mechanism also promotes arrhythmogenesis20. In accordance, we observed that VF incidence was increased in isolated hearts of rats exposed to IH.SNS activation coupled to reentry mechanisms has been linked to early ischemic ventricular arrhythmias21. Prolongation of the Tpeak-Tend interval, thought to reflect transmural dispersion of ventricular repolarization22, appears to be an even stronger predictor for arrhythmia-related SCD in patients with cardiovascular disease23.We demonstrated that chronic IH exposure alters ventricular repolarization leading to prolonged QTc and Tpeak-Tend intervals. A prolonged QTc is considered a marker of ventricular electrical instability and a risk factor for ventricular arrhythmias and SCD25. Moreover, CPAP withdrawal is associated with prolongation of both QTc and Tpeak-Tend intervals24 and a positive correlation has been shown between prolonged QTc and Tpeak-Tend intervals and AHI26.Several authors have reported increased QTc and/or Tpeak-Tend intervals in OSA patients27.Indeed, IH appears to be the most prominent arrhythmogenic factor in OSA patients since, even after accounting for co-morbidities, the main predictor of arrhythmia occurrence and severity is the level of nocturnal hypoxemiaet al. on the canine heart28, we observed that baseline endocardial APD values were significantly longer than those recorded in adjacent ventricular epicardial sites. Exposure to 14 days of IH significantly increased MAP duration in the endocardium but not in the epicardium. The resulting increase in the left ventricular transmural APD gradient could explain the prolongation in QTc and Tpeak-Tend intervals22, and the associated risk of SCD. Moreover, prolongation of APD is also well known to promote early afterdepolarizations, an important trigger for ventricular arrhythmias particularly in the presence of a prolonged QT interval29.In accordance with the initial observations of Sekiya 22. The transmural myocardial heterogeneity is also reflected by the fact that the subendocardium is more vulnerable than the epicardium to the effects of ischemia and hypoxia30. Thus, the severe oxygen desaturation seen in our IH model10 is likely to have a greater impact on the endocardium than on the epicardium. Moreover, the increase in blood pressure induced by IH exposure results in higher left ventricular pressure, which may induce subendocardial hypoperfusion31, and cardiac workload, which may increase myocardial oxygen demand.The left ventricular APD gradient has been linked to transmural differences in function and perfusion leading to heterogeneity in ion channel expression. Indeed, the electrophysiological characteristics of the cardiomyocytes vary from epicardium to endocardium leading to important distinctions in action potential morphology and ion currents2+ homeostasis can affect APD as well as promote ventricular arrhythmias32. More specifically, we investigated CaV and TRPC channels because they have been shown to be upregulated upon hypoxia by HIF-134, a transcription factor activated by IH with deleterious consequences on the myocardium, as shown by our group35. In accordance, we observed that IH significantly upregulated endocardial but not epicardial Cav1.2, TRPC1 and TRPC6 expression while endocardial Cav1.3 and TRPC4 levels did not vary. Interestingly, HIF-1 appears to promote the expression of Cav1.2, TRPC1 and TRPC6 but not of Cav1.3 and TRPC434.Based on these observations, we hypothesized that endocardial cardiomyocytes could be more susceptible to the effects of IH leading to differential transmural expression of ion channels involved in APD duration. We targeted calcium channels because dysregulation in Cav1.2, the ion-conducting α1 subunit of LTCC involved in phase 2 of the cardiac AP32, could explain the selective increase in endocardial APD induced by IH exposure and the associated increase in QTc and Tpeak-Tend intervals. Moreover, since both LTCC32 and TRPC36 contribute to Ca2+ entry into cardiomyocytes, their upregulation is associated with Ca2+ overload34 thus providing an important substrate for arrhythmogenic early afterdepolarization and premature ventricular contractions32. This is even more relevant in a context of SNS activation since catecholamines have the ability to increase LTCC32 and TRPC36 activity and in general, to promote calcium overload-related ventricular arrhythmias32.Endocardial upregulation of CaThis study is the first to demonstrate that chronic intermittent hypoxia exposure promotes SCD upon myocardial ischemia by inducing a pro-arrhythmogenic state characterized by sympathoactivation and alterations in ventricular action potential duration and repolarization associated with overexpression of myocardial calcium channels.In view of the major role of intermittent hypoxia in the development of these pro-arrhythmic alterations, assessment of coronary risk should be enforced in severe OSA patients presenting increased QTc interval and sympathetic activation in order to prevent both MI-induced lethal ventricular arrhythmias and SCD.Supplementary Information


The electrocardiogram (ECG) is an essential investigation in the evaluation of chest pain in the emergency room (ER). Correct interpretation of the ECG findings, determines the diagnosis and management strategy. This ECG spot diagnosis will improve the skills of the residents and physicians working in ER. A 46-year-old man, who was earlier in sinus rhythm, presented with anginal type of chest pain of three hours duration. The electrocardiogram recorded in emergency room (ER) is shown in The electrocardiogram shows ST segment elevation in inferior leads suggesting inferior wall myocardial infarction. The underlying rhythm is atrial fibrillation. The irregularly, irregular R-R interval coupled with the continuously varying morphology of the fibrillatory waves establishes the diagnosis of atrial fibrillation. Though the rhythm appears like atrial flutter, this is unlikely due to the above mentioned reasons. Atrial flutter is characterized by undulating sawtooth like monomorphic flutter waves and the R-R interval is regularly, irregular due to fixed heart block. The varying atrioventricular block results in long-short cycle sequences that are followed by QRS complexes with increased width 130 msec) (indicated by * in 30 msec (Atrial fibrillation complicating inferior wall myocardial infarction with intermittent ventricular premature beats.As the fast, irregular ventricular response aggravates myocardial ischemia, reverting to sinus rhythm is mandatory. Since it is a new onset atrial fibrillation, electrical cardioversion can be done safely. The patient also requires reperfusion of the infarct related coronary artery at the earliest. He underwent successful fibrinolysis and electrical cardioversion to sinus rhythm. Post cardioversion he was started on oral beta-blocker therapy. The further in hospital course was uneventful and he continued to be in sinus rhythm at 4 months of follow-up.Atrial fibrillation complicating acute myocardial infarction is associated with increased morbidity and mortality. The proposed mechanism of atrial fibrillation in acute myocardial infarction includes congestive heart failure, ischemia and infarction of the conduction system, atrial infarction or ischemia, and vagal reflexes or increased sympathetic activity . ElectriIn conclusion, electrocardiographic recognition of atrial arrhythmias is important to risk stratify acute coronary syndrome patients. Identification and prompt treatment of atrial arrhythmias improve outcomes.


The current work describes an anthropomorphic beating heart phantom constructed as a tool for the assessment of technological advances in cardiac X‐ray computed tomography (CT). The phantom is comprised of a thorax, a compressor system, an ECG system, a beating heart with tortuous coronary arteries, and the option to add or remove pathologies such as aberrant beats, stents, and plaques. Initial trials with the phantom have shown its utility to assess temporal resolution, spatial resolution, radiation dose, iodine contrast, stents, and plaques.PACS numbers: 87.59.Fm, 87.57.Ce A beating heart phantom is described that fully simulates the task of imaging of the heart with CT, including several of the variables described above.The intent of this work is to fabricate a repeatable cardiac imaging test that can facilitate identification of image acquisition protocols to accommodate a given patient's complexities.,6 A The physical attributes of the beating heart phantom were based upon a review of X‐ray CT examinations of 200 patients having received a CCTA using either a Siemens Somatom Sensation 64 CT scanner or a General Electric LightSpeed VCT 64 CT scanner. To assess thorax characteristics surrounding the heart, measurements were taken of the lateral width and the anterior to posterior length. The Hounsfield unit (HU) values within the lungs, soft tissue, and bone were measured and recorded. To assess heart chamber characteristics, measurements included the longest distance from valve to apex, anterior to posterior, and left to right dimensions within the heart. The myocardium was then measured for HU values, as was the blood within the ventricles and the mixture of blood and contrast material present following intravenous contrast injection. Inner diameters of the coronary arteries were also measured within image space. The left anterior descending (LAD), left circumflex (LCX), and the right coronary artery (RCA) were all measured at the proximal, medial, and distal segments. The resulting beating heart phantom includes multiple components fabricated to match the average patient values. These components are shown in Fig. The thorax phantom is intended to house the beating heart and to produce scatter as exhibited in actual patients. The phantom's thorax is fabricated with ribs, sternum, spine, soft tissue, and lung mimicking materials with densities and HU values matching human bone, soft tissue, and lung tissues. CT scanners that modulate the current (mA) exposure simultaneously with the X‐ray triggering to the ECG may suffer from higher noise when the quiescent time of the heart occurs during a time when X‐ray projections in the lateral direction are collected. Evaluation of CCTA image quality under these circumstances is preferable. A cavity for heart placement was constructed in the thorax, allowing the phantom heart position to match the heart position seen in the patient population. An air compressor system causes the heart to beat within the thorax. The compressor is connected to the heart with lengths of plastic tubing so that it can be located in the scan room or at the operator console.The compressor system has four components: the compressor, the air modulator, the tubing throughout the ventricular walls of the heart, and the LabVIEW signals.Simulating a CCTA exam requires an ECG trace for both gating the X‐ray exposure on the scanner  and causing the proper cardiac motion in the beating heart. An imaging protocol that needs to trigger a momentary exposure during minimal heart motion attempts to time the X‐ray exposure during the TP interval. The phantom's ECG trace allows for gating and represents true phantom motion during the QT interval and phantom quiescence during the TP interval. Figure LabVIEW, a software program capable of communicating with multiple hardware devices, is utilized to meet the several demands upon the ECG trace. The compressor's trigger signal and the scanner's gating signal both originate from LabVIEW and synchronize phantom motion to the QT interval registered on the scanner. Initial scanning with the LabVIEW program revealed that the phantom's ECG trace registered a QT interval on the scanner one half second before the compressor signal could initiate the associated movement in the heart. The ECG signal was modified to permit a timing offset in increments of one hundredth of a second and to facilitate matching.The phantom's heart chambers and coronaries can be sealed for use with contrast medium. The beating ventricles force fluid in and out of the atria and induce movement similar to atrial diastolic filling and systolic ejection. The left atrium and left ventricle allow fluid to flow from one chamber to the other. The right atrium and right ventricle allow fluid to flow from one to the other and into the aorta and coronary arteries. When the ventricles contract, fluid pushes out of the ventricles and into the atria and coronary arteries. Ventricular contraction and relaxation displace the coronaries by about one diameter, which is the distance found with actual patient measurements. Once placed within the thorax, the contrast‐filled beating heart phantom exhibits motion similar to that of a patient.Initial phantom trials involved the assessment of temporal resolution. Qualitative analysis of the phantom's motion artifacts provided insight into the temporal resolution achieved on a given CT scanner. Visual image comparisons were made between scans when the phantom was physically not beating and scans when the phantom was beating but imaged within the TP interval. Motion artifacts would be identified when viewing the two image sets. Ideally, little to no difference with images acquired of a stationary phantom would be identified.In order to evaluate a scanner's ability to perform multiple phase reconstructions , aberrant beats can be simulated in the ECG signal. In normal ECG signal production, the electrode box generates a changing voltage per second in the form of a sawtooth wave. The peaks in the sawtooth wave trigger a QT interval in the ECG monitor, achieving a steady ECG signal. To generate aberrant beats, a second wave was added to the ECG signal that changes voltage more slowly over time, resulting in an irregular peak every 7 seconds. These beats create motion and irregular ECG data during a phase of data collection, providing a means for postprocessing evaluation.Coronary plaques were designed in a 3D CAD environment called SolidWorks and custom machined to fit within the coronary arteries of the heart phantom.Initial use of the phantom occurred using the five cardiac CT protocols listed in Table Further studies, not reported here, have been initiated to more fully assess CCTA with the phantom. One ongoing assessment is radiation dose and image quality comparisons with multiple cardiac protocols on a single CT scanner, and between similar technologies on separate CT scanners. Another planned assessment is an evaluation of spatial resolution on multiple CT scanners during CCTA.The functional beating heart phantom can be seen in Fig. Ports for accessing the heart chambers through the inferior vena cava and the aorta are shown, as well as ports for filling the coronaries through their most distal portion. These arteries may appear large, but the inner diameters match those of an average patient. Phantom specifications were measured with the Retrospective Protocol 1 acquisition and compared with the CCTA patient population. Patient averages and the phantom specifications can be seen in Table Hounsfield unit measurements for the patient population and the phantom specifications were taken from images acquired using 120 kVp. The HU values for saline simulating blood in the phantom were measured within the chambers. Phantom densities are generally higher than the reported average patient densities, but the contrast ratio between the vessels and the contrast medium can be duplicated to make image quality evaluations applicable.After achieving accurate propagation of the ECG and compressor signals, typical patient heart rates were tested with routine scanning protocols. Comparison of beating and not beating phantom scan reconstructions were made to determine the level of cardiac motion artifact relative to motion artifact found in patients. Figure As seen in Fig. The completion of the ECG gating validation was followed by a study between retrospective versus prospective gating. Retrospective techniques, using pitch less than 0.3, continuously collect data from several heart beats during all heart cycle phases. This technique ensures complete coverage of the heart and allows for correction of motion artifacts caused by non‐steady cardiac rhythms. Prospective techniques only irradiate during the predicted TP interval, implying cardiac quiescence. This step‐and‐shoot mode reduces dose, but limits the ability to correct motion artifacts due to the smaller number of cardiac phases acquired. Once the beating heart phantom had been scanned with the Retrospective Protocol 1 and Prospective Protocol from Table Scanning the phantom with the aberrant beat signals simulates motion artifacts that the scanner and post processing should be able to eliminate given multiple phases. The phantom images with motion artifact in a phase reconstruction can be postprocessed to evaluate beat rejection software from a vendor. Alternatively, the beat rejection software during acquisition can be compared.Removable coronary plaques provide a test of iodine contrast enhancement and spatial resolution. The plaques themselves can be scanned free in air, immersed in saline, or immersed in contrast medium. The effects of increased contrast on perceived plaque HU can then be assessed as a function of scatter environment and/or kVp.In the left image of Fig. A beating heart phantom was constructed that reasonably duplicates an average patient's cardiac exam in terms of scatter, cardiac tissue densities, coronary size, motion, heart rate, and contrast material. Representative pathology can be simulated such as anomalous ECG activity, and stents and plaques located in the proximal, medial, and distal segments of the coronary tree. The phantom offers the ability to isolate X‐ray CT acquisition parameters and provides direction for optimal imaging strategies including: radiation dose, temporal resolution, spatial resolution, iodine image contrast, image reconstruction parameters, and accuracy of stenosis and plaque composition.The authors would like to thank Mayo Clinic Arizona and Arizona State University for providing the funds to build the beating heart phantom.