Super-responders to cardiac resynchronisation therapy (CRT) show an exceptional improvement in left ventricular ejection fraction (LVEF). Previous studies showed that apical rocking was independently associated with echocardiographic response to CRT. However, little is known about the association between apical rocking and super-response to CRT.To determine the independent association of LV apical rocking with super-response to CRT in a large cohort.A cohort of 297 consecutive heart failure patients treated with primary indication for CRT-D were included in an observational registry. Apical rocking was defined as motion of the left ventricular (LV) apical myocardium perpendicular to the LV long axis. ‘Super-response’ was defined by the top quartile of LVEF response based on change from baseline to follow-up echocardiogram. Best-subset regression analysis identified predictors of LVEF super-response to CRT.P < 0.001). In univariate analysis, female gender , lower LVEF at baseline (OR 0.91 95 % CI 0.87–0.95), non-ischaemic aetiology  and apical rocking  were associated with super-response. In multivariate analysis, apical rocking was still strongly associated with super-response . Super-responders showed an excellent clinical prognosis with a very low incidence of heart failure admission, cardiac mortality and appropriate ICD therapy.Apical rocking was present in 45 % of patients. Super-responders had an absolute mean LVEF increase of 27 % (LVEF 22.0 % ± 5.7 at baseline and 49.0 % ± 7.5 at follow-up). Apical rocking was significantly more common in super-responders compared with non-super-responders  contains supplementary material, which is available to authorized users. So, we do not think that timing of echocardiography caused misclassification of super-responders.The response to CRT can change over time, particularly shortly after CRT. In our cohort echocardiographic examination after CRT implantation was performed after a mean of 2.1 years (IQR 1.4–3.2). The time from implantation to follow-up echocardiogram was comparable in both groups [in non-super-responders 2.1 years (IQR 1.4–3.3) and in super-responders 2.1 years (IQR 1.4–3.1), The cumulative probability of all-cause mortality, heart failure hospitalisation, cardiac death and appropriate ICD therapy for VT or VF differed significantly across LVEF response categories at 6 years of follow-up, with improved event-free survival based on the magnitude of response Fig. . In the Identification of potential super-responders prior to implantation and during follow-up has several advantages. Super-responders have very good prognosis in terms of lower rate of heart failure hospitalisation and all-cause mortality. Furthermore, the incidence of cardiac death or appropriate ICD therapy is very low. These are important issues to discuss with patients prior to implantation. In super-responders, during follow-up when a device change is necessary due to battery depletion or dysfunction of a high voltage RV lead, downgrading from CRT-D to CRT-P can be discussed. Absence of apical rocking has a strong relation with ‘non-super-response’. It may therefore be used to identify the non-super-responders who may require more intensive monitoring during follow-up.Both the large size of the study population and the long-term clinical follow-up are probably the major strengths of the current study. For the definition of ‘super-response’ we used the top quartile of LVEF response based on change from baseline to follow-up, exactly the same definition as in the MADIT-CRT trial , whereasApical rocking is independently associated with super-response to CRT. Apical rocking may therefore play an important role in identifying these patients, who seem to have a good long-term prognosis. Absence of apical rocking has a high negative predictive value for prediction of non-super-response.None.(PPTX 13186 kb)


Electrical defibrillation and cardioversion are important and sometimes life-saving interventions. However, it remains controversial whether the intervention itself can significantly damage the heart. Myocardial edema is an early feature of myocardial injury that can be visualized by T2-weighted sequences. Newer approaches utilize T2 as well as T1 mapping techniques. We used T1 and T2 mapping to detect edema as a marker for defibrillation injury.Using a 3T clinical MRI system, we assessed 10 anesthetized pigs at baseline and hourly for 5 hours after 5 consecutive synchronized transthoracic shocks of 200J and acquired images for T1 maps  and T2 maps in three short-axis planes; basal, mid and apical. Six pigs undergoing the same protocol yet without shocks served as controls. After euthanasia and explantation of the hearts, tissue samples were obtained from regions of interest (ROI) defined by positive CMR results. Hematoxylin and eosin (HE) stains of these samples were then assessed for intercellular and interstitial edema using randomly sampled planimetry.In all 10 pigs undergoing shocks, we observed myocardial injury, which was located in the anterior and inferior wall (n = 8), septal and inferior segments (n = 1) or septal and lateral segments (n = 1). In T1 and T2 maps, myocardial edema was predominantly observed in the basal slices. T2 was significantly increased from baseline at the first hour and at hours 3-5 by up to 4.2 ± 0.9% (p < 0.05, Figure Repeated cardioversion/defibrillation consistently leads to cellular and interstitial myocardial and skeletal edema, which can be visualized by T1 mapping and T2 mapping.Funding is provided by the Montreal Heart Institute Foundation and the Canadian Foundation for Innovation.


Pre- (native) and post-contrast myocardial T1 time calculated from T1 mapping sequences on Magnetic Resonance (MR) is currently being applied to study diffuse myocardial fibrosis in various cardiac diseases both in research and clinical area. However, because myocardium is highly perfused, its T1 time may be influenced by that of blood. Our aim was to study this association in an animal model of left ventricular hypertrophy.23 "large white" pigs underwent contrast-enhanced 3.0 T MR  before and several times (up to 5) after surgical ascending aortic banding. T1 mapping was performed using MOLLI before and 40 minutes after administration of Gd-DTPA  and a continuous perfusion of Gd-DTPA (0.011mmol/kg/min), so-called equilibrium protocol. T1 maps were generated by pixel-wise fitting of the appropriate model curves to the signal intensities. Signal intensities in pre-and post-contrast images were determined in myocardium, skeletal muscle, fat and blood.Main findings, summarized in Table Myocardial T1 time appears to be highly influenced by T1 time of the blood. This influence was reduced or nonexistent in tissues with in tissues with intermediate or poor levels of perfusion, such as skeletal muscle or fat, respectively. These findings should be taking into account when interpreting myocardial T1 and its relation with interstitial fibrosis.N/A.


Cardiac septation defects (CHD) are the problems with the structure of the heart during the development and is one of the most common among congenital heart defect (CHD) which occurs ~1% in general population. The etiology for the majority of these defects may be multifactorial. However, advancement in understanding the molecular basis of normal heart development has revealed the necessity of numerous genes which are predominantly expressed during the heart morphogenesis. Many cohort studies have shown that cardiac transcription factors NKX2-5, GATA4 and TBX5 are the master regulators during heart development. The mutations in any of these genes results in the failure of normal development of heart leading to septal defects. The study was carried out to identify the nucleotide sequence variation in the patients with Atrial Septal Defects (ASD), Ventricular Septal Defects (VSD) and Atrioventricular Septal Defect (AVSD).Fifty seven patients with ASD (n=51) and VSD (n=6) were included in the study after a thorough evaluation of Echocardiography and clinical phenotypes. All the coding regions and flanking introns of NKX2-5 and GATA4 which are predominantly expressed in the heart were amplified by polymerase chain reaction and sequenced using ABI PRISM 3130 automated sequencer.No patient was found to have NKX2-5 and GATA4 mutations, however single nucleotide polymorphism  in NKX2-5 was observed in 20 patients with Ostium secundum ASD.Since the mutation frequency is very low  in these cases, we need to study more number of patients to get expected frequency.


Non-ischemic fibrosis (NIF) on cardiac magnetic resonance (CMR) has been linked to poor prognosis, but its association with adverse right ventricular (RV) remodeling is unknown. This study examined a broad cohort of patients with RV dysfunction, so as to identify relationships between NIF and RV remodeling indices, including RV pressure load, volume and wall stress.2 = 21; p<0.001]. NIF prevalence was higher in relation to PA pressure and RV dilation and was > 6-fold more common in the highest, vs. the lowest, common tertile of PASP and RV size (p<0.001).The population comprised patients with RV dysfunction (EF<50%) undergoing CMR and transthoracic echo within a 14 day (5±3) interval. Cardiac structure, function, and NIF were assessed on CMR. Pulmonary artery systolic pressure (PASP) was measured on echo. 118 patients with RV dysfunction were studied, among whom 47% had NIF. Patients with NIF had lower RVEF  but similar LVEF  and LV volumes (p = NS). RV wall stress was higher with NIF  corresponding to increased RV end-systolic volume , myocardial mass , and PASP . NIF was associated with increased wall stress among subgroups with isolated RV (p = 0.005) and both RV and LV dysfunction (p = 0.003). In multivariable analysis, NIF was independently associated with RV volume  and PASP  but not RV mass  [model χAmong wall stress components, NIF was independently associated with RV chamber dilation and afterload, supporting the concept that NIF is linked to adverse RV chamber remodeling. Right ventricular (RV) adverse remodeling is an important prognostic marker that has been linked to heart failure and death , 2. IncrThe study protocol was approved by the Weill Cornell Institutional Review Board. CMR and echocardiogram were performed for clinical purposes and data was retrospectively anonymized with written inform consent for use of anonymized data waived.The study population was comprised of patients with CMR-evidenced RV systolic dysfunction (RVEF <50%) in whom echo was performed within a 14 day (mean 5±3) interval for quantification of PA pressure. Patients with conditions known to preclude assessment of localized late gadolinium enhancement  or accurate echo quantification of pulmonary arterial pressure  were excluded. No other patients were excluded based on clinical condition or indication for CMR.Demographic indices were categorized using a standardized patient questionnaire; results were confirmed via review of medical records. RV dysfunction etiologies were assigned blinded to CMR results, including NIF status. This study was conducted with approval of the Weill Cornell Medical College Institutional Review Board.CMR was performed using 1.5 Tesla scanners . Exams consisted of two components: (1) cine-CMR for geometry/function and (2) delayed enhancement (DE-) CMR for tissue characterization. Cine-CMR was performed using a steady-state free precession sequence. DE-CMR was performed 10–30 minutes after administration of gadolinium (0.2 mmol/kg) using a segmented inversion recovery sequence , for whiCardiac chamber geometry and function were quantified via cine-CMR. RV end-diastolic and end-systolic chamber volumes were measured in contiguous short axis images using a validated automated segmentation algorithm , with re2 + right atrial pressure), for which tricuspid regurgitant peak velocity was measured via Doppler and right atrial pressure determined based on size and collapsibility of the inferior vena cava [Transthoracic 2D echocardiograms were acquired using commercially available equipment . Pulmonary artery systolic pressure (PASP) was calculated using the modified Bernoulli equation (4 [peak tricuspid regurgitant velocity]ena cava .) was calculated using an established formula [RV wall stress  were compared using Student’s t-tests for two group comparisons, and analysis of variance (ANOVA) for multiple group comparisons. Categorical variables were compared using Chi-square or, when fewer than 5 expected outcomes per cell, Fisher’s exact test. NIF was assessed in relation to RV afterload and structural parameters using univariable and multivariable logistic regression analyses. Two-sided p <0.05 was considered indicative of statistical significance. Statistical calculations were performed using SPSS 20.0 .118 patients with RV systolic dysfunction were studied, among whom 47% had NIF. Among patients with NIF (n = 56), 52% (n = 29) had isolated RV insertion site, 23% (n = 13) had mid-myocardial, and 25% (n = 14) had concomitant RV insertion and mid-myocardial LGE on DE-CMR.RV linear dimensions similarly demonstrated an association between NIF and RV dilation, as evidenced by increased RV short axis diameter (p = 0.04) and a similar trend for RV long axis (p = 0.08) diameter. Whereas RV mass (p = 0.04) and wall thickness (p = 0.01) were slightly increased among patients with NIF, both RV mass/volume and relative wall thickness (adjusted for short axis diameter) were similar (both p = NS), suggesting absolute increments in RV mass as a response to chamber enlargement.Echo-quantified PASP was higher among patients with NIF , paralleling increased prevalence of pulmonary hypertension  as defined via an echo-based established cutoff (≥40 mmHg).Cine-CMR also demonstrated evidence of increased RV afterload in association with NIF. Septal flattening was 2-fold more common among patients with NIF ; flattening occurred during both systole and diastole in nearly all affected patients (96%) suggesting concomitant RV pressure and volume overload.RV wall stress was nearly 1.4 fold higher among patients with NIF , consistent with parallel increments in RV chamber volume and afterload. RV wall stress was higher among sub-groups of patients with RV insertion site (16±6 vs. 12±6 kPa p = 0.002), mid-myocardial , and concomitant RV insertion site and mid-myocardial NIF , compared to those without NIF. Wall stress values were similar between affected patients partitioned based on NIF pattern (p = 0.97).As shown in Multivariable logistic regression models were constructed to test associations between NIF and individual components of RV wall stress—PASP, RV chamber volume and RV myocardial volume (RV mass). This study provides several new findings concerning myocardial fibrosis among patients with RV systolic dysfunction. (1) Among a broad population inclusive of differing etiologies of RV systolic dysfunction, NIF was common—identified by CMR in nearly half (47%) of patients. (2) NIF was more common among patients with markers of advanced heart failure, as evidenced by need for diuretic or inotropic therapy (both p<0.01) as well as patients with more advanced RV systolic dysfunction (p<0.001). (3) NIF was strongly associated with RV wall stress, which was higher among NIF patients with isolated RV dysfunction (p = 0.005) as well as those with biventricular failure (p = 0.003). (4) Among wall stress components, RV chamber volume and PA systolic pressure were each independently associated with NIF (p≤0.01), whereas RV mass was not (p = 0.5). NIF prevalence increased stepwise in relation to PA pressure and RV chamber dilation and was > 6-fold more common in the highest, vs. the lowest, common tertile of PASP and RV end-systolic volume (p<0.001).To the best of our knowledge, this is the first study to examine the independent associations of RV pressure overload and volume on NIF among a diverse population with RV remodeling. Prior CMR studies have shown NIF to be associated with adverse clinical outcomes , 21. HowOur finding of a strong association between NIF and RV wall stress extends upon prior studies that have examined cardiac chamber remodeling in relation to myocardial tissue properties. Paralleling current data among patients with RV dysfunction, prior research by our group among patients with LV dysfunction has shown NIF to be associated with increased LV wall stress, and independently linked to LV chamber dilation . ConcernBeyond volumetric analysis, our study assessed linear RV dimensions as a secondary measure of RV remodeling. Linear analysis paralleled volumetric data, as evidenced by an independent association between RV diameter and NIF even after controlling for RW wall thickness and PA pressure. Of course, a key advantage of RV volume concerns the fact that it reflects global, rather than regional, chamber remodeling. It remains uncertain as to the magnitude to which regional variability in RV remodeling impacts wall stress among patients with different conditions. On the one hand, it is possible that in some patients RV regional and global remodeling could change in parallel due to systemic increases in preload or afterload. On the other hand, other patients might demonstrate regional alterations in RV wall stress due to localized RV injury (e.g. coronary ischemia), targeted interventions , or intrinsic embryologic and geometric differences between different regions  of the RV.Several limitations should be noted. First, whereas the interval between CMR and echo was short (mean 5±3 days), RV volumes and PA pressure could have varied in the interim between tests and thus influenced study findings. It should also be noted that the majority of our cohort had concomitant RV and LV systolic dysfunction (EF < 50%), such that this is largely a study of NIF among patients with biventricular dysfunction rather than isolated RV failure. Last, echo was used to quantify PA pressure, rather than the reference standard of invasive hemodynamics. On the other hand, echo is well-validated and widely applied for assessment of PA pressure, as evidenced by its prior application for this purpose in several large-scale population-based studies , 25. MorThe results of this study demonstrate NIF to be independently associated with both RV pressure overload and volume, supporting the concept that NIF is a generalized marker of adverse remodeling stimuli that commonly produce increased RV wall stress.


While CMR has become instrumental in imaging complex congential heart disease (CHD), limitations remain including significant flow and metal artifact on cine images. 2D dark blood imaging generally requires gating to diastole which may not capture the maximal vessel dimensions, is time consuming and dependent on precise plane positioning. Traditional 3D whole heart sequences are also sensitive to flow and metal artifact. 3D respiratory navigated FLASH with an inversion recovery pulse (IR-FLASH) post-gadofosveset potentially overcomes all of these limitations. Furthermore, it is ideal for generating high resolution isotropic datasets of the blood pool for 3D modeling. We present our experience with IR-FLASH for imaging native and repaired CHD.We retrospectively reviewed our experience with IR-FLASH after gadofosveset. Respiratory navigating was employed with typical settings including isotropic voxels of 1.0 to 1.3 mm, TE 1.6 msec, TI 260 msec, and flip angle of 18 degrees. The TI was lowered to as low as 140 for systolic gating. Late systolic or diastolic quiescence was chosen for cardiac gating. We compared the IR-FLASH sequence to dynamic MRA, cine, and SSFP whole heart imaging when available.IR-FLASH after gadofosveset was performed in 48 exams on 47 pts, with a mean age of 10.8 years (range 3 days to 32 years). Gating was performed to both diastole and systole in 22 cases, only systole in 4 cases, and only diastole in 22 cases. Image quality was judged to be good to excellent in 41 cases, and poor in only 2 cases. Systolic gating was generally successful for TI's of 180 or greater. Diagnoses included tetralogy of Fallot in 6 patients, unicuspid or bicuspid aortic valve in 5 cases, truncus arteriosus after repair in 4 cases, heterotaxy in 4 patients, and single ventricle status post cavopulmonary connections in 7 patients. In all patients with truncus or aortic valve disease, systolic gating precisely defined the valve morphology (see Image IR-FLASH after gadofosveset can be routinely implemented in a wide range of heart disease. It is less sensitive to flow and metal artifact than SSFP sequences. It can be reliably gated to both systole and diastole. Gating to systole allows for better definition of semilunar valve morphology, RVOT morphology, and maximal root dimensions. The high resolution, contrast, and ability to scan with isotropic voxels makes it ideal for generating 3D models for computational analysis or printing.None.


The right ventricular (RV) size responds to many cardiopulmonary diseases characterized by chronic pressure and volume overload. Cardiovascular magnetic resonance (CMR) is considered the "gold-standard" for RV evaluation. The RV end-diastolic volume indexed to body surface area (RVEDVi) has been used for RV size assessment, but this parameter alone may not be sensitive enough to detect RV dilation due to its wide normal range and the lack of consideration of individual heart size. We sought to determine if the assessment of right to left ventricular end-diastolic volume ratio (RVEDV/LVEDV) in addition to RVEDVi increased the detection of RV dilation in the RV CMR analysis. The application of this ratio is investigated in a control and a Pulmonary Arterial Hypertension (PAH) population.Clinical CMR exams were performed on a 1.5T Siemens scanner  or a 1.5 T Philips scanner . CMR derived ventricular function and volumes were measured in a control group (n = 76) and in patients with pulmonary arterial hypertension (PAH) (n = 46) using QMASS . Different criteria for the detection of RV enlargement, including RVEDVi and RVEDV/LVEDV ratio, were evaluated in both groups.2 for females and >114 ml/m2 for males).The left and right ventricular volumes are shown in Table The addition of the RVEDV/LVEDV ratio to RVEDVi increased the sensitivity of detection of RV enlargement in a PAH population.Cardiovascular Medical Research and Education Fund.


Please see later in the article for the Editors' Summary PLOS Medicine:This Perspective discusses the following new study published in doi:10.1371/journal.pmed.1001699Callender T, Woodward M, Roth G, Farzadfar F, Lemarie J-C, et al. (2014) Heart Failure Care in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis. PLoS Med 11(8): e1001699. In a systematic review and meta-analysis, Kazem Rahimi and colleagues examine the burden of heart failure in low- and middle-income countries.PLOS Medicine, Rahimi and colleagues In this week's That is a euphemism, albeit a standard one. Outside the language of academic research, it could be bluntly rephrased as: “routinely doctors and healthcare systems cause needless death and major illness through failing to provide the care they should”. Recent work has suggested that 85% of all medical research is wasted through asking the wrong questions or asking questions badly, and more through difficulties in open access to useful knowledge Geographical discrepancies in the diagnosis and treatment of heart failure Diastolic failure is more likely in the elderly The finding that nearly half of heart failure in Africa is caused by hypertension suggests a substantial burden of potentially preventable disease and highlights uncertainty over the balance of systolic and diastolic failure. That only one population-based study estimating the incidence or prevalence of heart failure in LMICs could be found is remarkable; directing scarce resources needs better information. In South Africa, 16% of deaths in 2011 were attributed to “diseases of the circulatory system”, up from 14% in 2009 Heart failure is a growing global problem. Variations in diagnostic strategy undermine establishment of an optimal response, as does the focus in clinical trials on atypically youthful, male populations with systolic dysfunction. Future progress in reducing the burden of heart failure depends on attending to what makes the most difference, not what makes for the easiest trials. Treatment matters, even when treatment is palliative, but reducing cardiovascular risk in an effort to prevent heart failure may be the most important strategy. Determining what works best is important not only in the resource-poor settings of LMICs. Obesity and exercise are modifiable risk factors for the development of heart failure, but our ability to affect them is limited compared to our power to alter blood pressure and lipids.Rahimi and colleagues highlight likely therapeutic failures when it comes to prolonging and improving the lives of those suffering heart failure in LMICs


Nonketotic hyperglycemia often causes seizures. Recently, seizures associated with nonketotic hyperglycemia have been found to be associated with subcortical T2 hypointensity on magnetic resonance imaging, especially in the occipital lobes. However, the mechanism remains unclear, although iron accumulation is suggested. We present a case of occipital lobe seizures associated with nonketotic hyperglycemia supporting the hypothesis that the mechanism of subcortical T2 hypointensity is iron accumulation using gradient-echo T2*-weighted magnetic resonance imaging.A 65-year-old Japanese man complained of intermittent pastel-colored flashing lights. On neurological examination, he also had lower right-side quadrant hemianopia. No other abnormal neurological findings were found. On laboratory analysis, his blood glucose level was 370 mg/dL, HbA1c was 11.4 %, and serum osmolarity was 326 mOsm/L. No ketones were detected in urine. A magnetic resonance imaging scan of his head showed subcortical T2 and T2* hypointensity in his left occipital lobe. Single-photon emission computed tomography with I123-N-isopropyl-iodoamphetamine revealed hyperperfusion in the left dominant occipital lobe. These magnetic resonance imaging abnormalities resolved during clinical recovery and treatment to control his blood sugar level. Therefore, a diagnosis of occipital lobe seizures associated with nonketotic hyperglycemia was made.To the best of our knowledge, this is the first case of occipital lobe seizures associated with nonketotic hyperglycemia supporting the role of iron accumulation as a mechanism for subcortical T2 hypointensity using T2*-magnetic resonance imaging. Nonketotic hyperglycemia (NKH) is a clinical syndrome comprising hyperglycemia, serum hyperosmolality, and intracellular dehydration with little or no ketoacidosis. NKH has been associated with various neurological manifestations. Several cases of subcortical T2 hypointensity after seizures associated with NKH have been reported , 2. AlthA 65-year-old Japanese man who had a past medical history of chronic obstructive pulmonary disease and no remarkable family medical history reported seeing intermittent pastel-colored flashing lights in his lower right-side visual field. Two weeks later, the flashing lights increased in frequency and appeared every 15–30 minutes for approximately 3 minutes at each occurrence. Consequently, the patient visited our hospital.On neurological examination, in addition to intermittent flashing lights, our patient also had lower right-side quadrantanopsia. No other abnormal neurological findings were found. On physical examination, his height and body weight were 164.3 cm and 68.1 kg, respectively. He had no abnormal physical findings and his blood pressure, heart rate, and body temperature were 132/78 mmHg, 72/min, and 36.4 °C, respectively. On laboratory analysis, his blood glucose level was 370 mg/dL , HbA1c was 11.4 % , and serum osmolarity was 326 mOsm/L . No ketones were detected in his urine. A cerebrospinal fluid examination was within normal limits. A brain magnetic resonance imaging (MRI) scan demonstrated subcortical hypointensity in the left occipital lobe in gradient-echo T2-weighted MRI (T2-MRI) and T2*-MRI, and slight cortical hyperintensity in the adjacent area in diffusion-weighted imaging (DWI) Fig. –c. GadolConsequently, we initially diagnosed NKH, although he had not been diagnosed with diabetes mellitus (DM), and considered that occipital lobe seizures were associated with NKH. Subsequently, we started intensive insulin therapy, vildagliptin (100 mg/day), and rehydration to control blood sugar. As his blood glucose became stable, his intermittent pastel-colored flashing lights lessened and disappeared 3 days after initiation of treatment. His quadrant hemianopia gradually improved, and completely resolved 2 weeks after treatment. A follow-up brain MRI scan, performed 75 days after the first MRI, showed disappearance of subcortical T2 and T2* hypointensity, and DWI cortical hyperintensity Fig. . His HbANKH is a serious acute complication of DM, typically in patients over 50 years with type 2 DM, and a clinical syndrome comprising severe hyperglycemia, hyperosmolarity, and intracellular dehydration occurring with little or no ketoacidosis. NKH has been associated with various neurological manifestations such as delirium, seizures, hemichorea-hemiballism, dysphagia, hemianopia, hemiparesis, and hemisensory loss. Most seizures associated with NKH are partial seizures with or without secondary generalization, which are refractory to antiepileptic drugs. Optimal treatment is correction of fluid and electrolyte abnormalities, and glycemic control. Particularly, the occipital lobe is potentially the most affected area, and occipital lobe seizures associated with NKH can cause flashing lights, well-formed visual hallucinations, photopsias, headache, vomiting, gaze and head deviation, blurry vision, and homonymous hemianopia. Seizures associated with NKH occasionally accompany characteristic MRI abnormalities, comprising subcortical T2 hypointensity in the white matter, hyperintensity of the overlying cortex, and focal overlying cortical contrast enhancement, reversible with the course of clinical recovery –3. DespiGiven hypointensity on T2-MRI and T2*-MRI, and occipital lobe lesion, we investigated possible microhemorrhage or posterior reversible encephalopathy syndrome (PRES). However, hypointensity on T2*-MRI in our case was not spotty, and the boundary was unclear. Blood pressure was not high, and PRES generally presents with T2 hyperintensity and does not present with subcortical T2 hypointensity. Therefore, we confirmed the diagnosis of occipital lobe seizure associated with NKH.Despite increasing reports of similar cases, the detailed mechanism of T2 hypointensity remains uncertain. Neurons cannot exist without iron, which is an essential cofactor for enzymes involved with energy metabolism and synthesis of neurotransmitters. It is impossible to determine in our case and in similar cases whether excess iron caused neuronal cell damage or whether iron homeostasis was disrupted due to hyperglycemia. However, we speculate that accumulation of iron (enough to be reflected in T2-MRI and T2*-MRI) associated with disruption of axonal transportation, due to early cortical ischemia or excitotoxic damage from seizures, are potential mechanisms [Ischemia or seizures without hyperglycemia can result in similar MRI abnormalities, indicating that subcortical T2 hypointensity is not specific to seizures associated with NKH . HoweverTo the best of our knowledge, this is the first case of occipital lobe seizures associated with NKH supporting the role of iron accumulation as a mechanism for subcortical T2 hypointensity using T2*-MRI. However, the precise mechanism of iron accumulation remains uncertain. Further investigations are needed to reach verifiable conclusions.DM, diabetes mellitus; DWI, diffusion-weighted imaging; EEG, electroencephalography; HHS, hyperosmolar hyperglycemic syndrome; IMP-SPECT, single-photon emission computed tomography with I123-N-isopropyl-iodoamphetamine; MRI, magnetic resonance imaging; NKH, nonketotic hyperglycemia; PRES, posterior reversible encephalopathy syndrome; T2*-MRI, gradient-echo T2*-weighted magnetic resonance imaging; T2-MRI, gradient-echo T2-weighted magnetic resonance imaging


P < 0.01) and cTnI  and showed similar dependencies on age, renal function, and left ventricular function. We have developed a high-sensitivity assay for cMyC. Concentrations of cMyC in clinically stable patients are highly correlated with those of cTnT and cTnI. This high correlation may enable ratiometric comparisons between biomarkers to distinguish clinical instability.Cardiac troponins (cTns) are released and cleared slowly after myocardial injury. Cardiac myosin–binding protein C (cMyC) is a similar cardiac-restricted protein that has more rapid release and clearance kinetics. Direct comparisons are hampered by the lack of an assay for cMyC that matches the sensitivity of the contemporary assays for cTnI and cTnT. Using a novel pair of monoclonal antibodies, we generated a sensitive assay for MyC on the Erenna platform (Singulex) and compared serum concentrations with those of cTnI (Abbott) and cTnT (Roche) in stable ambulatory cardiac patients without evidence of acute cardiac injury or significant coronary artery stenoses. The assay for cMyC had a lower limit of detection of 0.4 ng/L, a lower limit of quantification (LLoQ) of 1.2 ng/L (LLoQ at 20% coefficient of variation [CV]) and reasonable recovery , dilutional linearity (101.0 ± 7.7%), and intraseries precision  and interseries precision . In 360 stable patients, cMyC was quantifiable in 359 patients and compared with cTnT and cTnI measured using contemporary high-sensitivity assays. cMyC concentration  was linearly correlated with those for cTnT (median, <3.0 ng/L; IQR, <3.0–4.9 ng/L; R = 0.56,  Marjot J, et al.Cardiac myosin–binding protein C (cMyC) is a protein with cardiac-restricted expression that we have previously shown appears in the systemic circulation after acute myocardial injury using a relatively insensitive assay. This article describes a high-sensitivity assay for cMyC, which demonstrates that it can be measured at baseline in almost all individuals, and in a stable population its concentration correlates with those for cTnI and cTnT.This article acts as the foundation for a study using the assay described here in patients presenting with suspected acute myocardial infarction to compare the diagnostic and prognostic performances of cMyC with cTnT and cTnI.Acute myocardial infarction (AMI) carries a poor prognosis that can be improved by timely intervention. It must therefore be rapidly identified and differentiated from other causes of chest pain.The concentration of cTn rises slowly after acute myocardial injury and does not peak until 16–18 hours after the onset of chest pain.The sarcomeric protein, cardiac myosin–binding protein C , is abundantWe have previously described the creation, biophysical selection, and organ specificity of mouse monoclonal antibodies recognizing cardiac-restricted epitopes within the N-terminus of cMyC.Magnetic microparticles  for capture were prepared by binding 25 μg of mouse monoclonal (1A4) per milligram of MPs. The coated MPs were diluted in assay buffer (Singulex proprietary mix with custom 450 mM NaCl and 0.5% Triton X-100) to 100 μg/mL. Serum, plasma, or analyte . The curve ranged from 0.58 to 2000 ng/L (S1–S11) with a 0 ng/L anchor of unadulterated standard diluent (Singulex). The lower limit of detection (LoD) was defined as 2.5 × standard deviation background divided by slope, and the LLoQ was defined as the lowest point on the standard curve, which has a coefficient of variation (CV) ≤20% where the back interpolated concentration had a recovery percent bias ≤20%.Interassay and intra-assay series precision was evaluated in human serum samples that were tested unadulterated and spiked with 200 ng/L of cMyC. The samples were diluted 2-fold in standard diluent (1:1 mix) before assaying 6 replicates per sample on Day 1 and 3 replicates per sample on Day 2. Spike recovery was calculated by subtracting the dilution-corrected endogenous cMyC concentration from the dilution-corrected spiked value divided by the expected value. Dilutional linearity was evaluated by serial dilution of spiked human plasma. Linearity was calculated by dividing the dilution-corrected cMyC concentration by the preceding value, expressed as a percentage.Between July 2009 and January 2014, 5329 patients were referred to the Kerckhoff Heart and Thorax Center for elective coronary angiography and provided written informed consent for their participation in blood-based biomarker studies as per institutional ethics board (FF 43/2010). The research was carried out according to the Code of Ethics of the World Medical Association (Declaration of Helsinki), informed consent was obtained, and the author's institutional review board has approved the study.From this population we selected 360 serum samples based on the absence of obstructive stenoses (<50%) on invasive coronary angiography and normal (<14 ng/L) high-sensitivity cTnT, renal function, and liver function. Further criteria used to choose samples were prior measurement of high-sensitivity cTnI and sufficient volume of stored serum to allow duplicate measurements of cMyC (>100 μL). cTnT was measured in serum with the high-sensitivity electrochemiluminescence immunoassay . For the cTnT assay, the limit of blank (LoB) = 3.0 ng/L, LoD = 5.0 ng/L, and LLoQ = 13.0 ng/L. The lowest concentration measurable with a CV <10% for this assay is 13.5 ng/L. The recommended clinical decision limit (99th percentile) for rule out of AMI using this assay is 14.0 ng/L. Concentrations of cTnT less than 3 ng/L (LoB) were not returned and therefore assigned a value of 1.5 ng/L in all analyses.cTnI was measured in serum with the high-sensitivity chemiluminescent immunoassay . For the cTnI assay, LoD = 1.2 ng/L and LLoQ = 4.7 ng/L at a CV <10%. The 99th percentile is 15.6 ng/L in women and 34.2 ng/L in men. Concentrations less than the LoD were returned and used for comparisons, because all were greater than the locally determined LoB.The methods used to calculate the LoDs and LLoQs for MyC are described previously.P < 0.05.The Kolmogorov-Smirnov and Shapiro-Wilk tests were used to test if cMyC, cTnT, and cTnI concentrations were distributed normally. Spearman's rank test was used to assess correlation between the serum concentrations of each biomarker and to correlate the concentration of each marker to the continuous demographic variables of the sample population. Differences in the distribution of biomarker concentration across categories of dichotomous variables were examined using the independent-samples Mann-Whitney test. Stepwise multiple logistic regression analysis was used to assess independent association between the variables and biomarker concentrations. All analyses were carried out using SPSS v22. Normally distributed data are presented as the mean ± standard deviation. Statistical significance was set at 2 = 0.9995), where [MyC] is in nanograms per liter. The LLoQ is 1.2 ng/L and the calculated LoD is 0.4 ng/L.The 12-point calibration using recombinant C0C2 domain of cMyC in standard diluent is shown in Sera from 5 individuals were spiked with 200 ng/L of cMyC and subjected to repeated measurement. Six repeated measurements were made on Day 1 and 3 on Day 2. Dilutional linearity was tested using the finalized assay in plasma see . The resThe demographics of the population cohort used to compare biomarker concentrations are shown in Three hundred sixty serum samples with [cTnT] <14 ng/L were analyzed. In one of these samples, cMyC was less than the LLoQ. Our subsequent analysis was of the 359 patients with an evaluable cMyC. Of these 274 patients had cTnT (<5 ng/L), and 52 patients cTnI (<1.2 ng/L), concentrations less than the LoD. The resulting truncation of the leftmost portion of the concentration-frequency distribution is therefore evident for cTnT and cTnI but not for cMyC see . None ofBecause the biomarkers are co-correlated we looked at the demographic variables known to influence [cTnT] and [cTnI] to determine if they similarly influence cMyC. The continuous variables are shown in P < 0.05), R2 = 0.198, n = 346. Because left ventricular ejection fraction (LVEF) was only known for 189 samples, LVEF was omitted from the analysis to preserve sample size and statistical power. With LVEF included in the analysis, only creatinine, LVEF, and age significantly predicted cMyC (P < 0.01), R2 = 0.22, n = 183 (see P < 0.05), R2 = 0.153, n = 346. cTnT was significantly predicted by age, gender, family history of heart disease (see P < 0.05), R2 = 0.299, n = 346. A distinctive feature of MyC was its association with β-blocker use.A stepwise multiple logistic regression analysis was performed to determine which independent variables statistically significantly predicted the serum biomarker concentrations, independently of other covariates . In this 183 see . The samWe have developed a high-sensitivity assay to measure cMyC in serum or plasma. In 360 stable patients with a cTnT <14 ng/L, cMyC was quantifiable in 359 patients, a sensitivity much greater than that achieved with cTnT (4 patients with greater than LLoQ = 13.0 ng/L) or cTnI (78 patients with greater than LLoQ = 4.7 ng/L). cMyC is the first cardiac-specific marker of injury to be described since cTnT and cTnI. Generally, concentrations of cMyC were highly correlated with those of cTnI and cTnT and were influenced by the same demographic features including gender, age, renal function, left ventricular function, medication, and heart rhythm.The close correlation between cMyC and cTnT/cTnI is surprising because their locations within the sarcomere differ.Although, the factors affecting cTnI, cTnT, and cMyC are broadly very similar see , serum cOur ultimate aim is to determine if cMyC is a “better” diagnostic biomarker of acute myocardial injury than cTnT or cTnI. On the basis of our previous findings with a much less sensitive assay, after iatrogenic myocardial injury cMyC is released and cleared more rapidly from the peripheral circulation than cTnT.One of the major limitations of the present study is that the study population was not healthy, and we therefore cannot estimate the 99th percentile concentration for cMyC. In choosing the population to validate our novel assay, we thought it more important to have a complete description of their demographics with the availability of other laboratory measures, including contemporary high-sensitivity cTnI and cTnT. This choice was consolidated by the lack of guidance on how rigorously to exclude covert cardiac disease in a healthy cohort and the influence this uncertainty has on the 99th percentile returned by that particular unique healthy cohort. Finally, we reasoned that the patient population we studied is more representative of those that will attend with a suspected NTSE-ACS event than a healthy younger cohort without cardiac risk factors. Nonetheless, the 99th percentiles returned in our population closely match those defined in healthy control populations for the assays we used for TnT  and TnI .A further limitation is that the Erenna platform on which the cMyC assay is performed is currently only available for research purposes and cannot provide the flexibility or turn-around times required for clinical use. These deficiencies could be addressed by migration to another platform or through the development of the Erenna platform.Another “high-sensitivity” assay for cMyC has been described recently.We have developed and validated a sensitive assay for cMyC, which for the first time allows this cardiac-specific marker of myocardial injury to be quantified in ambulatory patients. The diagnostic performance of this assay is yet to be compared with cTnI and cTnT in the setting of NSTE-ACS.


Objective: Prior studies have demonstrated the relationship between cardiovascular diseases and fragmented QRS (fQRS). fQRS was also associated with ventricular arrhythmias. Our objective was to find out the relationship between fQRS and paroxysmal atrial fibrillation (PAF).Method: A total of 301 patients without overt structural heart disease were prospectively included in the study. Patients were divided in to 2 groups according to presence of fQRS. Multivariate logistic regression analysis was used to assess the predictive value of fQRS for predicting PAF.Results: One hundred and three patients had fQRS. Patients with fQRS were older , with larger left atrium (LA) , with thicker interventricular septum (IVS) , more diabetic  and have more PAF episodes  in comparison with patients without fQRS. fQRS was an independent predictor of detecting PAF episode . Hypertension and diabetes mellitus were also predictive.Conclusion: The presence of fQRS independently predicted PAF episodes in holter monitoring (HM). Further studies are needed to clarify the clinical implications of this finding. Indeed it was demonstrated that the fQRS was as predictor of the occurrence of post-operative atrial fibrillation (AF) in isolated coronary artery by-pass surgery.9The reason for all the above mentioned associations between fQRS and various cardiovascular diseases was found to be cardiac fibrosis.We hypothesized that presence of fQRS may be useful for predicting atrial arrhythmias, especially paroxysmal AF (PAF) which is the most common cardiac arrhythmia with important clinical implications.Study design: This was a prospective observational study.Study population: A total of 301 patients, who were referred for 24 h Holter ECG monitoring because of complaint of palpitation, at our institution between June 2012 and December 2012 were enrolled consecutively.Pediatric Holters, pacemaker-dependent patients, patients with complete bundle branch block and patients with ongoing antiarrhythmic therapy, patients with thyroid disorders, patients with severe cardiac diseases including valvular disease, heart failure and cardiomyopathies were excluded. We also excluded the Holters which were performed to hospitalized patients The study was carried out in accordance with Declaration of Helsinki principles and was approved by the Local Ethics Committee.Study protocol: The patients referred for 24 h Holter ECG monitoring were evaluated by a cardiologist before holter evaluation. Each patient’s history and examination was collected by a cardiologist. We recorded the baseline characteristics, which included hypertension (HT), smoking status, diabetes mellitus (DM), family history of CAD, height and weight and medication. Routine laboratory measurement, which were obtained after at least 8 h fasting, including glucose, creatinine, lipid profile, thyroid stimulating hormone (TSH) and hemogram were recorded.10 and recorded on echopacs.Basic echocardiography measurements including chamber diameters, wall thicknesses an ejection fraction(EF) obtained with Vivid 7  according to the guidelines of the American Society of EchocardiographyElectrocardiography: A 12 lead surface ECG was obtained from all patients before connecting the Holter device to the patient. This 12- lead ECGs  were analyzed by 2 independent cardiologist who were blinded to Holter data. fQRS was defined as presence of different RSR’ patterns (QRS duration <120 ms) which include an additional R wave (R’ prime) or notching of the R wave or S wave, or the presence of more than one R’ prime without typical bundle branch block in two contiguous leads corresponding to a major coronary artery territory. The inter-observer concordance rate for determining fQRS was 98.2% between two readers. In case of disagreement, the final decision was made mutually. We also evaluated the number of fQRS, because fragmentation in only one lead is not accepted as the presence of fQRS; we accepted as absence of fQRS if the number of fQRS was zero or one.Holter monitoring and interpretation: Then two independent cardiologist evaluated the recordings for presence of any AF episodes. More than 3 consecutive QRS complexes without P wave and with irregular RR intervals was accepted as PAF. The inter-observer concordance rate for determining AF episodes was 99.7% between two readers. If the device software defined AF or supraventricular arrhythmia these tracings were evaluated visually to confirm the presence of AF episodes.Statistical analysis: All statistical studies were carried out with the program SPPS . Quantitative variables were expressed as the mean value ±SD or median (minimum-maximum), and qualitative variables were expressed as percentages (%). All measurements were evaluated with the Kolmogorov-Smirnov test. A comparison of parametric values between two groups, according to presence of fQRS, was performed using the Mann-Whitney U-test or student t test. The study population was divided into three groups based on fQRS number. Groups 1, 2 and 3 were defined as the presence of fQRS in 0 or 1 lead, in 2 or 3 leads, and in ≥4 leads in electrocardiogram, respectively. A comparison between these groups was performed using Kruskal-Wallis test and if there was significance, a Mann-Whitney U test was used for post hoc analysis. Categorical variables were compared by the likelihood-ratio χ2 test or Fisher’s exact test. two-sided) was considered significant. A backward stepwise multivariate logistic regression analysis which included variables with p < 0.1 was performed to identify independent predictors of AF episodes. Age ≥65, increase left atrium diameter (≥35 mm), increase interventricular septum diameter (≥11 mm), male gender, DM, HT, family history, beta-blocker treatment using and presence of fQRS were entered into the model. A p <0.05  curve values for the presence of fQRS and number of fQRS to detect PAF on HM were 0.704 and 0.797 . PresencThe main finding of our study is that presence of fQRS on 12 lead surfaces ECG is related with presence of PAF episodes in 24 h ambulatory HM. Additionally, increasing number of fQRS leads were also associated with increased presence of PAF episodes. To our knowledge this is the first study that demonstrates the relationship between fQRS and presence of PAF episodes in 24 h ECG monitoring.11 Mean catastrophic consequences of AF is stroke; the risk of stroke is 5 times higher in patient with non valvular AF than the general population.12 Because of these important clinical implications of AF, timely diagnosis and management is mandatory. The problem for diagnosing AF is that, it is not always symptomatic and not always detectable during examination or surface ECG due to its transient episodic nature. To detect PAF extended ECG monitoring is usually needed. Thirty seconds cut off for duration of PAF is used generally since it was first mentioned in the 2006 American Heart Association atrial fibrillation guidelines but this has been questioned nowadays, because it has been suggested that PAF episodes shorter than 30 sec may be indicator of longer episodes.13 These short episodes may become longer and finally may persist over time.14 Additionally, premature atrial contractions (PACs) detected by HM were found to be associated with recurrence of AF.15 In addition to PACs, other silent brief atrial tachyarrhythmias may result in increased stroke risk and finally may convert to clinically certain AF.16 As a consequence, it will not be wrong if we suggest that any brief atrial arrhythmia may predict future AF occurrences. Indeed longer rhythm monitoring showed that substantial proportion of patients, who were initially diagnosed as cryptogenic stroke, have AF episodes.17AF is most common cardiac rhythm disorder and it significantly increases mortality and morbidity.18 In our study we found that fQRS, HT, and DM were independently associated with the presence of PAF. Male predominance was observed in our study but it was not statistically significant. Age is also important for developing AF, although our study included relatively young patients, patient with fQRS were significantly older. LA diameter was found to be associated with AF development.19 In our study, although they were in normal range, LA diameter was significantly higher in patients with fQRS. This finding suggests that fQRS is not only associated with ventricular abnormalities, but it may also be associated with atrial structural abnormalities that need further investigation. Interestingly, others found that fQRS was associated with left ventricular mass index in patients with HT, which may also be associated with LA enlargement and AF development.20 In accordance with this finding IVS diameter was significantly greater in patients with fQRS. Thyroid disorders were also associated with AF, although we excluded the patients with thyroid diseases, TSH levels were higher in patients with fQRS, but this was not significant.There are many causes of AF and it is beyond the scope in this paper to discuss all of them but there are some changes in atrium that cause AF, regardless of the cause. Initially electrical remodeling of atrium occurs and then anatomic remodeling occurs which include; patchy fibrosis, excessive collagen deposition, fatty infiltration and apoptosis, finally resulting in an enlarged atrium.2-5 Main causative mechanisms were explained by myocardial fibrosis that is expressed on the ECG as fQRS.7 Magnetic resonance imaging and myocardial perfusion studies showed the value of fQRS for detecting myocardial fibrosis 7. Except for fibrosis, myocardial ischemia may also cause fQRS due to altered myocardial depolarization of the myocardium8 Thirdly; some recent studies have demonstrated the role of inflammation for fQRS formation.21,22 So explaining the association between ventricular structural abnormalities, ventricular arrhythmias and fQRS is relatively easy. We could explain the association between fQRS and PAF as follows: fibrosis, ischemia, and/or inflammation alters both ventricular systolic and diastolic functions that results in elevated left ventricular end diastolic pressure (LVEDP) and this elevation in LVEDP reflects to the atrium and the atrium tries to adapt new condition and becomes vulnerable to arrhythmias.Many studies have demonstrated a relationship between various cardiovascular diseases and fQRS. The presence of fQRS was found to be associated with adverse cardiac events including; mortality, lethal arrhythmia, sudden cardiac death in these studies.Study limitations: Firstly, this study involves a relatively small number of patients. Secondly, we didn’t evaluate the patients with magnetic resonance imaging (MRI) or myocardial perfusion scintigraphy to detect the myocardial abnormalities attributable to fQRS Thirdly, this is an observational study, further studies are needed to clarify whether the presence of fQRS is associated with clinical consequences of AF.In conclusion; fQRS is a sign of structural (fibrosis) and functional  myocardial abnormality and independently associated with presence of PAF in HM. Presence of fQRS seems to be a useful marker to help decision making for extended rhythm monitoring and managing patients to reduce the AF-related complications.


To evaluate if the combination of several quantitative parameters into a mathematical model would enhance the detection of myocardial ischemia during dobutamine stress echocardiography (DSE) when compared to conventional wall motion analysis.In a prospective study design 151 patients (age 61.8 ± 9.2) in test group and 105 patients (age 64.0 ± 10.6) in validation group were selected and underwent DSE between January 2008 and December 2012. In all patients coronary angiography was performed within 6-8 weeks from DSE, considering at least one stenosis ≥50 % per patient as significant coronary artery disease (CAD). Results of DSE visual assessment and myocardial velocity, strain and strain rate parameters derived from speckle tracking imaging were imported automatically to an originally created software. A mathematical model calculating prognosis of at least one stenosis per patient and stenosis in separate arteries was constructed.Myocardial ischemia was visually detected in 60 (39.7 %) and in 58 (54.2 %) patients of the test and validation group, respectively. A total of 76 (50.3 %) patients in the test group and 69 patients (65.7 %) in the validation group had ≥50 % coronary stenosis. Sensitivity and specificity of the mathematical model per patient in the test group were 91.6 % and 86.3 % compared to 76.8 % and 89.0 % of the visual assessment, respectively. However, in the validation group the sensitivity, specificity, positive predictive value and negative predictive value dropped down significantly becoming lower to visual assessment.Myocardial deformation imaging may potentially replace visual assessment with an automated predictive model for stress-induced ischemia detection. However, a multiparametric mathematical model based on quantitative deformation markers did not demonstrate incremental value to visual assessment of wall motion. Several studies have proposed a number of quantitative parameters vs. visual assessment for ischemia detection during dobutamine stress echocardiography (DSE) –7. Howevn = 35 in the test group and n = 40 in the validation group) or suspected CAD . Patients were included in the study if coronary angiography was performed within 6-8 weeks after DSE. Exclusion criteria were: previous myocardial infarction, previous cardiac surgery, non-sinus rhythm, significant valvular disease, left ventricular hypertrophy [One hundred fifty-one prospectively enrolled consecutive patients in the test group underwent DSE between January 2008 and December 2010 and 105 patients in the validation group underwent DSE between January 2011 and December 2012. Decision for DSE indication was made by consulting cardiologists not involved in the research project, in the course of routine diagnostic workup. DSE was performed for recurrent symptoms in patients with known coronary artery disease (CAD) , and echocardiographic monitoring. When no end point was reached, atropine (up to a maximum of 1 mg) was added to the continuing 40 μg/kg/min dobutamine infusion. Non-echocardiographic diagnostic end-points were the following: peak atropine dose; 85 % of target heart rate; development or deterioration of wall-motion abnormalities, severe chest pain and/or diagnostic ST segment changes. The test was also stopped for one of the following reasons: intolerable symptoms, systolic blood pressure increase to >220 mmHg or hypotension, severe arrhythmias.Transthoracic stress echocardiographic studies were performed with commercially available ultrasound machine  with 1,5 – 4,6 MHz transducer. The long and short axis of the LV from parasternal window, 4- and 2-chamber views from apical window were acquired for comparison in four stages of stress test. Regional wall motion was assessed according to the recommendations of the European Association of Echocardiography dividing LV into 16 myocardial segments. In all studies, segmental wall motion was semiquantitatively graded as follows: normal = 1; hypokinetic, marked reduction of endocardial motion and thickening = 2; akinetic, virtual absence of inward motion and thickening = 3; and dyskinetic, paradoxic wall motion away from the center of the left ventricle in systole = 4. It was considered that in some cases of normal variant basal inferior and basal inferoseptal segments could be scored as hypokinetic. The sum of all segment scores divided by the number of interpretable segments made WMSI. Test positivity was defined as the occurrence of at least one of the following conditions: 1) new dyssynergy in a region with normal resting function ; 2) worsening of a resting dyssynergy .Speckle tracking images (STI) were recorded at baseline and peak dobutamine levels with breath-holding. The frame rate of stored apical 2 and 4-chamber cine-loops for speckle tracking analysis was in the range of 70–90 frames/sec. The loops were stored digitally and analysed off-line using customised software . After manual tracing of endocardium borders in the end-systolic frame of the 2-D images, the software automatically tracked myocardial motion, creating 6 regions of interest in each apical image, with tracking quality labelled as verified or unacceptable. In segments with unacceptable tracking, the observer readjusted the endocardium trace line until a verified tracking was achieved. If this was not attainable, that segment was excluded from analysis. Graphical displays of deformation parameters  were then automatically generated for 6 segments in each view.PSI = peak post-systolic strain - peak systolic strain. Speckle tracking parameters were automatically imported to multiparametric model integrated in local Access DSE database.Peak longitudinal systolic (S’), diastolic  velocities, time to peak systolic velocity, peak longitudinal and radial systolic, post-systolic and maximal strain, peak longitudinal systolic and diastolic strain rate, radial systolic displacement at rest and during stress were measured using automated vendor-suggested software. Maximal strain coincided with systolic or post-systolic strain whichever was found larger. Parameters of 12 myocardial segments (6 in 4-chamber and 6 in 2-chamber views) were manually approved and automatically exported to Excel tables using commercially available software . Post-systolic index (PSI) was defined by formula Coronary angiography was performed in all patients of both groups referred to DSE within 6–8 weeks after dobutamine challenge according to the standard Judkins technique adopting femoral or radial approach with Inova2100 . Clinical decision to perform coronary angiography was made independently of the study by consulting cardiologists, who were aware of DSE test results for conventional wall motion criteria. At least five views  were acquired for the left and at least two orthogonal views for the right coronary artery, respectively. Additional appropriate projections were obtained in case of superimposition of side branches or foreshortening of the segment of interest. Coronary angiographic data were analysed by 2 experts blinded to the clinical data and the results of DSE. Obstructive CAD was defined as a quantitatively assessed coronary stenosis ≥ 50 %.Study variables are presented as mean values ± SD. Interobserver agreement was determined by having two independent investigators measure representative parameters using STI and assess WMSI in 15 randomly selected patients. Intraobserver agreement was determined by having 1 investigator repeat STI measurements and WMSI evaluation in other 15 randomly selected patients 1 month later, while being blinded to the previous measurements. Reproducibility is expressed as the mean percentage difference .a and obtained in the first step, whereas βα0, βα1 denote the estimated model parameters. For a particular value x dependent of parameter a calculated in step 1, we defined new rescaled logistic regression response (step 2).Construction of the underlying statistical model consisted of two steps. The first step was intended for selection of predictive visual assessment and speckle tracking variables. As the amplitude of quantitative covariants depends on the location of the segment in the left ventricle, analysis was performed separately for each segment location. The level of significance was set at 0.05. Simple logistic regression model was fitted for each of the study variable. If a parameter was significant it was included into the set of predictors used in the second step Table . Moreoveφ(y) = ey/(1 + ey). Now for observation number i with particular value of a equal to xi putwith Transformation allows use missing values set as zero, otherwise calculated rescale transformation (positive/negative) is more informative in logistic regression. Multiparametric mathematical model construction steps are shown in Fig. After replacement the data set did not contain missing values and included only those covariants which were selected in the first step. For this full data set stepwise logistic regression was applied. Hence final model could be treated as some kind of voting neural network with unusual fitting method. Described procedure was applied for prognosis of stenosis in separate arteries: left ascending artery (LAD), right coronary artery (RCA), left circumflex artery (LCX) as well as for prognosis of presence of at least one stenosis per patient. Covariants and cutoff included in models are shown in Table “Test group” provided a dataset used for model construction (151 consecutive patients enrolled between January 2008 and December 2010); “validation group” yielded an independent dataset used to estimate how accurately the model will perform in practice (105 consecutive enrolled between January 2011 and December 2012).To make model convenient for practitioners a software was incorporated within an existing Access data collection form. Calculations of sensitivity, specificity and accuracy were performed according to standard definitions. The 95 % CIs were calculated and the individual intervals were compared. Differences were considered significant at the 0.05 level when 95 % CI did not overlap.Clinical and echocardiographic characteristics of the study population are reported in Table After exclusion of poorly visualized segments, the stored data of 1466 (97.1 %) and 1017 (96.9 %) myocardial segments in the test and validation group, respectively, were finally analysed. The prevalence of uninterpretable signals due to inadequate tracking in the segments included in the final analysis was found to be 2.1 % and 2.5 % at rest and 5 % and 5.2 % during stress in the test and validation group, respectively.The mean percentage differences of inter- and intraobserver measurements of velocity, strain, strain rate and WMSI are summarized in Table A total of 76 (50.3 %) patients in the test group and 69 patients (65.7 %) in the validation group had ≥50 % coronary stenosis, see Table Diagnostic performance of models created per patient and per vessel in the test group appeared to be superior to visual assessment Table , 4 and 5This study represents further consecutive step in attempts to implement quantitative tools in the detection of myocardial ischemia during stress echocardiography. It is based on the number of previous investigations showing the significant links of several myocardial motion and deformation markers with induced ischemia –8, 12–15However, in the vast majority of publications the diagnostic accuracy of the quantitative markers is demonstrated to be lower or only comparable to the visual assessment of stress echocardiography , 12–14. Prior research , 4–8 wasTheoretically, such mathematical model could better reflect the complicated nature of the biological phenomenon of regional ischemia and incorporate relevant interdependencies between physiologically different parameters. The feasibility was considered as one of the main requirements to the quantitative tool for routine clinical practice, therefore automatically obtainable data of speckle tracking were chosen for model creation.In parallel with previous studies the set of predictive markers included blunted response of systolic velocity, prolonged time to peak systolic velocity , 12, 14,The constructed mathematical analysis tool represents a kind of machine learning methodology, namely a type of neural network with unusual fitting method. Machine learning technology is currently well suited for analysing medical data, and in particular there is a lot of work done in medical diagnosis in small specialized diagnostic problems –22. ThisFailure of model validation recalls the shortcomings of single quantitative markers, having rather modest predictive ability of significant coronary stenosis (AUCs 0.60-0.72) , 14. LimIn this study coronary angiography was used as the reference method. However, relationship between stenosis severity and physiological reduction of coronary flow is quite variable. Angiographic coronary stenosis does not always reflect the potential alteration in the regional myocardial perfusion.Acquisition of quantitative parameters was based on the commercially available software, therefore relying on implemented methods of noise and artefacts handling. Creating a multiparametric mathematical model, the main challenges remain related to identifying the best methodology for data transformation and critical clinical data. Finally, there is need to understand how to deal with missing data. The study model was constructed on a relatively small data base with possible over fitting.Myocardial deformation imaging provides potential for creation of automated predictive model for stress-induced ischemia detection. However, a multiparametric mathematical model based on quantitative deformation markers did not demonstrate incremental value to visual assessment of wall motion.


The prognostic significance of tricuspid regurgitation (TR) and right ventricular (RV) function in patients undergoing aortic valve replacement (AVR) for severe aortic stenosis (AS) is unknown. The aim of the present study was to evaluate the impact of TR and RV systolic dysfunction on early and late mortality in this setting.This was a prospective single-center observational study. 465 consecutive patients who were referred to AVR for severe AS were investigated. Significant TR was defined as TR≥moderate by transthoracic echocardiography.At baseline, significant TR was present in 26 (5.6%) patients. Patients with TR presented with a higher EuroSCORE I (p = 0.001), a higher incidence of previous cardiac surgery (p<0.001), pulmonary hypertension (p = 0.003), more dilated RVs (p = 0.001), and more frequent RV dysfunction (p = 0.001). Patients were followed for an average of 5.2 (±2.8 SD) years. By multivariable Cox regression analysis TR (p = 0.014), RV dysfunction (p = 0.046), age (p = 0.001) and concomitant coronary artery bypass graft surgery  were independently associated with overall mortality. By Kaplan-Meier analysis, survival rates were significantly worse in patients with significant than with non-significant TR (log rank p = 0.001).TR, RV dysfunction, age, and concomitant CABG are associated with outcome in patients undergoing AVR for severe AS. This finding underlines the importance of a thorough echocardiographic evaluation with particular consideration of the right heart in these patients. The prognostic impact of tricuspid regurgitation (TR) in patients undergoing aortic valve replacement (AVR) for isolated severe aortic stenosis (AS) is unknown. The few existing studies on the prognostic significance of TR in various other disease settings, however, indicate a strong association of TR with clinical outcome . TR is aThe present study evaluated the predictive value of TR and/or RV systolic dysfunction prior to AVR in 465 AS patients.Between January 1998 and January 2005 465 consecutive patients with isolated severe AS necessitating valve replacement who agreed to participate were included in this observational, non-interventional study.Patients who needed emergent surgery and those with moderate and severe mitral regurgitation were excluded. Furthermore, patients who were primarily referred to coronary artery bypass graft (CABG) surgery and additionally received an aortic prosthesis for AS were also excluded.Clinical, echocardiographic, operative and outcome data were prospectively collected in a computerized database.The ethics committee of the Medical University of Vienna approved the present study “Ergebnisse nach Herzklappenoperationen” , including the consent procedure. Verbal informed consent was obtained from the patients for participation in the study and was documented in the medical records.2 in the presence of normal left ventricular function) and presented with symptoms  or with reduced left ventricular function (ejection fraction ≤50%).All patients suffered from severe AS  , PH was RV function was assessed according to recent recommendations by including information on size, visual assessment of contractility, and tricuspid annular plane systolic excursion (TAPSE) . RV dysfStatistical analysis was performed using SAS 9.1 for Windows . Continuous variables were summarized as mean ± standard deviation, median and quartiles; categorical variables were summarized as percentages. Differences in baseline characteristics, echocardiographic, and operative data between patients with or without significant TR were assessed using a t-test for continuous data and a chi-squared test for categorical data.Kaplan-Meier estimates were used to calculate 1, 3, 5, and 7-year survival rates. Differences in these and all other tests were considered significant at p <0.05.To determine influence factors on overall mortality, univariate Cox regression models for each influence variable were performed. Additionally, multiple stepwise Cox regression analyses were performed accounting for all variables being significant (p<0.05) in the univariate analyses. Similar analysis was performed for operative mortality, using logistic regression models instead of Cox regression models.The following influence factors were assessed: Age, body surface area, enddiastolic diameter of left and RV (continuous variables); NYHA and CCS functional class, additive EuroSCORE I ; gender, PH, significant TR, renal failure, concomitant CABG, extracardiac arteriopathy, chronic obstructive pulmonary disease, diabetes mellitus, coronary artery disease, left ventricular ejection fraction ≤50%, previous cardiac surgery and RV dysfunction (factor variables).To validate the influence factors found by the statistical analysis described above, we additionally performed variable selection for the final model using bootstrap methods. For each of 5000 bootstrap samples we calculated univariable and corresponding multivariable regression models with stepwise selection . The final model was then performed with the influence factors being selected with the multivariable model in more than 60% of the bootstrap samples.Patients with significant TR were more often female (p = 0.034), presented with a higher additive EuroSCORE (p = 0.001), a higher incidence of previous cardiac surgery (p<0.001), and previous valve surgery (p = 0.003), and a higher frequency of PH (p = 0.003). Only 12 patients in the cohort carried implanted pacemakers prior to surgery, three of them among patients with significant TR.Baseline echocardiographic data are shown in Left atrial size, reflecting left ventricular filling pressure, was significantly correlated with peak TR velocity, .Operative data are displayed in 28 short-term deaths (6.0%) were observed. Causes of deaths are shown in The variables found to be associated with short-term mortality in the univariable analysis were age (p = 0.005), body surface area (p = 0.007), EuroSCORE (p<0.001), significant TR (p = 0.007), concomitant CABG (p = 0.001), coronary artery disease (p = 0.002) and previous cardiac surgery (p<0.001). In the multivariable model, only EuroSCORE (p = 0.007), CABG (p = 0.002) and previous cardiac surgery (p = 0.009) remained significant predictors of short-term mortality. However, using variable selection by the bootstrap method, only the result for previous cardiac surgery (p<0.001) was approved.Follow-up was complete in 99.8% of patients. Patients were followed for an average of 5.2 (SD ±2.8) years. 108 late deaths were observed. Late mortality was not significantly different between patients with and without significant TR pre-operatively , body surface area (p = 0.006), preoperative NYHA functional class (p = 0.048), EuroSCORE (p<0.001), PH (p = 0.009), significant TR (p = 0.001), RV dysfunction (p = 0.015), CABG (p = 0.001), diabetes (p = 0.010), coronary artery disease (p = 0.002), and previous cardiac surgery (p = 0.017).By multiple Cox regression analysis, only age (p = 0.001), CABG (p = 0.003), significant TR (p = 0.014), and RV dysfunction (p = 0.046) remained significant predictors of overall mortality. The results of the multivariate analysis are shown in Using bootstrap methods for variable selection approved the influence of significant TR (p = 0.007) and CABG (p = 0.006) on overall mortality, which were also identified by the conventional statistical analysis described above. Neither age, nor previous cardiac surgery or RV dysfunction were selected for the final model.Symptoms and functional status at last follow-up were significantly worse in patients with significant pre-operative TR .We studied a cohort of 465 consecutive patients who underwent AVR for severe AS. Significant TR and RV dysfunction pre-operatively were both found to be independently associated with overall outcome. This novel observation provides important additional information for the risk assessment of the growing AS patient population.Existing evidence suggests that TR is not a benign disorder and carries a considerable impact on morbidity and mortality . TR has The present study is dedicated to the prognostic impact of significant pre-operative TR in patients undergoing AVR for isolated severe AS, which has not been assessed so far. The development of TR in this setting is the consequence of a pathogenetic process involving the left ventricle, the pulmonary vascular bed, and finally the RV. Due to the outflow obstruction, left ventricular filling pressures rise and cause a subsequent increase of left atrial and capillary wedge pressures. Pulmonary vascular compliance declines and adds to the increasing resistance against the RV, causing an increase in RV end-diastolic pressure. Two additional mechanisms may aggravate RV pressure overload: diffuse fibrosis / extracellular matrix expansion of the left ventricular myocardium , leThe RV eventually fails to compensate the pressure overload and dilates. Tricuspid annular dilatation finally leads to the development of TR . The occRV dysfunction was independently associated with mortality in the Cox regression model. However, after bootstrap analysis, significant TR was the most robust parameter associated with adverse outcome. Our data suggest that TR is an indicator of RV uncoupling from its afterload consisting of left ventricular filling resistance, pulmonary vascular resistance and compliance. Bearing in mind this pathophysiologic cascade, TR stands at the end of a disease process, which in its course includes the progression of myocardial fibrosis and stiffness, both found to impact on mortality and morbidity in AS , 16.It has previously been shown that PH in isolated AS is related to elevated left ventricular end-diastolic pressures . Data onOur own data indicate no independent influence of PH as determined by echocardiography on short- or long-term mortality. TR and RV dysfunction on the contrary, were significantly associated with outcome in the multivariable analysis. One explanation for this observation might be the imprecision of Doppler echocardiography as described by Fisher et al . InaccurHowever, while the estimation of pulmonary artery pressures by echo may be imprecise, the detection of more than mild TR should be more reliable. As TR indicates not only a rise of the pulmonary artery pressure but also a change of RV geometry, it may be a sign of incipient RV failure.Whether patients with significant TR may also benefit from a surgical correction of TR at the time of AVR is unclear, longitudinal data will be necessary to clarify this question.Our data have been collected in a single center, therefore a center-specific bias cannot be excluded. On the other hand, major advantages of limiting data collection to a single center are: inclusion of a homogenous patient population, adherence to a constant clinical routine, constant quality of echocardiographic work-up, and constant surgical quality over a time-period of 11 years.In patients with severe AS, left ventricular longitudinal function is often impaired despite normal ejection fraction and this dysfunction has prognostic value . The preQuantification of TR was performed by both qualitative and semi-quantitative measurements. Nevertheless, exact quantification may be demanding. To account for potential inaccuracy TR severity was divided into significant and non-significant TR for further analysis.This approach has previously been deemed reasonable , 3, 5, 9Furthermore, only 0.7% of patients underwent concomitant tricuspid valve surgery. In the absence of a clear recommendation concerning tricuspid valve repair in patients undergoing aortic valve surgery in the 2006 AHA guidelines , tricuspSignificant TR is associated with outcome in patients undergoing AVR for severe AS, in addition to RVD, age, and CABG. This finding underlines the importance of a thorough echocardiographic evaluation with particular consideration of the right heart in these patients.S1 STROBE ChecklistAll applicable points have been addressed.(DOC)Click here for additional data file.


Life-threatening ventricular arrhythmias (VA) are a major cause of death in patients with cardiomyopathy. To date, impaired left ventricular ejection fraction remains the primary criterion for implantable cardioverter-defibrillator therapy to prevent sudden cardiac death. In recent years, however, advanced imaging techniques such as nuclear imaging, cardiac magnetic resonance imaging, and computed tomography have allowed for a more detailed evaluation of the underlying substrate of VA. These imaging modalities have emerged as a promising approach to assess the risk of sudden cardiac death. In addition, non-invasive identification of the critical sites of arrhythmias may guide ablation therapy. Typical anatomical substrates that can be evaluated by multiple advanced imaging techniques include perfusion abnormalities, scar and its border zone, and sympathetic denervation. Understanding the principles and techniques of different imaging modalities is essential to gain more insight in their role in identifying the arrhythmic substrate. The current review describes the principles of currently available imaging techniques to identify the substrate of VA. Sudden cardiac death (SCD) is a major health problem as it accounts for half of total cardiac mortality with an annual incidence of approximately 100 per 100.000 in the general population.The pathophysiology of VA is complex and multifactorial. Traditionally, they are believed to be the result of a complex interplay between an anatomical substrate and transient triggers leading to electrical instability including increased automaticity, triggered activity, and re-entry.37Nuclear imaging provides the unique ability to target different pathophysiological aspects of the arrhythmic substrate, depending on the biological pathway of the utilized tracer. Consequently, nuclear techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) allow the evaluation of perfusion, scar, metabolism, and sympathetic innervation Figure . Aspects201TI, [99mTc]tetrofosmin, and [99mTc]sestamibi. Based on relative tracer uptake in the myocardium during resting conditions and exercise or pharmacologically induced stress, information is obtained on the size of resting perfusion defects (reflecting scar or hibernating myocardium), stress perfusion defects , and their reversibility (reflecting ischemia).201TI SPECT to identify voltage-defined scar, border zone, and normal myocardium during electroanatomic mapping in order to guide VT ablations. It was demonstrated that impairment of 201TI uptake could accurately predict endocardial voltage-defined scar, which was the site of successful ablation in all patients  after comparing with template scans of healthy control patients. Interestingly, SPECT assessed border zone was shown to be significantly larger in patients who showed inducible sustained VA during an electrophysiological study as compared with non-inducible patients. The study, however, did not assess the site of origin of the induced VAs.To date, the most widely used nuclear imaging technique to evaluate the extent and location of myocardial perfusion abnormalities is SPECT. Frequently used SPECT tracers in clinical practice include s Figure . Most cr201TI SPECT, in particular within the infarct area. No differences in fixed perfusion defects were observed, suggesting that residual ischemia might lead to additional vulnerability to VA.Residual ischemia after myocardial infarction may contribute to the electrical instability of the myocardium. This was revealed in a study by Paganelli et al15O]H2O, [13N]NH3, and 82Rb have a higher extraction fraction and short physical half-life.−1·g−1. Of the available PET tracers, [15O]H2O is considered the most ideal tracer for flow quantification as it is freely diffusible and metabolically inert with an extraction of 100% from arterial blood, whereas 82Rb and [13N]NH3 are actively transported across the cell membrane with incomplete extraction and subsequently are metabolically trapped.15O]H2O PET quantifies MBF in viable tissue which is capable of exchanging water rapidly.15O]H2O PET were significantly related with VA inducibility during an electrophysiological study in 30 patients with ischemic cardiomyopathy who were referred for ICD implantation . Furthermore, commonly used PET perfusion tracers such as [n Figure .28 These18F]fluorodeoxyglucose (FDG) PET in clinical practice. [18F]FDG is a glucose analogue which is taken up into the cardiomyocytes by glucose transporters and subsequently become trapped after being metabolized. Preserved [18F]FDG uptake is considered a highly reliable marker for viable myocardium in patients with ischemic heart disease whereas severely reduced [18F]FDG uptake indicates non-viable scar tissue.18F]FDG PET is well validated18F]FDG PET/CT fusion imaging could be integrated into clinical mapping system to visualize the 3D arrhythmogenic substrate in patients who were referred for VT ablation. A cut-off value of <50% [18F]FDG activity predicted voltage defined myocardial scar with a sensitivity and specificity of 89 and 93%, respectively, whereas voltage defined infarct borderzone contained a mean metabolic activity of 67±15%. These results imply that scar evaluation with [18F]FDG PET is able to identify critical arrhythmogenic substrates and may assist VT ablation therapies.56Nuclear metabolic imaging to evaluate myocardial viability is commonly assessed using [18F]FDG uptake and perfusion), hibernation (enhanced [18F]FDG uptake but impaired perfusion), and normal viable myocardium (preserved [18F]FDG and perfusion). The detection of increased uptake in hibernating myocardium is based on a metabolic shift from fatty acid to glucose consumption as the myocytes are hypoperfused and become dependent on anaerobic metabolism.63When combined with perfusion imaging, viable myocardium can be further differentiated into the presence of subendocardial scar (mildly reduced [123I]metaiodobenzylguanide (MIBG) for SPECT and [11C]hydroxyephedrine (HED) for PET. Both tracers are resistant to metabolic enzymes and show high affinity for presynaptic NE uptake-1 allowing the visualization of presynaptic sympathetic nerve function.11C]epinephrine, [11C]phenylephrine, and 18F-LMI1195 while [11C]-CGP12177 is the most commonly used tracer for postsynaptic beta-adrenergic receptors.69Targeting the cardiac sympathetic innervation using nuclear imaging has become an emerging approach to visualize the VA substrate. As discussed, the sympathetic nervous system may give rise to VA in several pathophysiological pathways including increased global sympathetic activity and regional cardiac sympathetic denervation resulting from ischemia, hibernation, or infarction.123I]MIBG SPECT typically includes the assessment of early and delayed planar as well as tomographic images at 15-30 minutes and 3-4 hours after tracer injection, respectively. In planar images, global myocardial uptake is evaluated by calculating the heart to mediastinum (H/M) uptake ratio. Furthermore, [123I]MIBG washout rate (WR) is defined as the difference between the early and delayed H/M ratios and primarily reflects presynaptic NE turnover, a marker for sympathetic activity  of [11C]HED, Harms et al recently demonstrated the feasibility of assessing perfusion and innervation defects to evaluate mismatch areas using a single dynamic [11C]HED PET scan.11C]HED uptake including prolonged refractoriness and supersensitivity to catecholamines.11C]epinephrine and [13N]NH3 PET was associated with inducible VTs in a porcine model. Importantly, the area of denervated but viable myocardium was related to the site of initiation of the induced VTs as well as decreased endocardial voltage obtained by voltage mapping , visible as bright areas when compared to the normal remote myocardium on the T1-weighted images.Several limitations of LGE-CMR should be acknowledged. First, standardization of imaging protocols and analyses is lacking as different SI thresholds are used for scar and border zone definitions. Second, LGE is based on relative differences in SI between fibrotic tissue and supposedly normal myocardium. Consequently, LGE is only able to detect focal areas of fibrotic tissue, whereas diffuse interstitial fibrosis cannot be identified. The occurrence of diffuse interstitial fibrosis, however, is not an infrequent pathological phenomenon in cardiomyopathy, not merely in nonischemic etiologies, but also in ‘remote’ areas of ischemic cardiomyopathy.111Contrast enhanced CT is an alternative modality for scar evaluation with high spatial and temporal resolution. Comparable to LGE-CMR, late enhancement CT can be acquired approximately 10 minutes after contrast injection with a standard single-energy or dual-energy cardiac CT. Both have been demonstrated to correlate well with LGE-CMR assessed scar as well as histopathologic findingsAdvanced non-invasive imaging techniques such as nuclear imaging, CMR, and CT have emerged during the past decades to evaluate multiple aspects of the substrate of VA. Typical imaging targets include myocardial perfusion abnormalities, hibernation, scar, scar border zone, and sympathetic innervation. Their role in identifying the origin of VA has been shown in multiple studies suggesting significant value in diagnosis and risk assessment of VA, and a potential role in guiding ablation strategies. For detecting perfusion abnormalities, most experience has been gained using SPECT and PET, whereas LGE-CMR is the preferred modality for scar and border zone evaluation. More biological aspects of the arrhythmic substrate such as metabolism and sympathetic nerve function are well performed using PET. As targets of multiple imaging modalities may be intertwined, studies are warranted that compare imaging parameters of the arrhythmic substrate obtained by different modalities to define the preferred method to identify the substrate of VA.