Parameters of involved muscles showed no different from those of NAEOMs excluding 25th, 50th percentiles, and standard deviation (SD) (p < 0.05). NAEOMs displayed higher values of 90th, 95th percentiles, SD, skewness, inhomogeneity, and entropy than HCs (p < 0.05). ROC curve analysis of entropy yielded the best area under the ROC curve  for differentiating NAEOMs and HCs. After treatment, histogram parameters including 5th, 75th, 90th, and 95th percentiles, SD, kurtosis, inhomogeneity, and entropy were reduced in NAEOMs (p < 0.05). T2 histogram analysis could detect early involvement of EOMs in TAO prior to detection on conventional orbital MRI.Using histogram analysis of T2 values to detect early involvement of extraocular muscles (EOMs) in patients with thyroid-associated ophthalmopathy (TAO). Five EOMs of each orbit were analyzed for 45 TAO patients and 22 healthy controls (HCs). Patients’ EOMs were grouped into involved or normal-appearing EOMs (NAEOMs). Histogram parameters and signal intensity ratios (SIRs) of EOMs were compared; receiver operating characteristic (ROC) curve analysis was performed to differentiate NAEOMs from EOMs of HCs. 24 patients were reassessed following immunosuppressive treatment. For SIRs, involved muscles showed higher values than those of NAEOMs and HCs ( The current evaluation system is primarily based on the anterior visible part of the orbit and ignores deep structures, such as the extraocular muscle (EOM)2. EOM is one of the target organs of immune attack in TAO, its enlargement can produce severe complications3. As early as 19794, researchers found that approximately 70% of patients with Graves’ disease, who commonly characterized by subclinical ophthalmopathy, can present with EOM enlargement on computed tomography (CT) or magnetic resonance imaging (MRI). Therefore, the involvement of EOM may begin much earlier than is currently clinically recognized; the ophthalmic signs or symptoms-based evaluation system may be inaccurate, thus, lead to untimely and inappropriate treatment.Thyroid-associated ophthalmopathy (TAO) is an autoimmune disease characterized by orbital tissue inflammation, expansion, fatty infiltration and fibrosis5. However, most of the MRI methods are either semi-quantitative or based on signal intensity, which are not typically directly proportional to specific tissue properties. Additionally, these techniques mainly quantify disease activity, severity or therapy response; there is minimal attention to detection of the early involvement of EOMs. Politi et al.2 and Kilicarslan et al.6 suggested that diffusion-weighted imaging (DWI) could detect early asymptomatic involvement of EOMs prior to abnormality on conventional orbital MRI. However, DWI exhibits some inherent limitations in orbital imaging, particularly in terms of susceptibility to artifacts and signal loss7.Multimodality orbital , for its excellent soft tissue contrast, is viewed as an objective and sensitive tool to assess the EOMs from anatomy to tissue components in TAO8 and effectively characterize subtle changes from disease process or therapy before they manifest as signal abnormalities10 However, T2 values are frequently obtained from manually traced regions of interest (ROIs) on a single slice11, rather than integral muscle, resulting in measurement sampling errors and subjective bias. Recently, application of T2 for TAO have been reported10, but they also focused on staging and activity and have not yet been used to identify early involvement of EOM, and the information typically provided by mean T2 is rather limited. Volumetric histogram analysis of T2, measure the variations and frequencies of T2 values within whole tissues, can provide comprehensive and informative T2 parameters, is expected to potentially detect early EOM involvement even when there are no changes on conventional images.T2 mapping was considered as a tissue-specific technique can reflect biochemical components within EOMsBased on previous reports and on our own clinical observations, we developed the hypothesis that all EOMs of TAO patients may experience immune damage during early disease stage. Therefore, we aimed to detect this early involvement using volumetric T2 histogram analysis.In this study, 383/450 EOMs of untreated TAO patients were designated as the “involved muscle group” (n = 383) and 67/450 were designated as the “normal-appearing muscle group (NAEOMs)” (n = 67) by assessment of muscle involvement on conventional T2WI images. In addition, 220 EOMs of healthy controls (HCs) were included. In total, 191/240 involved EOMs and 49/240 NAEOMs of 24 patients who received treatment were also compared following therapy.Overall, the inter-observer agreement between the two readers was good to excellent for SIRs and volumetric T2RT histogram parameters (Table p < 0.001), and between involved and NAEOMs (p = 0.04). There was no statistical difference between NAEOMs and HCs (p = 0.21) . Heterogeneous metrics, in addition to the 5th and higher  percentiles of T2 of NAEOMs showed marked reductions after therapy  elevated percentiles and increased heterogeneous distribution of T2 can occur in all EOMs of TAO patients, including involved or NAEOMs on conventional MRI; (2) the NAEOMs exhibited similar changes in percentiles and non-uniform T2 distribution in comparison to involved muscles; (3) NAEOMs showed much higher values in 90th and 95th percentiles T2 than those of HCs.13 and pelvic limb muscles14. Ishu et al.9, demonstrated that the lower leg muscles of boys with Duchenne muscular dystrophy exhibited elevated percentiles and heterogeneities on T2-mapping histogram analysis. Inflammation, fatty degeneration and fibrosis were main pathological changes of EOMs in patients with TAO, there is no absolute boundary between the fatty infiltration and edematous, and both of them can lead to increased T2 values15. Heterogeneous expression at the cellular and molecular levels, including fibroblast phenotypes, cytokine profiles, and disparate T cell subsets16, may produce the asynchronous and non-uniform pathological changes in each EOM within the same orbit, thus the microstructural component distribution within each EOM may be uneven. The varying deposition of macromolecules , interstitial edema, and fibrous scar tissue and fatty infiltration within the involved muscles can result in greater distribution of T2 values18. Factually, uneven distribution of pathological components in EOMs in patients with TAO has been reported by Yokoyama et al.19 and it was observed to have correlation with the therapeutic response to corticoid treatment. However, the uniformity in Yokoyama’s report was based on visual observation of T2 signal intensity of EOMs on conventional MRI; notably, T2 SI is variable and does not directly reflect tissue properties, such as density or molecular composition.We found that the involved EOMs exhibited overt increase in point-specific parameters (excluding the 5th percentile) and more inhomogeneous distribution of the T2 than EOMs of HCs. Histogram features provide novel quantifications of the intrinsic distributions of different tissues, such as percentiles providing a greater range of T2 values to reveal complex tissues; these have been widely used to quantify the T2 distribution in muscles such as myocardium6, who observed changes in diffusion values but without significant differences. We speculate the changes in NAEOMs are from the following factors: (1) previous T2 studies on EOMs in TAO primarily focused on altered T2, averaged over one or several image slices20, which may harbor or mask small pathological changes. These subtle pathologies could be diffusely or focally distributed throughout the EOM, such that they could not be captured by conventional MRI. Histogram-derived percentile parameters, in which the T2 values were arranged from small to large, may enable distinction of subtle differences. (2) Lower percentiles of T2 represent authentically normal muscle area, while the mean and higher percentiles  of T2 may represent abnormal voxels. In NAEOMs, large amounts of normal voxels masked tiny amounts of abnormality; consequently, only very high percentiles of T2 reflecting extremely abnormal voxels could detect this subtle modification. (3) Secondary to long-standing systemic immunoreactions, NAEOMs also experience lymphocyte infiltration and accumulation of granular material. These microstructural changes precede functional, morphological, and signal changes, which may be a hallmark of early muscle involvement and are difficult to discern by conventional means.Interestingly, the NAEOMs exhibited larger values in both inhomogeneity metrics and higher percentiles (90th and 95th) of T2 values, relative to those of HCs. However, no differences were observed in the SIR, mean, and lower percentiles of T2. Our findings regarding the early involvement are similar to, but more obvious than, those reported by Kilicarslan et al.Notably, overtly involved muscles displayed higher 25th and 50th percentiles, compared to those of NAEOMs. This is potentially because both 25th and 50th percentiles were located in borderline areas between minimal abnormality and disease. Most of the distribution shape-related scalars of NAEOMs (with the exception of SD and inhomogeneity) displayed no obvious differences from those of involved muscles. These results further supported the immunologic injury in NAEOMs.mean value had lower AUC when compared to the higher T2 percentiles and entropy. It demonstrated that conventional MRI features and commonly used T2 may have some limitations in detecting the early changes of EOMs in TAO. The entropy refers to irregularity of gray-level distribution, higher entropy reflects greater complexity of specific tissue21 and indicates the diversity tissue component. This finding suggest that the quantification of macromolecules can be used as a direct imaging marker of early involvement.In our present findings, the entropy had the best diagnostic performance among the T2 histogram parameters and SIRs. Both the SIRs on conventional MRI and the usually used T2In this study, in patients who displayed clinical amelioration, apart histogram parameters for involved EOMs changed. The 5th and higher  percentiles of T2 and all uniformity-related parameters of NAEOMs decreased markedly after therapy. Therapy-induced modifications of NAEOMs indirectly demonstrated that they exhibited some pathology.Our results are consistent with the immunological nature of TAO: when immune activity is triggered, all EOMs experience varying degrees of immune reactions. EOM damage begins much early prior to the onset of overt clinical signs and symptoms, as well as before detection on routine orbital MRI; thus, comprehensive and meticulous evaluations should be performed to detect such changes. This rationale explains the phenomenon we frequently encountered in clinical practice: many patients who initially manifested with mild involvement in some EOMs, which quickly progressed to severe ophthalmopathy and involved all EOMs. It can also partially explain why local therapy is less effective than systemic intravenous injection, even in TAO patients with isolated muscle involvement. Thus, our results may promote recognition of the traditional definition of “non-involvement” based on clinical assessment, gross morphology or signal intensity on conventional MRI. The histogram parameters of T2 may offer an data-based evidence to facilitate improved clinical treatment of TAO.This study had some limitations. First, it did not include a “gold standard,” such as histological or immunohistological analyses, which could have verified the microscopic alterations behind the image analysis. Notably, this verification may be conducted in appropriate animal models. Second, the neuroradiologists were aware of the subjects’ conditions when identifying muscle involvement on conventional T2WI images; they assumed that the EOMs of HCs were normal and did not assess their involvement. Third, the T2 mapping technique were performed without fat suppression, and we cannot really distinguish the altered value were from fat or edemas, but both of them were pathology changes in TAO. Fourth, the T2 values calculated in this research still failed to overcome the inherent drawbacks that the contamination from stimulated and indirect echoes, which thus give rise to deviated and inaccurate T2 values. Finally, the sample size of NAEOMs was limited, and patients were not classified into subgroup according to varying activity, which may have reduced the statistical power of the study.The combination of histogram analysis and T2-mapping imaging can detect early pathology in EOMs without obvious involvement on conventional orbital MRI. This multiparametric approach may provide a breakthrough for exploring early injuries in EOMs for patients with TAO. Early intervention may be started in patients with highly abnormal histogram parameters regardless of the CAS score and when there is no evidence of EOM involvement on conventional imaging. This information may aid in the management of TAO.This retrospective study was approved by the institutional review board of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Written informed consent was obtained from all patients for MRI scanning, but the written informed consent of the data usage for this research was waived as the MRI protocol is conventional in our hospital and this is a retrospective study.22. Patients were enrolled if they met the following criteria: (1) initially diagnosed with active moderate-severe TAO; (2) showed no other accompanying orbital disease; (3) had no prior orbital therapy or surgery; (4) successfully completed MRI examinations.Between May 2017 and Apr 2018, TAO patients and healthy controls (HCs) were recruited. An endocrinologist and an ophthalmologist jointly diagnosed the TAO according to the consensus of the European Group on Graves' OrbitopathyFinally, 45 active moderate-severe TAO patients  met the inclusion criteria. In addition, 22 HCs  were included; they were euthyroid healthy volunteers without any ocular symptoms or signs of exophthalmos .24 patients who completed therapy and exhibited a favorable therapeutic response were further assessed. And all of them were received the standard therapy regimen which were recommended by 2016 EUGOGO guidelines: intravenous methylprednisolone (Pfizer Manufacturing Belgium NV) 0.5 g per week for 6 weeks, followed by 0.25 g per week for 6 weeks. The total therapy course lasted for 12 weeks.Orbital MRI was performed 1 week before the initial treatment for patients. Patients who underwent therapy were re-scanned within 2 weeks after the completion of therapy. All MRI scans were performed on a 3T MRI scanner  with a 32-channel head coil. Subjects were asked to keep their eyes closed during scanning, to facilitate the subjects to keep the eye closed, some auxiliary does not interfere with magnetic fields were covered on their eyes.The MRI protocol was as follows: (1) axial T2WI ; (2) coronal T2-IDEAL . (3) coronal T2-mapping with eight consecutive echoes  and the following parameters: TR, 2000 ms; section thickness of 3 mm, gap of 0.6 mm; FOV, 180 × 180 mm; matrix, 256 × 256; and bandwidth, 15.63 kHz/pix. Acquisition time for T2-mapping was approximately 6 min 24 s.The axial T2WI images were traditional orbital images to exclude other obvious ocular disease. The T2-IDEAL technique was utilized to observe morphological changes and assess SIRs. The coronal T2-mapping sequence was employed to assess T2 values.The following image analyses were performed by two experienced neuroradiologists with more than 7 years of experience. The neuroradiologists were blinded to the clinical data and subjects’ conditions (patients or HCs), although the images may have suggested some characteristics of the subjects.(1) Signal intensity measurements24, on a GE AW 4.6 workstation . The neuroradiologists manually outlined the ROIs of five EOMs  for each orbit. They delineated the muscles on the slice with the most prominent signal intensity alterations on water images of the coronal T2-IDEAL sequence. Because separation of the superior rectus and levator palpebrae superioris is difficult, these muscles were sketched together as the superior muscle group  Volumetric T2 histogram analysisMRI data for the T2 maps were digitally transferred to a personal computer and processed with custom-developed software . Post-processing was conducted using the monoexponential T2-mapping fitting model.All ROIs of EOMs were traced by the two neuroradiologists. The ROIs were manually drawn on all contiguous slices  along the edge of the EOMs to encompass the whole muscle. The neuroradiologists were careful to mitigate partial volume effects from orbital fat and air-filling in the paranasal sinuses Fig. b.25, including (1) point-specific parameters, which directly mirrored the T2 values: mean  and other cumulative T2 histograms: lower percentiles  , higher percentiles , where the nth percentile was the point at which n percent of voxel values were situated on the left area of the histogram27; and (2) histogram shape-related parameters, which indirectly reflected the heterogeneous distribution of T2: (a) standard deviation ; (b) skewness (reflecting asymmetry of the histogram distributions); (c) kurtosis (representing the peaked nature of the histogram); (d) entropy (describing irregularity or complexity of the distribution of a parameter of interest); and (e) inhomogeneity .Based on histogram analysis of the ROIs, T2 histograms and a variety of parameters were generated through combined analysis by Fire Voxel and SPSS software . These parameters were divided into two categoriesEOMs were divided into involved or normal-appearing in a binary manner. Involvement was visually evaluated as the presence of swelling and brightness signal intensity  on T2-IDEAL imaging. EOMs without these manifestations were designated as normal-appearing extraocular muscles (NAEOMs). The two neuroradiologists determined muscle involvement for TAO patients, but not for HCs. Disagreements regarding classification were resolved by a third neuroradiologist with 15 years of experience. The SIR and T2 parameters were classified based on the involvement evaluation.Data are expressed as the mean ± SD. A significance level of P < 0.05 was considered statistically significant. All statistical analyses were performed using the SPSS statistical software package.t-tests or paired Wilcoxon signed-rank tests were conducted to investigate changes in histogram parameters and SIRs of EOMs in patients who achieved good therapeutic responses.Interobserver agreement for histogram parameters and SIRs was assessed using the intraclass correlation coefficient. The Kolmogorov–Smirnov test was used to assess the normality of continuous variables with regard to the SIRs and histogram parameters. Based on the results of the Kolmogorov–Smirnov test, comparisons among the three groups were performed using the ANOVA or independent-samples Kruskal–Wallis test. Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic performance of the SIRs and T2RT histogram parameters to differentiate the really normal EOMs and the early involved EOMs (that is NAEOMs). Paired This study was approved by the Institutional Review Board (IRB) of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, and we pledged to abide by the declaration of Helsinki (2000 EDITION) in accordance with the relevant medical research rules of China in the study. Written informed consent was obtained from all patients for MRI scanning, but the written informed consent of the data usage for this research was waived as the MRI protocol is conventional in our hospital and this is a retrospective study. All patient-sensitive information was kept with confidentiality and used only for the purpose of the study.All procedures performed in the studies involving human participants were in accordance with the ethical standards of our institutional review board and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.Written informed was accepted from all patient.


Background and Objectives: This study evaluated the clinical characteristics of the acute coronary syndromes (ACS) in chronic kidney disease (CKD) patients and established prognostic values of the biomarkers and echocardiography. Materials and Methods: 273 patients admitted to the cardiology department of the Clinical County Emergency Hospital of Oradea, Romania, with ACS diagnosis were studied. Two study groups were formed according to the presence of CKD (137 patients with ACS + CKD and 136 with ACS without CKD). Kidney Disease: Improving Global Outcomes (KDIGO) threshold was used to assess the stages of CKD. Results: Data regarding the medical history, laboratory findings, biomarkers, echocardiography, and coronary angiography were analysed for both groups. ACS parameters were represented by ST-segment elevation myocardial infarction (STEMI), which revealed a greater incidence in subjects without CKD (43.88%); non-ST-segment elevation myocardial infarction (NSTEMI), characteristic for the CKD group ; unstable angina and myocardial infarction with nonobstructive coronary arteries (MINOCA). Diabetes mellitus, chronic heart failure, previous stroke, and chronic coronary syndrome were more prevalent in the ACS + CKD group . N-terminal pro b-type natriuretic peptide (NT-proBNP) was statistically higher (p < 0.01) in patients with CKD; Killip class 3 was evidenced more frequently in the same group (p < 0.01). Single-vessel coronary artery disease (CAD) was statistically more frequent in the ACS without CKD group  and three-vessel CAD or left main coronary artery disease (LMCA) were found more often in the ACS + CKD group . Conclusions: Extension of the CAD in CKD subjects revealed an increased prevalence of the proximal CAD, and the involvement of various coronary arteries is characteristic in these patients. Biomarkers and echocardiographic elements can outline the evolution and outcomes of ACS in CKD patients. The risk of coronary artery disease (CAD) in patients with chronic kidney disease (CKD) is comparable with the risk of CAD in patients with traditional risk factors. The association of the classic cardiovascular risk factor and the specific uraemia-related risk factors accelerates the atherosclerosis process, explaining the increased incidence of the major adverse cardiac events (which is the main cause of death in CKD subjects) ,2. Non-tAcute coronary syndromes (ACS) encompass non-ST-segment elevation myocardial infarction (NSTEMI), unstable angina, ST-segment elevation myocardial infarction (STEMI), and myocardial infarction with nonobstructive coronary arteries (MINOCA) . In CKD The impaired renal function interferes with the excretion of the cardiac necrosis biomarkers—the cardiac troponins (cTn), making the diagnosis of the ACS challenging. Myocardial infarction is defined as elevation of the cardiac necrosis biomarkers above the 99th percentile myocardial infarction of the healthy reference population, corroborated with specific chest pain and electrocardiographic signs of cardiac ischemia . GuideliAn important aspect, the renal nihilism, illustrates a predisposition for choosing medical management in subjects with impaired kidney function instead of the interventional or surgical myocardial revascularization. The outcome of the ACS in CKD subjects is negatively influenced by the mentioned therapeutic attitude and the underuse of appropriate doses of antiplatelet therapy or thrombolytic therapy explaining the increased rate of these patients’ cardiovascular mortality . The treThe coronary angiography followed by either PCI or coronary artery bypass grafting (CABG) should represent the treatment of choice in ACS irrespective of the CKD stage. A study that consisted in a five-year follow-up of the patients from the Syntax trial revealed the fact that patients with CKD undergoing PCI have a higher rate of negative outcome than subjects with impaired renal function undergoing CABG, especially in the subgroup of subjects with diabetes mellitus and extensive CAD .The present study aimed to evaluate the clinical features of ACS in patients with CKD in north-western Romania and to highlight the evolutionary particularities of these patients, in order to establish an optimal case management in the emergency department. Predictors of unfavourable evolution were also relevant, in order to apply an immediate myocardial revascularization even in the case of those diagnosed with NSTEMI.A prospective study was performed, including 273 patients admitted with the diagnosis of ACS in the Cardiology department of the Clinical County Emergency Hospital of Oradea, Oradea, Romania, between 1 July 2018 and 1 September 2019. Inclusion criteria were as follows: new evidences of myocardial ischemia on the electrocardiography (ECG), with or without elevation of the myocardial necrosis enzymes as high-sensitivity troponins (hs-cTn); presence of typical angina or dyspnoea that could be interpreted as an angina-equivalent or asymptomatic cases with signs of myocardial ischemia; normal or decreased glomerular filtration rate (GFR). Exclusion criteria were represented by previous ECG changes consistent with myocardial ischemia without new signs of acute coronary disease; myocardial injury described as nonspecific elevation of cardiac necrosis enzymes in other conditions (like sepsis); advanced heart failure, chronic kidney disease, cerebrovascular accidents, myocardial trauma, or decreased value of the GFR due to dehydration and no other signs of kidney function alterations .The study lot was divided into two groups depending on the presence of normal kidney function: the reference group was represented by 137 subjects with ACS+CKD, and the control group included 136 patients with ACS and normal renal function.The entire research study was conducted respecting the World Medical Association Declaration of Helsinki ; in addition, it was approved by the Ethics Committee of the Clinical County Emergency Hospital of Oradea, Bihor County, Romania (decision no. 30088/10 December 2019). Each patient included in the study signed the informed consent form.2, for more than 3 months, or kidney damage for more than 3 months with or without alterations of the GFR, involving either functional or morphological abnormal changes of the kidneys ..20].Subjects with previous chronic coronary syndrome were included in the study lot and the thoracic pain was described using the Canadian Cardiovascular Society grading of angina . First sThe performance of the LV was appreciated according to the ejection fraction (EF), calculated using the Simpson’s method, the recommended formula specified in the guidelines elaborated by the American Society of Echocardiography and the European Association of Cardiovascular Imaging, corroborated with the value of N-terminal pro b-type natriuretic peptide (NT-proBNP), a product synthetized due to peripheral congestion . NT-proBUrea and uric acid were spectrophotometrically measured using the Architect c4000 analyser . The values of urea were defined as normal if they were between 15–55 mg/dL. In the case of uric acid dosing, the values that were within the limits of 3.5–7.2 mg/dL were considered appropriate. C-reactive protein (CRP) was assayed using the turbidimetric method, from patients’ sera, using the same analyser as that used previously; the values of this biomarker (specific for inflammatory syndrome) <0.50 mg/dL were considered normal.Urgent coronary angiography was performed in patients with STEMI and suitable coronary anatomy, amendable by the procedure at admission or in less than 2 h from presentation, whereas subjects with multi-vessel CAD or significant left main stenosis were treated according to the ESC guidelines using surgical myocardial revascularization (CABG) .p < 0.05 was considered statistically significant. When comparing the prevalence of a certain element in the two groups, a chi-squared test was applied, considering α = 0.05 as the confidence level.The database was gathered in a Microsoft Excel document. The statistical analysis was made using the Biostat Programme. The Kolmogorov–Smirnov test was applied to determine the data distribution. For the comparison of variables that were not normally distributed, the Mann–Whitney test was used. A value of p = 0.76) among the reference and the control lot. The only statistically significant demographical elements were represented by the mean age (p < 0.01), with a high mean age of 68.62 in the reference lot and the environment of origin  (p < 0.01), with the urban being more important in the reference lot. Comparison of demographic characteristics inside the same group showed that the masculine gender developed ACS much more frequently in both CKD groups and the normal kidney function group (p < 0.01)  . Stagingn = 59 cases, p = 0.19), followed by the unstable angina in subjects with normal kidney function  and NSTEMI in the CKD group (n = 39 cases) with statistical significance (p = 0.04), compared to the reported number in the non-CKD group (n = 25 cases). MINOCA had higher incidence in the CKD group (n = 13 cases) without statistical significance (p = 0.26), compared with the non-CKD group (n = 8 cases)  . The posp < 0.01) compared to the percentage reported in the non-CKD group. Previous heart failure was quantified through the NYHA classes and reflected a frequency of 41.61% in the CKD group, with statistical relevance (p < 0.01) compared to the non-CKD group (19.85%). Other comorbid conditions such as sequelae of myocardial infarction in the inferior territory (p = 0.01), previous ischemic stroke (p < 0.01), and diabetes mellitus (p < 0.01) were significantly different in the groups (p < 0.01) in the non-CKD group, whereas dyspnoea was specific in the CKD group (p < 0.01). Loss of consciousness at admission was detected more rarely, without statistical importance (p = 0.16).The medical history of the study groups illustrated an increased percentage of previous chronic coronary syndrome and stable angina in the CKD group, with an important statistical value (e groups . Symptomp < 0.01) of Killip 1 class in non-CKD group, and Killip 3 class had a significant incidence (p < 0.01) in the CKD group, as shown in The assessment of Killip class at admission in patients with STEMI demonstrated a high incidence (p = 0.07). Left bundle branch block identified on the ECG was significant (p = 0.04) in the CKD group. New necrosis waves (Q wave) expressed statistical relevance (p < 0.01) in the non-CKD group. Electrocardiogram changes, presented at admission in both ACS with/without CKD subgroup, are shown in The incidence of cardiogenic shock in patients with ACS was higher in the CKD group without statistical relevance (The biomarker attesting the cardiac origin of dyspnoea (NT-proBNP) is a predictor of the prognosis for subjects diagnosed with ACS and CKD. The mean value of the marker was increased in subjects with impaired renal function (8259.67), standard deviation , thus explaining the significant incidence of acute pulmonary oedema and cardiogenic shock in these subjects. The group of patients with ACS and normal renal function showed lower mean values of the biomarker, with the rate of complications also being reduced  .p < 0.01) and akinesia of the basal segment of interventricular septum (p < 0.01) in the CKD group. Hypokinesia of the apical segment of the interventricular septum (p = 0.03) and akinesia of the middle portion of the interventricular septum (p < 0.01) were significant in the non-CKD group.The echocardiogram wall-motion abnormalities were characteristic in the CKD group with ACS. Normal LV contraction was found mostly in the non-CKD patients. Assessment of the regional LV wall motion abnormalities revealed significant elements such as dyskinesia of the basal segment of interventricular septum (p < 0.01). Medical management was selected for 11.68% of the cases from the CKD group, in contrast with the low rate of 0.74%, used in the non-CKD group. The disturbances of contractility in LV wall segments in both ACS with/without CKD subgroups are revealed in p < 0.01) compared with the decreased incidence from the CKD group (10.95%). LMCA and three-vessel CAD were mostly detected in the CKD group, without statistical relevance (p = 0.13 and p = 0.42) compared to the non-CKD group  in the CKD group. In addition, the obtuse marginal branch and the intermediate branch were mostly affected in the CKD subjects, with statistical significance  compared to the non-CKD group , left anterior descending artery (LAD), and LMCA, were statistically significant (KD group .p < 0.001). In the case of cardiac troponin I (cTnI), a value of p = 0.226 was obtained; in the case of high sensitive troponin I (hs-TnI), the p-value was 0.120; in the case of the number of coronary arteries affected in CAD, p = 0.083. Thus, for these three cases, there were no statistically significant differences (p > 0.05). In order to identify if the biomarker values change within the two groups, a Mann–Whitney test was applied; statistically significant differences were obtained in the GFR, creatinine, urea, uric acid, NT-proBNP, CRP, and Fe cases ;for the association between the GFR, creatinine, urea, uric acid, cTnI, hs-cTnI, NT-proBNP, CRP, and the EF values, a positive significant medium correlation resulted .for the second case, where the association between GFR, creatinine, urea, uric acid, cTnI, hs-cTnI, NT-proBNP, CRP, and the number of coronary arteries affected in CAD were tested, a positive significant weak correlation was obtained  and both the EF and the number of coronary arteries affected. Therefore, a multilinear analysis was applied, and the following results were observed:This study showed that symptomatology in ACS is usually atypical and thoracic pain is predominantly described in the case of subjects with normal kidney function. Dyspnoea expressed statistical significance in CKD subjects, and studies revealed the fact that silent ischemia or atypical symptomatology is more frequently observed on admission in patients with impaired renal function. In a trial which enrolled 356 patients, painless myocardial infarction had an increased incidence in the CKD group versus the non-CKD subjects with statistical relevance . The posACS presenting dyspnoea as the main symptom can be mistaken for angina equivalent. Sosnov et al. reported that subjects with CKD were 43% less likely to describe specific thoracic pain in comparison with the subjects without CKD, regardless of the presence of diabetic neuropathy. This observation is similar to the present study, which revealed an important incidence of shortness of breath in the CKD subgroup .The paucisymptomatic clinical picture and the anginal equivalences characteristic to ACS, highlighted in the case of subjects with CKD, are essential elements in the elaboration of a rigorous screening procedure . The rolp < 0.01).Electrocardiogram findings consistent with ischemia are not characteristic in CKD patients, because these subjects usually have left ventricular hypertrophy (LVH) or left bundle branch block. The present study revealed that left bundle branch block and QS waves are mostly present in the CKD subjects being statistically relevant , demonstrated that left bundle branch block incidence was higher in the advanced CKD group compared to the other CKD subjects .The different evolution of ACS in CKD and normal renal function is explained by the particularities of the atherosclerotic process in the uremic environment. Thus, the interaction of classic and non-traditional cardiovascular risk factors will generate a chronic inflammatory process, also materialized by increased CRP values in CKD subjects. The chronic inflammation will be the substrate of endothelial dysfunction. Ventricular remodelling occurring after the acute coronary event is more common in subjects with CKD. The clinical study published by Naito et al.  illustraHerzog et al. conducted a study that compared the characteristics of 3049 dialyzed patients with those of 534,395 non-CKD subjects [A cross-sectional study in the chronic renal insufficiency cohort (CRIC study) evaluated the high-sensitivity troponin in subjects with impaired renal function without myocardial ischemia and revealed that a high-sensitivity troponin, more than 3 ng/L, correlates with the LV mass and impaired LV performance (EF < 40%). Increased values of the mentioned cardiac necrosis enzymes predict high incidence of heart failure in CKD subjects .2 can identify subjects with high mortality risk [NT-proBNP negatively influences the prognosis of the CKD subgroup. Though the elevation of the biomarker is common in asymptomatic subjects with impaired renal function, one study revealed that high values of NT-proBNP associated with a decreased GFR less than 60 mL/min/1.73 mity risk . Thus, NCAD has several particularities in CKD consisting in high incidence, rapid progression, elevated prevalence of multi-vessel disease, and presence of vascular calcifications that interfere with proper stent expansion. Results regarding the high incidence of three-vessel CAD and LMCA in CKD patients were similar to other findings of similar studies, but they did not reach the statistically significant number due to the low number of patients and a single experimental centre ,37,38,39Another aspect is illustrated by lack of retrospective studies comparing the two myocardial revascularization methods, due to the exclusion of subjects with deteriorated renal function or inclusion of an irrelevant number of subjects. The existing observational studies are the only source of analyses regarding the benefits of both PCI and CABG in CKD patients. Chan et al. revealed that three-year major adverse cardiac and cerebrovascular events (MACCE) and survival were lower after the CABG versus the interventional myocardial revascularization using drug eluting stents (DES) in 893 subjects with CKD . A largeThe discrepancy between these trials is due to the different generation of DES used in the PCI groups. The Syntax trial reports usage of first-generation DES and Bangalore mentions usage of second-generation DES (paclitaxel eluting stents) with obvious superiority .In this study, most of the patients diagnosed with STEMI and CKD benefited from the same therapeutic approach, adopted also in the subjects with normal renal function, namely, the interventional or surgical myocardial revascularization. There were seven patients who had STEMI and impaired renal function; they refused the coronary procedure, after the risks and benefits of the procedure were explained to them, being treated conservatively. Fibrinolysis was not performed in these patients, as they were not indicated for this procedure . In addition, conservative treatment was an option in eight of the cases with NSTEMI that refused the intervention or surgical revascularization.Complications (such as acute pulmonary oedema or cardiogenic shock) were more frequently detected in the group of CKD patients, compared to the group of subjects with normal renal function. Severe CAD, EF impairment of left ventricle, ischemia of papillary muscles of the mitral valve, and secondary severe mitral valve insufficiency in conjunction with impaired renal function are responsible for the negative prognosis and complications commonly encountered in these patients.The group of subjects with ACS and normal renal function showed a favourable evolution of ACS, with the rate of lung oedema and cardiogenic shock being lower. The results of the present research indicate that the management of patients with ACS and CKD in the emergency department should consider certain evolutionary features and the negative prognosis. Given the increased frequency of multivessel coronary disease and hemodynamic instability commonly encountered in CKD, special attention will be paid to echocardiographic examination aimed at identifying the severity of parietal kinetic disorders and the estimated EF. The evaluation will be performed at the presentation of the patient in the emergency service, without delaying the coronarography. The highly responsive NT-proBNP biomarker and severely impaired renal function are other useful predictors in identifying patients with ACS and CKD, likely to develop acute pulmonary oedema or cardiogenic shock. Additionally, the arrhythmogenic potential is considerable for the subjects with ACS and CKD, and the therapeutic target will focus on the early myocardial reperfusion and the correction of various dyselectrolytemias.The above-mentioned observations outline the hypothesis that myocardial revascularization performed in the shortest period of time in CKD patients, even in the case of NSTEMI, improves the prognosis and reduces the risk of hemodynamic instability. The Sweetheart registry has shown that early myocardial reperfusion positively influences short-term survival in patients with mild or moderate CKD and NSTEMI .CKD may be associated with CAD. The present research revealed that subjects with CKD with coronary events associate coexisting pathologic conditions such as diabetes mellitus, heart failure, previous ischemic stroke, and chronic CAD. Elements such as NT-proBNP and echocardiography should be included in the evaluation of these patients, considering the great contribution to establish the overall prognosis. Proximal and severe CAD are characteristic for subjects with deteriorated renal function. New trials including large numbers of subjects with CKD and ACS should be performed to evaluate the clinical characteristics and the evolution of the subjects, and a strategy to improve the outcome in CKD subjects with ACS should be developed.


Heart disease is the leading cause of death in schizophrenia. However, there has been little research directly examining cardiac function in schizophrenia.To investigate cardiac structure and function in individuals with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity.In total, 80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity and glycated haemoglobin levels. Individuals with schizophrenia (‘patients’) and controls were matched for age, gender, ethnicity and body surface area.d = −0.82, P = 0.001), LV end-systolic volume , LV stroke volume , right ventricular (RV) end-diastolic volume , RV end-systolic volume , and RV stroke volume  but unaltered ejection fractions relative to controls. LV concentricity  and septal thickness  were significantly larger in the patients. Mean concentricity in patients was above the reference range. The findings were largely unchanged after adjusting for smoking and/or exercise levels and were independent of medication dose and duration.Patients had significantly smaller indexed left ventricular (LV) end-diastolic volume (effect size Individuals with schizophrenia show evidence of concentric cardiac remodelling compared with healthy controls of a similar age, gender, ethnicity, body surface area and blood pressure, and independent of smoking and activity levels. This could be contributing to the excess cardiovascular mortality observed in schizophrenia. Future studies should investigate the contribution of antipsychotic medication to these changes. People with schizophrenia have a two- to threefold greater mortality compared with the general population,2 and their life expectancy is 10–25 years shorter.3 In addition to the higher suicide risk, mortality due to natural causes has been estimated to be up to eight times higher than expected.2 Despite reductions in mortality in the general population over the past 30 years ,4 the mortality gap between people with schizophrenia and the healthy population is not reducing, and may even be increasing.5 Cardiovascular disease (CVD) accounts for a large proportion of the loss of life in schizophrenia,6 accounting for 14.3 life-years lost7 or 60% of deaths,8 on average, and its importance as a cause of death has been increasing in both US-based8 and northern European4 populations. Moreover, people with schizophrenia are less likely to receive investigation and treatment for cardiometabolic comorbidity than the general population,9 which may contribute to their excess cardiac mortality.Schizophrenia is a major mental illness, affecting approximately 0.4–0.7% of the world population,12 However, interpretation of these findings is complicated, as the studies did not consistently control for known determinants of cardiovascular structure and function, including body mass index (BMI), gender and comorbid metabolic conditions, which are factors that could independently account for the changes that were found. Consequently, it remains unknown whether schizophrenia is associated with cardiac structural or functional alterations, or whether potential confounds, such as medical and metabolic comorbidity explain the differences reported. Furthermore, previous studies have used transthoracic echocardiography to assess cardiac function, which provides less accurate and less reproducible volumetric and functional assessment of the heart compared with cardiac magnetic resonance imaging (CMR).13Despite this wealth of epidemiological evidence that associates schizophrenia with cardiovascular disease and premature death, few studies have directly investigated cardiac function in people with schizophrenia. These have generally shown reductions in left ventricular ejection fraction and increases in left ventricular mass in schizophrenia.in vivo measure of cardiac structural and functional assessment.14 Using a cohort of people with schizophrenia free from metabolic or medical comorbidities and healthy controls matched for known determinants of cardiovascular structure and function, including age, gender, ethnicity and body surface area (BSA), we tested the hypothesis that people with schizophrenia show heart changes that could account for the increased cardiovascular mortality independent of established cardiovascular risk factors such as medical and metabolic comorbidity.In view of this, we aimed to determine whether cardiac structure and function is altered in people with schizophrenia using CMR, the gold standard 15). Recruitment took place between September 2015 and December 2018.A total of 40 people with schizophrenia  were recruited from South London and the Maudsley NHS Foundation Trust and from Central and North West London NHS Foundation Trust in London, UK. A further 40 matched healthy controls  were recruited after matching for age (±3 years), ethnicity, gender and body surface area  through the Hammersmith Hospital Healthy Volunteer Panel in London and from the UK Digital Heart Project at Imperial College London . Participants were seated in a quiet, temperature-controlled waiting-room and given time to relax. A study doctor then performed a screening interview, clinical examination and supervised the CMR scan. The presence of medical comorbidities was assessed directly by interviewing the participants, by examining the list of active prescriptions and, where in doubt, by examining general practice records. Brachial blood pressure measurement was performed following 5 min rest using a validated oscillometric device . The first of three measures was discarded, and the second two values were averaged to provide the final reading. Physical activity grading was based on the Copenhagen City Heart Study Leisure Time Physical Activity Questionnaire, performed on the same day as the CMR. Categories of activity were based on participants' level of activity over the preceding 12 months, ranging from level 1  to level 4 (>5 hours of exercise per week).17 Plasma HbA1c was analysed using the Tosoh G8 HPLC Analyzer . Antipsychotic doses were converted into chlorpromazine equivalents as described by Andreasen and colleagues.18Physical assessment, study questionnaires, and CMR were all performed during the same study visit. All patients were assessed at the time of CMR imaging using the Positive and Negative Syndrome Scale (PANSS) for Schizophrenia19 Participants whose images were degraded by respiration or ECG synchronisation artefacts to such an extent that cardiac contours could not be clearly identified were excluded from the analysis. Images were stored on an open-source database.20 Volumetric analysis of the cine images was performed using CMRtools  for Windows by experienced operators masked to the diagnosis. The epicardial and endocardial borders were manually contoured at end-diastole and end-systole in each of the short-axis slices. Semi-automated, signal intensity-based thresholding was then used to identify the papillary muscles; these were included in the left ventricular mass and excluded from volumetric measurements. To increase the accuracy of the analysis, the valve positions at end-diastole and end-systole were manually identified on the three long-axis images, allowing the valve planes to be tracked through the cardiac cycle (21 Stroke volume (SV) was calculated as EDV − ESV and ejection fraction as SV/EDV × 100. Left ventricular mass was the total epicardial volume minus the total endocardial volume multiplied by the specific density of the myocardium (1.05 g/mL). Maximal end-diastolic wall thickness was measured through the basal anteroseptal wall using a short-axis CMR image  using a 32-channel cardiac coil and the remaining 19 patients and matched controls were scanned on a 3 T Siemens Magnetom Prisma  using a combination of the 18-channel body coil and 12 elements of the 32-channel spine coil. Matched patients and controls were scanned on the same scanner. All images used a vectorcardiographic technique for electrocardiogram (ECG) synchronisation and were acquired during breath-hold at expiration. A standard clinical protocol for assessing biventricular function and volumes was followed according to published international guidelines.ac cycle . VolumesMR image . Left veet al.22 .Fig. 1M2-tests for categorical variables, Wilcoxon rank sum tests for non-normally distributed values and analysis of variance (ANOVA) for normally distributed measures. Effect sizes were calculated using Cohen's d measure.Differences among patients and controls were tested using χ23 and between physical activity levels and CVD;24 (b) both the number of cigarettes and the physical activity scale were approximately linear ; and (c) categorisation of continuously distributed exposure variables requires a step-function of risk that assumes homogeneity of risk within groups, leading to both a loss of power and inaccurate estimation.25As there were significant group differences in smoking and physical activity levels, sensitivity analyses were conducted using generalised linear models with smoking, physical activity levels and scanner (1.5 T or 3 T) as covariates, the cardiac measures as the dependent variables and group as the independent variable. Both smoking and physical activity were used as continuous variables , because (a) there is a dose–response relationship between smoking and CVDR2 measures.To explore the possibility of a dose–response relationship between medication and cardiac phenotypes, linear regression was used to correlate cardiac measures with the natural logarithm of total chlorpromazine equivalents . The overall proportion of variance explained by linear models was calculated using P-values were adjusted using the Benjamini–Hochberg method, and results were considered significant when the false-discovery rate (q) was <0.05. Statistical analyses and graph plotting were performed in R  for Mac Os 10.13.n = 28; olanzapine, n = 10; and risperidone, n = 2). There were no significant group differences for age, gender, ethnicity, BSA, HbA1c, systolic and diastolic blood pressure. However, smoking levels and weekly physical activity levels were significantly different between groups.A total of 80 participants were recruited for this study. One healthy control had to be excluded because of poor image quality on CMR. Participants' characteristics are described in https://doi.org/10.1192/bjp.2019.268) and d = −0.82, F = −11.90, P = 0.001), LVESVi , left ventricular stroke volume  , RVESVi  and right ventricular stroke volume , with large effect sizes  and septal thickness  were significantly larger in the patients than in the matched healthy controls, with large to very large effect sizes . The means of all other parameters were within reference ranges in both patients and controls (supplementary Table 1). There were no significant differences between groups in left ventricular mass, biventricular ejection fractions or pulse-wave velocity .Supplementary Table 1 (available at = 0.001) , RVEDVi ct sizes . Left vect sizes . Mean coP = 0.004), LVESVi (P = 0.04), LVSVi (P = 0.003), RVEDVi (P = 0.006), RVESVi (P = 0.04) and RVSVi (P = 0.003), whereas left ventricular concentricity (P = 0.02) and septal thickness (P < 0.001) were both still significantly larger. Significant results were essentially the same if analyses were adjusted for smoking binarised as smoking/not smoking instead (supplementary Table 2). After covarying for physical activity levels, patients exhibited significantly smaller LVEDVi (P = 0.04), LVSVi (P = 0.04), RVEDVi (P = 0.04) and RVSVi (P = 0.04), whereas left ventricular concentricity (P = 0.04) and septal thickness (P < 0.001) were both significantly larger. As smoking and physical inactivity may co-occur, we repeated the analyses covarying for both smoking and physical activity levels. The results remained essentially the same as the physical activity-adjusted analyses (supplementary Table 1). Adjusting for scanner (1.5 v. 3 T) did not affect the significance of any of the results (supplementary Table 3).In sensitivity analyses, we explored whether significant differences between patients and controls in terms of cigarettes smoked per day and number of hours of weekly exercise contributed to the differences in cardiac measurements we observed. Supplementary Table 1 shows that, after adjusting the model for the number of cigarettes smoked per day, patients still exhibited significantly smaller LVEDVi  or with total chlorpromazine equivalents/years (supplementary Table 5).1c levels or blood pressure – something that previous studies12 could not consistently exclude and that could therefore account for the difference in results.In this study we found that people with schizophrenia show clinically significant reductions in indexed end-diastolic, end-systolic and stroke volumes in both ventricles (with large effect sizes), while showing an increase in concentricity and septal thickness (with large to very large effect sizes), compared with healthy controls of a similar age, gender, ethnicity, BSA and blood pressure. Mean concentricity in patients was above the reference range, whereas other measures were significantly different compared with controls, but mean values were within reference ranges. These findings were unchanged in sensitivity analyses adjusting for smoking or exercise levels, other than biventricular end-systolic volumes, which were no longer significantly different. In other words, for the first time to our knowledge, this study shows evidence consistent with concentric remodelling of the heart in schizophrenia. Cardiac remodelling is caused by heart myocytes' response to noxious stimuli, leading to structural changes, a process that can become pathogenic. Specifically, concentric remodelling is defined as that happening when volumes are normal or reduced, but the left ventricular mass-to-volume ratio is increased. Furthermore, the changes found in our sample of individuals with schizophrenia were independent of conventional cardiometabolic risk factors such as differences in age, gender, ethnicity, medical comorbidity, BSA, HbA26 In a separate study, Bluemke and colleagues found a hazard ratio for coronary heart disease of 2.1 per g/mL and for stroke of 4.2 per g/mL increase in cardiac concentricity.27 Concentric heart remodelling was also shown to be a predictor of higher mortality  even in people with normal ejection fractions, such as our sample.28 Finally, increased left ventricular septal thickness, which is increased in our sample, also confers higher cardiovascular morbidity and mortality.29 The cardiac changes we report could therefore account for part of the increased cardiovascular morbidity and mortality seen in schizophrenia, independent of the increased prevalence of conventional cardiovascular risk factors, such as smoking, associated with schizophrenia.Concentric cardiac remodelling has been shown to be among the best CMR predictors of future myocardial infarction, coronary insufficiency, heart failure and stroke in healthy adults: individuals in the highest tertile of concentricity showed the lowest cardiovascular disease-free survival over time and steepest slope curves among other common CMR measures, with a hazard ratio for CVD of 1.40 per 0.2 g/mL increase in concentricity.30 However, we found that in patients with schizophrenia concentric remodelling was present in the absence of signs of clinical or preclinical vascular disease, as demonstrated by blood pressure and pulse-wave velocity, which were both within normal range in patients, and not significantly different from controls. Our findings therefore suggest that concentric heart remodelling in schizophrenia might be a consequence of a separate pathophysiological process.The most common cause of concentric heart remodelling in the general population are hypertensive changes, characterised by arterial stiffening causing elevated blood pressure.31 and cardiomyopathy and cardiac adverse outcomes32 later in life; these associations might be mediated by inflammation and other factors. Additionally, an unhealthy adult lifestyle is an established factor in increasing cardiac risk;33 individuals with schizophrenia have a tendency to lead a more unhealthy lifestyle than the general population . Finally, people with schizophrenia take antipsychotic medication, a medication class, especially second-generation antipsychotics, that has been associated with metabolic syndrome36 and other cardiovascular risk factors.Until now, it was thought that most of the additional cardiometabolic risk in schizophrenia was due to unhealthy lifestyles and antipsychotic medication. However, a systematic review of potential aetiologies would include both genetic and environmental causes. First, genetic elements might exist that increase the risk of both schizophrenia and cardiac remodelling . Second, environmental factors might also play a role. Prenatal and early life stressors have been linked to increased risk of both schizophrenia2 dopamine receptor signalling contributes to regulating cardiac function.37 There is also evidence that antipsychotics impair cardioprotection by blocking D2 receptors in a rat model of hypoxia-induced cardiomyocyte injury,37 thus potentially contributing to cardiac fibrosis. In rats, antipsychotics are also associated with the development of inflammatory lesions and lymphocytic infiltrates within the myocardium.38 In humans, it remains to be determined whether antipsychotics directly act on cardiomyocytes. Aside from this, some, but not all, antipsychotics have been associated with higher rates of metabolic syndrome,36 which might mediate cardiovascular changes. Therefore, antipsychotic treatment could account for some of the cardiac changes we demonstrate. However, in our sample we did not find a linear relationship between cardiac changes and current or lifetime antipsychotic dose. The absence of a linear relationship reduces the probability that a causal relationship exists,39 even if it cannot be ruled out. Additionally, a proportion of our study participants were taking clozapine, a medication that in rare, idiosyncratic occurrences can cause clozapine-induced myocarditis (CIM)40 and cardiomyopathy (CIC); the estimated combined prevalence of CIM and CIC in clozapine-treated patients is 0.93% . Furthermore, the median time to onset of myocarditis since starting clozapine is 15 days,40 and we excluded participants with a history of myocarditis, cardiomyopathy or other cardiac disease. However, could participants with subclinical CIM/CIC be driving our findings? This is unlikely to have a major effect, as (a) less than 1% of clozapine-treated patients experience CIM or CIC so, even if the prevalence of subclinical changes is fourfold higher than the prevalence of clinical CIM/CIC, we would expect it to affect at most one patient in our sample; and (b) clozapine-induced myocarditis/cardiomyopathy generally shows an acute presentation over a few days, so it is unlikely that we have scanned patients with emergent CIM/CIC. Moreover, the major long-term sequela of CIM is dilated cardiomyopathy with chronic heart failure,42 and our findings point in the opposite direction: we find no evidence of heart failure (no change in ejection fractions) and evidence of concentric, rather than dilatatory, changes in our study population. Notwithstanding this, future studies will be useful to clarify the role of clozapine and other antipsychotic medication in the cardiac remodelling we find in schizophrenia.With regard to antipsychotic treatment, there is animal evidence that D43 This would suggest that concentric heart remodelling and cardiac fibro-inflammatory changes could both be driven by systemic inflammation, leading to pro-fibrotic stimuli and hence cardiac remodelling with deposition of collagen. In support of this theory, there are established cross-sectional associations between schizophrenia and elevations in peripheral pro-inflammatory cytokines, including interleukin-6 (IL-6) and transforming growth factor β (TGF-β).44 Furthermore, elevated plasma levels of inflammatory cytokines early in life increase the risk of the subsequent development of a psychotic illness,45 suggesting that inflammation and psychosis might share a common early developmental aetiology. In particular, TGF-β has been consistently found to be elevated in peripheral blood in the early phases of schizophrenia as compared with healthy controls in several meta-analyses.44 Finally, animal studies support an aetiological role for TGF-β in causing cardiac fibrosis: in mice, TGF-β1 has been shown to have cardiac pro-fibrotic properties in vivo; in a transgenic model, overexpression of TGF-β1 resulted in a 38% increase in heart weight, with fibroblast proliferation and collagen synthesis in the myocardium.46 Therefore, inflammation and elevations in specific pro-inflammatory and pro-fibrotic factors might be mediating cardiac remodelling in schizophrenia, but this will need testing specifically in future studies.We previously found evidence suggesting that an early diffuse myocardial fibrosis and/or subclinical myocardial inflammation are present in the hearts of people with schizophrenia.14 Key advantages of CMR over echocardiography are (a) that ventricles can be imaged in their entirety and no geometrical assumptions need to be made in order to derive global whole-organ data;13 and (b) that we were able to perform image analysis masked to participant diagnosis.A strength of this study is the use of CMR, which is the gold standard for left ventricular function and mass quantification.47 However, although we excluded diagnosed cardiometabolic disorders, we cannot exclude the possibility of subclinical changes, although we found no significant difference between patients and controls in systolic and diastolic blood pressure or in pulse-wave velocity, and no significant difference in HbA1c in a subsample of our cohort, suggesting that subclinical differences are unlikely to be large.Another strength of our study is that, for the first time to our knowledge, participants with a pre-existing diagnosis of any medical condition, including ischaemic heart disease, hypertension, diabetes or dyslipidaemia, were excluded, and we matched patients and controls for BSA, age, gender and ethnicity, all potential confounders in analyses of cardiac function and structure.48 suggesting that the change in equipment is unlikely to have had a major effects on our results.A limitation of this study is that it involved people with chronic schizophrenia (median duration of treatment of 12 years), who were all taking antipsychotic medications. In addition, 70% of the patient group were taking clozapine and are therefore likely to be treatment resistant, which could affect the generalisability of our findings. We were not powered to detect differences in cardiac structure and function between antipsychotic treatments, and it would be useful for a future study to do this. Thus, a future study in antipsychotic-naïve patients would be useful to determine whether the cardiac differences we detect are associated with treatment or chronicity. Another consideration is that participants were scanned on two different scanners. However, findings remained significant when scanner was included in the analysis. Moreover, recent evidence shows that 1.5 T and 3 T scanners yield similar results for measuring cardiac structure and function,We observed biventricular volume reductions and evidence of concentric cardiac remodelling in patients with schizophrenia compared with matched healthy controls in the absence of concurrent established metabolic or medical risk factors. These are prognostically adverse changes and, in the absence of concurrent conventional metabolic or medical risk factors, could explain part of the additional cardiovascular morbidity and mortality seen in schizophrenia. Further work involving untreated participants is required to disentangle the contribution of antipsychotic medication to cardiac changes in schizophrenia.


Hyperammonemic encephalopathy secondary to heart failure is rare and there had been little reports about effective treatment. Organ hypoperfusion or congestion by heart failure may lead to various organ dysfunctions, and liver and intestinal circulatory impairment might cause ammonia metabolic failure. Here, we report on the case of a patient with hyperammonemic encephalopathy that was secondary to heart failure, which was effectively treated by lactulose. Heart failure is associated with various organ dysfunctions such as hepatic or renal dysfunctions due to the impairment of organ perfusion ,2. HepatHere, we report on a case of heart failure with hyperammonemic encephalopathy, which was treated successfully by the addition of lactuloses.An 81-year-old male, who had suffered from heart failure with moderate to severe mitral regurgitation (MR), was hospitalized at our hospital. One year ago, he had been hospitalized for worsening heart failure, but did not wish to undergo valve surgery, hence, was followed up with medical therapy including beta-blockers and diuretics at the Outpatient Department. Right heart catheterization at that time revealed slight venous congestion  without low output and the increase of pulmonary capillary wedge pressure. The complication of membrane nephropathy was diagnosed 20 years ago, though his renal function was moderately decreased leading to a slight increase in blood urea nitrogen (BUN) and creatinine (Cre). Despite the medication for his heart failure, there had been slight increases in the concentration of total bilirubin (1.5–2.3 mg/dL), BUN, and Cre (1.6–2.2 mg/dL), partly due to medically intractable hepatic and renal congestion. In addition, his level of consciousness and physical activities had gradually decreased, which led to his hospitalization. His social history included some alcohol intake, which had significantly decreased in the last few years. On admission, the physical findings revealed flapping tremors, which is an involuntary low amplitude movement induced by actions such as hyperextension of the fingers keeping the wrist joint bent. His laboratory tests were as follows: white blood cell counts 3000/μL, hemoglobin 9.3 g/L, platelet counts 82,000/μL, BUN 56.3 mmol/L, Cre 1.67 μmol/L, bilirubin 2.0 μmol/L, albumin 3.2 g/L, aspartate aminotransferase (AST) 36 U/L, alanine aminotransferase (ALT) 17 U/L, alkaline phosphatase 760 U/L, C reactive protein 0.21 mg/dL, and prothrombin time of 28.4 s. These data showed that there had been a little change in his indices within the previous weeks. However, we checked the blood ammonia level for the first time and it was as high as 221 μg/dL. Electrocardiogram revealed atrial fibrillation, but there was no evidence of myocardial ischemia or infarction . Chest xIn this case, hyperammonemic encephalopathy developed in a patient with a medically intractable heart failure, who had no other apparent liver disease other than congestion. The treatment with lactulose and BCAA led to an improvement in the hyperammonemia and the encephalopathy receded following treatment for heart failure.Consciousness disorders are sometimes complicated with heart failure . MetabolOn the other hand, there have been few reports on metabolic conditions where elevated serum ammonia co-occurs with heart failure. There are several case reports of hyperammonemic encephalopathy in patients with right heart failure ,9. IndeeOn the other hand, ammonia might be produced by myocardial injury due to heart failure and it may be an upstream stress that worsens the heart failure, which might be attenuated by ammonia-reducing treatments. The stress, from a variety of causes , induces myocardial injury leading to increased ammonia production from the breakdown of cellular material , endoplaTo improve hyperammonemic encephalopathy, ammonia production needs to be reduced and any ammonia that has already been formed should be eliminated efficiently. For cases where there is no factor that can cause hepatic encephalopathy other than heart failure (as in the present case), there were hitherto no specific treatment other than the reinforcement of the heart failure therapy. However, this case suggests that lactulose (which suppresses the absorption of ammonia) and BCAA (which reduces blood ammonia concentration) may improve hyperammonemic encephalopathy. Lactulose is often used as a treatment for hepatic encephalopathy to remove ammonia and other toxins by inhibiting ammonia-producing bacteria in the intestinal tract. BCAA could also have a beneficial effect on hepatic encephalopathy by supporting ammonia detoxification in the tricarboxylic acid (TCA) -cycle in muscle tissues, leading to a reduction of plasma ammonia concentration ,22. In tHeart failure may be associated with various organ dysfunction due to hypoperfusion or congestion. This case suggests that severe right heart failure could cause the metabolic failure of ammonia, leading to hyperammonemic encephalopathy. This should be considered as a cause of impaired consciousness in severe congestive heart failure. Furthermore, this case suggests that lactulose might have dual beneficial effects in patients with hyperammonemic encephalopathy due to heart failure: improving ammonia balance and reducing circulatory volume overload .In conclusion, it is important to consider the possibility of hyperammonemic encephalopathy when cases of impaired consciousness present with congestive heart failure. Serum ammonia should be measured if patients with heart failure suffer from impaired consciousness. In addition, lactulose might be effective for hyperammonemic encephalopathy secondary to heart failure.


Cardiovascular imaging is developing at a rapid pace and the newer modalities, in particular three-dimensional echocardiography, allow better analysis of heart structures. Identifying valve lesions and grading their severity represents crucial information and nowadays is strengthened by the introduction of new software, such as transillumination, which provide detailed morphology descriptions. Chambers quantification has never been so rapid and accurate: machine learning algorithms generate automated volume measurements, including left ventricular systolic and diastolic function, which is extremely important for clinical decisions. This review provides an overview of the latest innovations in the echocardiography field, and is helpful by providing a better insight into heart diseases. Since its introduction into clinical practice in early 2000s, three-dimensional (3D) echocardiographic imaging has represented a major innovation in cardiovascular ultrasound. Like computed tomography (CT) and magnetic resonance imaging (MRI), 3D echocardiography allows the acquisition of real-time 3D data sets with adequate spatial and temporal resolutions. Image cropping and rotation with infinite cut planes, both on- and off-line, generate anatomically orientated views, which are extremely useful in various clinical settings.The areas of application of 3D echocardiography have gradually expanded: the analysis of geometry and function of the heart chambers , the evaThis review describes the newer modalities of transthoracic (TTE) 3D echocardiography that may enhance valve disease characterization and heart chamber volume quantification as well.Echocardiography is the method of choice to evaluate patients with valve disease. It allows the accurate assessment of severity of valve lesions, etiology, mechanisms and anatomic lesions, left ventricle (LV) and left atrial (LA) remodeling, right chamber dimensions and function and consequently defines the indication and the probability of successful of percutaneous or surgical procedures. Recent guidelines stated that real-time three-dimensional (RT3D) imaging modalities are useful in the presentation of realistic views of heart valves and are ideal to investigate the anatomy and function of each of the heart valves . In mitral valve (MV) disease, 3D imaging enhance the evaluation of all anatomic and functional details, including subcomponents of the MV apparatus . Both qualitative and quantitative evaluations of degenerative MV disease have been substantially improved by 3D echocardiography.In 2012, ESC guidelines . Three-dOne of the main indications for 3DTTE is the morphologic description of MV leaflets in several diseases, mainly MV regurgitation and MV stenosis. The first studies in the early 2000s were concentrated on the planimetry of the valve in MV stenosis  and in tThe evaluation of MV morphology and identification of scallop lesion is fundamental in patients with MV prolapse. In a routine TTE, a comprehensive evaluation contributes to the diagnosis, prognosis and surgical timing of severe degenerative MV regurgitation: heart chamber dimensions and function, detailed MV morphology, site and severity of the regurgitation, pulmonary systolic pressure ,14. In tMoreover, 3DTTE diagnostic accuracy is still improving thanks to new transducers, software and transillumination (TI) techniques . ComprehStarting from the morphology and dimensions of the valve annulus, 3DTTE has been proposed as an ideal method to analyze the mitral, tricuspid and aortic annula. The MV annulus has been studied in patients with organic or functional mitral regurgitation and after surgical and percutaneous procedures ,19,20. The evaluation of TV leaflets is limited by the standard 2DTTE. It is rarely possible to simultaneously visualize the three leaflets and their recognition needs a very accurate and comprehensive evaluation from different views. By contrast, 3DTTE is generally easy and has the unique capability of obtaining a simultaneous visualization of the three leaflets, commissures and their attachment to the annulus. Badano et al. demonstrated the clinical utility of 3DTTE in the assessment of functional TV regurgitation ,9, combiSeveral other pathologies may benefit from 3DTTE diagnosis such as tricuspid endocarditis, valve tumors, congenital and acquired pathologies. Although quantitatively less relevant than the contribution offered for evaluation of morphology and function of atrioventricular valves, 3D echocardiography, especially from the transesophageal approach, has become critical for evaluation of the anatomy of the aortic valve . In aortIn aortic insufficiency, 3DTTE is used to define the anatomy of the valve, the mechanism of insufficiency, and to indicate the need for eventual reconstructive surgery .Accurate quantification of mitral, aortic and tricuspid regurgitation is important for decisions regarding surgery and predicting risk. Current guidelines  propose Recent technological advances in 3DTTE and 3DTEE have provided new tools for MR quantification. As concerns 3DTTE, images are generally acquired from the apical view with settings similar to the standard 2D Doppler approach. Newer ultrasound systems will allow real-time optimization of the 3D color Doppler in live 3D mode or single heart-beat full-volume mode, but the acquisition should still be gated. End-expiratory breath-hold is desirable for gated acquisitions, and all 3D volumes should be checked perpendicular to the ultrasound sweep plane to ensure that stitching artifacts are absent. 3D VCA measurements by TEE is superior to the 2D PISA method in determination of regurgitation severity in multiple native and prosthetic valves. However, new methods for automated quantification of regurgitant jets are still under evaluation and probably will very soon be available in clinical practice .In the near future, we may also foresee that the “true hole” of the regurgitant lesion may be reconstructed from 3D data sets . In ordeIn left heart valve disease, LV and LA evaluation is crucial for the diagnosis, prognosis and timing of surgery or for percutaneous procedures. Indeed, both in aortic and mitral stenotic or regurgitant lesions, clinical and therapeutic decision are based not only in severity of the lesion but also on LV dimensions and systolic function and LA dimensions ,14,28. ITherefore, as from these quoted guidelines, M-mode diameters and 2D biplane LV volumes were considered the standard method for the assessment of surgical timing. Recently 3D echocardiography, tissue Doppler and strain rate imaging have been proposed as useful techniques, particularly in patients with borderline LVEF, where they may help in the decision for surgery ,40,41,42Moreover, after launching the acquired 3DE dataset (after a few seconds’ acquisition from the 4-chamber view), the examiner has immediately (about 30 s) automated chambers assessment on the display. LA and LV contours on 4-, 3-, and 2-chamber cut-planes are extracted from the 3DE datasets, providing the ideal recognition of the 2 cavities and LV/LA reciprocal volumetric changes throughout the cardiac cycle. All measurements are also included in the display . The different phases of the cardiac cycle are identified using maximum and minimum values of the volume curves and their first time-derivative LV and LA curves . In the Thus, a comprehensive TTE may include not only all 2D echo and Doppler parameters but also 3D evaluation of valve morphology and 3D measurements of left heart chambers . Figure Right ventricular (RV) dimensions and function are known to be of clinical importance in many cardiac diseases. The 3DTTE determined RV ejection fraction (RVEF) was independently associated with cardiac outcomes in patients with diverse backgrounds including valve disease . RVEF ofWe recently demonstrated that patients undergoing MV surgery and TV annuloplasty with an increased TV annulus dimensions and a marked right chambers remodeling, probably had an advanced stage of the disease . The 3D Imaging of the heart and related structures has progressively evolved over the last few years. Three-dimensional (3D) echocardiography has come a long way from its debut and represents the most useful innovation in cardiovascular ultrasound. Its use can be helpful for gaining a better insight into valve diseases and for rapid and accurate volumes and function assessment. Further improvements of the image quality and resolution associated with the use of artificial intelligence techniques, for automated quantitative analysis of the data, will allow 3DTTE to reduce analysis time and make quantitative assessments more objective and reproducible.


The underlying cause of asystole was found to be due to the atrial capture management (ACM) algorithm of the CRT-P device, temporarily converting biventricular to right ventricular–only pacing as part of the algorithm. This case highlights implications of the ACM algorithm in devices with a similar platform for pacemaker-dependent patients.Capture management algorithms in current cardiac implantable electronic devices (CIEDs) can enhance device performance and battery longevity. Although generally safe, these algorithms have on rare occasions been implicated in the onset of significant complications, especially in pacemaker-dependent patients. CIEDs implanted in patients with postoperative congenital heart disease (CHD) often require epicardial pacing leads rather than transvenous leads; unfortunately, epicardial leads can experience higher rates of malfunction. We herein report on a young adult with a status of postoperative CHD and complete atrioventricular block following implantation of a epicardial dual-chamber cardiac resynchronization therapy pacemaker (CRT-P; Consulta The older model 4965  right ventricular (RV) lead was incorporated in this system, as its performance at surgery was judged to be acceptable . Therefore, his pacing system at the time of this admission consisted of a Consulta® CRT pacemaker (CRT-P) generator , the 13-year-old unipolar lead connected to the RV port, and three-year-old bipolar epicardial leads  on the left atrial appendage (LAA) and left ventricle (LV). About two years prior to the current admission, however, the older RV lead had developed markedly elevated capture threshold and lead impedance. As this device platform does not permit reprogramming to entirely isolate this lead, the RV channel was programmed to minimal output (0.5 V at 0.03 ms) to minimize battery drain and maximal sensing threshold (11.3 mV) to reduce the chance for oversensing of nonphysiologic electrical transients. Fortunately, echocardiography performed with the device essentially programmed with LV pacing only indicated the existence of preserved ventricular systolic function.Our patient was a 25-year-old male with tricuspid atresia and normally related great arteries (type Ic) who had undergone pulmonary artery banding at one month of age and bidirectional Glenn anastomosis at 16 months of age. Extracardiac Fontan operation and subaortic resection were performed at 5.5 years of age, complicated by postsurgical CAVB and left middle cerebral artery stroke. An epicardial dual-chamber pacemaker was implanted at that time. Except for requiring chronic treatment of a seizure disorder, the patient had been otherwise clinically stable from this point onward. In subsequent years, however, his atrial and ventricular epicardial leads failed, prompting multiple surgical revisions via sternotomy and thoracotomy. Serial outpatient evaluations revealed sinus node dysfunction, persistent CAVB, and progressive pacemaker-dependence with only intermittent intrinsic escape rhythm. His last pacemaker surgery at three years prior to this most recent admission included an upgrade to an epicardial dual-chamber CRT pacing system to provide an extra ventricular lead given his prior lead failures and pacemaker-dependenceAt 25 years of age, the patient was referred by his primary cardiologist for cardiac catheterization to evaluate Fontan anatomy and physiology, to be followed by hospitalization to evaluate increasingly frequent neurological “spells” possibly related to his remote perioperative stroke. Catheterization showed acceptable Fontan pressures and mild left pulmonary artery stenosis that was treated uneventfully by balloon angioplasty and stent placement. Following catheterization, he was admitted to a telemetry unit in an adjacent adult community hospital for neurology consultation.. Device interrogation confirmed that the device was programmed in the DDD mode  with 87% atrial sensing–ventricular pacing and 13% AV pacing. Bedside interrogation revealed stable LAA and LV lead characteristics . The RV lead characteristics were as expected, with noncapture at all outputs, 5.3 mV sensing of very rare intrinsic beats, and an impedance of 1,957 Ω. Further assessment showed no baseline “noise” or evidence of electrical transients on the RV channel nor monitored ventricular events (with VT zone programmed to > 154 bpm). Capture management algorithms were programmed as follows: atrial to “adaptive,” RV to “off,” and LV to “monitor.” Automated device diagnostics indicated a “possible high LV threshold” recorded the day before this interrogation and an inability “to measure LV thresholds in the last seven days.”On the night of catheterization, continuous electrocardiogram telemetry recorded several periods of asystole lasting between 10 seconds and 12 seconds in the early morning hours Given these findings and this patient’s clinical history, we suspected his episodic asystole might reflect LV lead failure; other considerations included intermittent RV oversensing and automated device algorithms. He was transferred to an intensive care unit and prepared for emergency implantation of a new ventricular lead, a proposition that would require extensive open-chest surgery. The output on the LV channel was increased and intravenous dopamine was made available for cardioaccelerator therapy if necessary. Overnight, similar pauses were again seen on telemetry. The device mode was then reprogrammed to VOO, and subsequent inpatient telemetry showed no more pauses. confirmed pauses occurring in the early morning hours during a period of slightly faster atrial rhythms with mildly varying P-wave morphologies; atrial pacing spikes were not clearly consistent at this time. ACM algorithms of the Medtronic Consulta® CRT-P device  were nominally performed around 1:00 AM, beginning with atrial pacing slightly faster than the prevailing sinus rhythm to evaluate responses to varying outputs. In patients with AVB, atrial capture is confirmed by atrial chamber reset (ACR). After review of the manufacturer’s manual, we learned that, during ACR, the device’s baseline biventricular pacing temporarily converts to RV-only pacing to enhance the detection of atrial signals. As our patient’s RV lead had ventricular noncapture, we surmised the ACR algorithms could be responsible for our patient’s intermittent asystole.Close review of telemetry recordings during asystolic periods The device was programmed back to DDD and ACM was turned off. Inpatient telemetry over the next five days showed appropriate pacemaker performance and no pauses. The LV channel was programmed to a unipolar configuration given a lower capture threshold as compared with a bipolar configuration, and recent automated LV capture management had indicated a possibly elevated LV capture threshold .Of note, formal neurology consultation concluded that the patient’s recent “spells” were not consistent with intermittent asystole but instead reflected progression in chronic encephalopathy and seizure disorder. Our patient responded to medical treatment.This case illustrates a previously unreported example whereby an ACM algorithm in a biventricular pacemaker introduced significant consequences in a pacemaker-dependent patient with CAVB and RV lead failure. In our patient, upgrading to a dual-chamber biventricular system was intended to provide a safety net given his pacemaker-dependence and history of multiple epicardial lead failures as well as the possible benefits of cardiac resynchronization; this strategy, however, turned out to be a double-edged sword. Although he benefited from having a second ventricular lead, which ultimately obviated the need for surgical revision, leaving the ACM algorithm engaged caused frequent periods of asystole in the early morning hours after his RV lead failed to capture. Indeed, he may have been experiencing frequent periods of asystole for many months, but this was only discovered incidentally by inpatient telemetry during evaluation for another reason. This important ACM-related problem had gone unnoticed for several reasons, including that periods of asystole occurred during typical sleeping hours, serial device interrogations alone would not reveal the problem, and outpatient ambulatory electrocardiogram recordings are not routinely obtained in similar patients unless specific questions arise from patient symptoms or worrisome findings on device interrogation.6 Automated capture management algorithms require precise engineering to confirm pacing-induced myocardial depolarization, either by discerning evoked responses from polarization afterpotentials in ventricular leads or by evaluating AV conduction or resetting of intrinsic sinus rhythm in atrial leads. These algorithms have been shown to be generally accurate and safe in diverse adult and pediatric patient populations across a broad spectrum of pacing lead types and implant locations. However, a few case reports reveal such algorithms can place patients with AVB at risk for serious consequences. Ho et al.8 described a patient with AVB status after implantation of a Concerto® CRT defibrillator  for ventricular fibrillation who developed intermittent ventricular nonoutput due to cross-talk inhibition from atrial afterdepolarizations that were oversensed on the ventricular channel during automated LV capture management algorithms. Separately, Suri et al.7 reported on a pacemaker-dependent patient with a St. Jude Pacesetter Affinity DR generator  who developed 10-second periods of ventricular asystole during ventricular autocapture related to increasing lead capture threshold and an internal “housekeeping function” in the device designed to improve the estimation of battery longevity.Over recent decades, device manufacturers have developed several approaches to minimize battery drain by facilitating lower paced outputs in a reliable and safe manner.® CRT-P device’s ACM algorithm in patients with AV block; notably, this algorithm is found in multiple Medtronic devices with a similar platform. ACM algorithms in the Consulta® CRT-P device  are performed only when the device is programmed DDD or DDDR. Because prior studies have shown diurnal variations in capture thresholds with the highest thresholds in the early morning hours,16 device diagnostics including ACM are conventionally performed around 1:00 AM. Once the device determines the patient’s rhythm is stable, ACM threshold testing is initiated by pacing the atrium slightly faster than the prevailing sinus rate. This device uses two distinct methods to determine atrial capture thresholds. In patients with stable 1:1 AV conduction during atrial pacing, the AV Conduction algorithm is used, which monitors responses recorded on the ventricular channel to determine the loss of atrial capture. In patients with AV block, the ACR method is employed. ACR relies on expected electrophysiological resetting of the sinus node to determine a loss of atrial capture; when an atrial sensed event occurs soon after an impulse is delivered , the algorithm “decides” that the sinus node had not been reset by that impulse and therefore atrial myocardium has not been captured. If ACM is programmed to “adaptive,” the device automatically adjusts pacing outputs according to responses to changed outputs, while, when programmed to “monitor,” similar automated maneuvers are performed and responses tracked, but no reprogramming occurs. Importantly, during ACM threshold testing, the Consulta® CRT-P device  temporarily disables biventricular pacing, converting to RV-pacing only; this circumstance caused ventricular noncapture and asystole in our patient due to pre-existing RV lead failure. Turning ACM off eliminated this temporary RV-only pacing and associated asystole in our patient.Our case revealed recurrent periods of ventricular asystole caused by an underappreciated feature of the Consulta4 this problem has not been previously reported. The lack of detection of this problem in these case series may reflect limitations similar to those described above for our patient but may also reflect the superior long-term performance of transvenous leads in older sedentary adults versus epicardial leads in younger and more active patients. However, after our recent institutional understanding of this issue, an older adult with a transvenous biventricular ICD and similar platform was found to also have this problem during incidental ambulatory monitoring, and this was promptly corrected by turning off ACM.Despite several large case series demonstrating accurate and reliable performance of this algorithm in similar Medtronic devices,® CRT-P device  can cause periods of ventricular asystole in patients with AVB and RV lead failure due to temporary conversion from biventricular to RV-only pacing as part of the ACR subalgorithm. This may be occurring in other patients with similar circumstances or in those with RV pacing output essentially disabled for other reasons, whether or not they are postoperative CHD with epicardial leads. We recommend that, for new implants of this device in similar patients, clinicians consider inserting the newest (or most reliable) ventricular lead into the RV port. For devices currently in use, clinicians should not be reassured by the use of redundant ventricular leads but instead should closely monitor RV lead performance and examine the risk–benefit profile of ACM for each patient. Periodic ambulatory electrocardiogram recordings may provide helpful surveillance. As for managing devices from other manufacturers, clinicians should consult user manuals, field representatives, or company engineers to determine the possibility that this problem might be occurring in some of their patients.In summary, our case highlights that the ACM algorithm in the Consulta