Computed tomography feature tracking (CT-FT) has emerged as a valuable method for the assessment of cardiac function. However, no studies have investigated the usefulness of CT-derived assessments of left ventricular (LV) strain in coronary artery disease (CAD). Our aim was to evaluate regional LV systolic deformation in patients with left anterior descending coronary artery (LAD) stenosis using CT-FT.Seventy-six patients with LAD stenosis were enrolled. The patients were divided into four groups according to the percentage of LAD stenosis: ≤25% was defined as group I (24 patients), 26 to 49% as group II (17 patients), 50 to 74% as group III (21 patients), and ≥ 75% as group IV (14 patients). Thirty-two sex- and age-matched healthy subjects were included as controls.p = 0.07; − 18.6% vs − 21.9%, p = 0.024; − 17.5% vs − 20%, p = 0.032, respectively). The severity of LAD stenosis was positively correlated with the LS of the LAD territory .No intergroup differences were found between groups I-IV and the controls in terms of the left ventricular ejection fraction, end-diastolic volume and end-systolic volume. However, the longitudinal strain (LS) of the LAD territory was significantly reduced in groups I-IV compared with the controls . The circumferential strain (CS) of the LAD territory was significantly reduced in groups III and IV compared with the controls and groups I and II . Compared with the non-LAD territory, the LAD territory in groups II-IV showed significantly increased LS (− 18.6% vs − 21.9%, CT-FT can detect decreasing LV systolic function in patients with LAD stenosis. LV regional systolic deformation of the LAD territory was reduced with increasing LAD stenosis severity. In the past decade, the burden of ischemic cardiovascular disease has risen to the leading cause of morbidity and mortality worldwide , notablyCardiac strain imaging is a quantitative tool used in the early evaluation of regional systolic cardiac function using echocardiography and cardiac magnetic resonance (CMR) , 9. CTA-Consequently, we aimed to evaluate the feasibility of CTA-derived assessments of strain for regional left ventricular (LV) systolic deformation in patients with different degrees of isolated LAD stenosis.A total of 119 patients with suspected coronary heart disease were prospectively screened by the multidisciplinary thoracic oncology group at the Union Hospital of Tongji Medical College. Among them, 87 patients were diagnosed with LAD stenosis. Then, 32 sex- and age-matched normal subjects were included as controls.The inclusion criteria for the LAD stenosis patients were (1) patients diagnosed with LAD stenosis (not including stenosis of the left circumflex coronary artery or right coronary artery); (2) clinically confirmed subjects aged between 30 and 80 years; and (3) no wall motion disorder on echocardiography. The exclusion criteria were (1) a history of MI or Q-waves on ECG; (2) known MI, congestive heart disease, heart valve disease, or structural heart disease; (3) atrial fibrillation; and (4) arrhythmias. All individuals were examined with a cardiac CT scan.Data regarding demographics and medical comorbidities were collected prospectively before the cardiac CT scan. Nonsmoking was defined as lifetime exposure to fewer than 100 cigarettes, and the remaining patients were categorized as ever-smokers. Patients who consumed alcohol were defined as having a positive alcohol consumption history, and the others were classified as never consumers. Written informed consent was obtained from all participants.CT examinations were performed using a DSCT scanner , and the CTCA scanning parameters were as follows: detector collimation 32 × 0.6 mm, slice acquisition 64 × 0.6 mm by means of a z-flying focal spot, gantry rotation time 330 ms, pitch of 0.2–0.39 adapted to the heart rate, reference tube current-time product 400 mAs, and tube voltage 120 kV.Prior to the examination, patients with a heart rate higher than 75 bpm were treated with a β-blocking agent  to control the heart rate below 75 bpm, and all patients were instructed regarding breath holding to minimize artifacts during examination. Nitroglycerin spray  was used sublingually 5 min before the examination to dilate the coronary arteries. The CTCA scan was started by continuously injecting a total of 70 ml of iopamidol  followed by 40 ml of saline solution into an antecubital vein via an 18-gauge catheter (injection rate 4 ml/s) by an automatic injector. Bolus tracking was used to start the scan with a tracking area set at the root of the descending aorta. The image acquisition started 5 s after the signal attenuation reached the predefined threshold of 100 Hounsfield units. A retrospective gating technique was used to synchronize the data reconstruction with the ECG signal. We reconstructed 20 phases in 5% steps of the R-R interval within the full window. The data constructive section thickness was 0.75 mm, the increment was 0.5 mm, and the reconstruction kernel was B26f heart view smooth without using the iterative reconstruction technique. The image postprocessing methods on the workstation included 3D volume rendering (VR), multiplanar reconstruction (MPR), curved planar reconstruction (CPR), and maximum intensity projection (MIP) using Circulation software.The percentage of LAD stenosis was defined by coronary CT angiography (CTA) Fig. . Two radA commercial software package ) was used to analyze the original three-dimensional (3D) dataset package to generate two-dimensional (2D) cine loops of three long axis (LAX) slices , three short axis (SAX) slices , and a SAX stack with a slice thickness of 0.75 mm and a reconstruction increment of 0.4 mm. Images were generated at a time resolution of 10 phases per cardiac cycle, increasing from 10% increments from the early systolic (0% cardiac cycle) to the end-diastolic (90% cardiac cycle). This was performed to ensure that the 2D cardiac CT reconstruction closely matched the anatomical location of the image.Cardiac volumetric and functional parameters were quantified based on the manual delineation of the endocardial and epicardial borders using a stack of continuous SAX slice cine images (after excluding the papillary muscles from the myocardium). The left ventricular EDV, ESV and EF were obtained automatically.Longitudinal strain (LS) was assessed by averaging the peak systolic strain values of 17 segments extracted from three LAX images Fig. a, while t tests were used to compare two groups of normally distributed variables, and chi-square tests were used to compare categorical variables. Clinical characteristics and CT findings were compared among groups I-IV and the controls by one-way ANOVA. Normally distributed variables were analyzed by Pearson’s correlation analysis, and nonnormally distributed data were analyzed by the Spearman correlation analysis. Multiple linear regression analyses were performed to identify the determinants of myocardial LS in patients with LAD stenosis. All candidate variables (p < 0.2 on univariable linear regression without collinearity) were entered into the multiple stepwise regression model. Repeatability between observers was evaluated with 25 randomly selected patients with the Bland–Altman test. A p value < 0.05 (two-tailed) was considered statistically significant. Statistical analyses of all data were carried out using SPSS software .For all continuous data, the normality of the distribution was checked using the Kolmogorov-Smirnov test. Normally and nonnormally distributed data and categorical variables are expressed as the means ± standard deviations and the medians (interquartile ranges) and frequencies (percentages), respectively. Independent sample Student’s p = 0.986).Among the 87 screened patients, eight were excluded because of poor-quality CT images, and three were excluded because of too many segments with poor tracking. Three of our patients had CAG results, and the percentages of LAD stenosis were 60, 75, and 90%. The remaining 73 patients were assessed by CTA. Then, the patients were divided into four groups according to the percentage of LAD stenosis: ≤25% was defined as group I (24 patients), 26 to 49% as group II (17 patients), 50 to 74% as group III (21 patients), and ≥ 75% as group IV (14 patients). Additionally, thirty-two sex- and age-matched healthy subjects were included as controls. During CTA examination, no significant difference in the average heart rate was found between the CAD groups and the controls , end-diastolic volume (EDV) (p = 0.719) and end-systolic volume (ESV) (p = 0.257) (Table No significant intergroup differences were found between groups I-IV and the controls in terms of the left ventricular ejection fraction (LVEF)  p = 0.79 and endThe longitudinal strain (LS) of the LAD territory was significantly reduced in groups I-IV compared with the controls . The peak value of LS decreased as the stenosis degree of the LAD increased; specifically, the higher the degree of stenosis was, the lower the LS value. In addition, the circumferential strain (CS) of LAD territory was significantly reduced in groups III and IV compared with the controls and groups I and II , but the amplitudes of radial strain (RS) showed no significant differences among the five groups , which was not observed in the controls or group I. Group III had a significantly increased CS of the LAD territory compared with that of the non-LAD territory , which was not observed in other groups. However, no significant differences were found between the RS of LAD territory and that of non-LAD territory in the five groups  , the level of high-density lipoprotein cholesterol (HDL-C) , and LVEF . In addition, the CS of the LAD territory showed a significant negative correlation with the LVESV  and LVEF . The RS showed a negative significant correlation with the LVEDV . However, no significant associations were observed between cardiac strain  in the LAD territory and age, heart rate, hypertension, history of smoking, history of alcohol consumption, BMI, DM, or other medications.These results are shown in Table The intra-class correlation coefficient (ICC) value in the intraobserver analysis was 0.973 for the percentage of LAD stenosis on CTA. The ICC of variability was good for the global strain values and the average segmental amplitude of strain in the LAD territory Table .Table 5Decreased regional LV dysfunction in patients with critical stenosis of the LAD was detected by 2D speckle tracking echocardiogram (STE) by Iva et al. . HoweverInterestingly, in our study, the LS of the LAD territory was significantly reduced in groups I-IV compared with the controls, while the CS of the LAD territory was reduced in the group with coronary stenosis ≥50%, and the RS and LVEF showed no significant differences among the groups. Meanwhile, compared with non-LAD territory, groups II-IV had a significantly increased LS in the LAD territory, but only group III had a significantly increased CS in the LAD territory, even though no significant differences were found between the RS of the LAD territory and the non-LAD territory in all groups. These results suggested that LS was more sensitive for detecting impaired myocardial function than CS or RS. A previous study indicated that as the degree of ischemia worsens, ischemia and necrosis spread across the wall from the endocardium to the epicardium in CAD patients . TherefoIn addition, our findings showed that ACEI treatment was significantly correlated with greater segmental myocardial LS. This suggests a protective effect of ACEI on myocardial systolic function. Previous meta-analyses have shown that ACEIs have multiple potential cardioprotective effects: controlling blood pressure and reducing LV hypertrophy as well as potentially exerting anti-atherosclerotic effects , 27. FurThe present study has several limitations. First, this study was conducted in a single center with a small sample, limiting the generalizability of the conclusions. Second, the patients with CAD were not verified by CAG. An invasive examination was inappropriate for patients without an MI history. None of our patients had a history of myocardial infarction, and CTA was used to rule out coronary heart disease. Most patients had mild to moderate stenosis; therefore, no further coronary angiography was performed in most patients. Although CAG was not performed in all patients (only three patients underwent CAG), we used coronary CTA images to assess the degree of coronary stenosis. Third, the heart rates of some patients during CTA examination were higher than 60, which might have influenced the strain assessment. However, no significant difference in the average heart rate was found between the CAD groups and the controls. Fourth, coronary artery calcification scores were not calculated for these patients. Considering the radiation dose during examination, non-enhanced cardiac CT scans were not performed. Lastly, we did not obtain comparison data for cardiac strain on CT with 2D-strain echocardiographic or cardiac MR feature tracking in our subjects, which limits the impact of the findings. However, CT-derived strain has been shown to be closely correlated with both echocardiography and CMR in multiple studies –13.Using the CT-derived strain, our study showed that the subclinical regional LS was significantly reduced in LAD stenosis patients compared with the healthy controls and was inversely correlated with the severity of LAD stenosis. Moreover, ACEI treatment can ameliorate decreased regional LS. In the future, a comprehensive, large-scale study is warranted to further explore the effects of the degree of stenosis in the three coronary vessels and medication on LV systolic function in this population. CT-derived strain may be a novel biomarker to support early myocardial function assessments and therapeutic decision-making in ischemic cardiomyopathies or other related diseases.


TM algorithm combines data from five sensors of cardiac implantable electronic devices into a cumulative index value. It has been developed for early detection of fluid retention in heart failure patients. This review aims to provide an overview of the current literature and experience with the HeartLogicTM algorithm, illustrate how the index can be implemented in daily clinical practice and discuss ongoing studies and potential future developments of interest.Heart failure (HF) hospitalisations due to decompensation are associated with shorter life expectancy and lower quality of life. These hospitalisations pose a significant burden on the patients, doctors and healthcare resources. Early detection of an upcoming episode of decompensation may facilitate timely optimisation of the ambulatory medical treatment and thereby prevent heart-failure-related hospitalisations. The HeartLogic Heart failure is a syndrome that is defined by the European Society of Cardiology as “a clinical syndrome characterized by typical symptoms  that may be accompanied by signs  caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress” . It resuThe mainstay of preventing heart failure admissions is early detection of an episode of upcoming decompensation. Timely recognition, however, remains challenging as in daily practice worsening symptoms occur relatively late . RecentlTM sensor is a permanent pulmonary artery wireless microelectromechanical sensor that enables daily measurement of filling pressures, which have been shown to increase several weeks before a period of decompensation becomes clinically apparent [TM group as compared to the standard care group [TM sensor in broader cohorts of heart failure patients and in different healthcare settings are ongoing, including the MONITOR-HF study that investigates the efficacy and cost-effectiveness of hemodynamic pulmonary artery monitoring in addition to contemporary standard heart failure care in a high-quality western European healthcare system [TM sensor.Another management strategy is remote monitoring through implantable hemodynamic monitors. For example, the CardioMEMSapparent . In the re group . Severale system . DespiteTM and CorVueTM that measured changes in the intrathoracic impedance. Studies evaluating intrathoracic impedance measurements revealed that this single marker is not robust enough in predicting an upcoming episode of decompensation [TM . This algorithm collects data regarding heart sounds, respiration, thoracic impedance, heart rate and activity data and combines them into an automatically calculated daily heart failure index. The United States Food and Drug Administration approved implantation of CIEDs with this feature in 2017. Since then, the number of patients in clinical practice with a CIED with the ability to measure the HeartLogicTM index has been vastly increasing.An alternative approach, taking advantage of the fact that many heart failure patients with a reduced left ventricular ejection fraction have a CIED, is telemonitoring through parameters that can be sensed by this device. Without additional effort of the patient, data can be continuously gathered and automatically transferred through the remote monitoring platform of the CIED. Earlier examples of these kinds of applications are OptiVolensation ,29,30,31TM algorithm. Furthermore, three cases are presented to illustrate how the algorithm can be implemented in daily clinical practice, future studiesand potential developments of interest are discussed. In this paper, we demonstrate that the HeartLogicTM algorithm is validated for early detection of fluid retention and highlight ongoing and future studies regarding the clinical implementation of the algorithm.The aim of this review is to provide an overview of the current knowledge and literature on the HeartLogicTM algorithm is installed on implantable cardioverter defibrillator devices (ICDs) or cardiac resynchronisation therapy devices (CRTs) of the manufacturer: Boston Scientific. The following CIEDs  are compatible with the HeartLogicTM algorithm: PERCIVATM, CHARISMATM, MOMENTUMTM, RESONATETM and VIGILANTTM. The algorithm combines data obtained from five sensors . An example of a HeartLogicTM report is provided in The HeartLogic sensors  of the dTM index . Data frTM index . IntrathTM index . RespiraTM index . Night hTM index is associated with fluid accumulation. A low index is suggestive of a stable clinical status of the patient without signs of fluid retention. If the index surpasses the defined value of 16, a digital alert is given off in the home monitoring system and the medical team is alarmed. The threshold is dynamic and automatically lowers to 6 when an alert state (index of 16 or higher) is reached. The system will subsequently give weekly alerts until the index falls below 6.After a CIED implantation, the algorithm is calibrated during a 30-day period. After this calibration period, deviations of the data provided by the five sensors are compared to the daily variations measured during the calibration period. Significant alternations in one or more of the sensors will result in a change of the composite index. Increased absolute value of the HeartLogicThere are a couple of features of the algorithm that need to be specifically mentioned: data are automatically transferred by the home monitoring system and no (auditory) alarms are given off to the patient directly. Patients need basic IT skills and a functional internet connection to transfer data via the home monitoring system. Data are reviewed at the hospital via a product specific platform by the dedicated heartcare professionals and alerts are not communicated by other means. Patients are therefore unaware of alerts until they are contacted by the healthcare professional. No additional hospital visits are required for data retrieval.TM algorithm to date (31 December 2020) was performed. PubMed, Web of Science and Scopus were searched using the following terms: “heartlogic” and “heart failure”. The search was restricted to human studies in adults with heart failure and a CIED with the possibility to activate the HeartLogicTM features. Editorials, case reports, reviews, book chapters, practice guidelines and abstract publications were excluded. The titles and abstracts of all studies retrieved from the literature search were screened. Studies, of which the relevance could not be ascertained based on the abstract, were screened in full text format. Extracted data included details of the study population, study design, statistical analysis, adjusted variables for multivariate analysis and duration of follow-up. Data on the primary and secondary endpoints regarding the performance of the alert (including sensitivity and specificity) and outcome measures (fluid retention/decompensated heart failure) were extracted.A structured review of the published studies on the HeartLogicThe above strategy resulted in 80 citations, from which 21 duplicates were removed. The remaining 59 citations were screened based on the title and abstract. Of these, 15 articles were additionally screened in full text format. In total, nine citations were excluded, five case reports and four articles that did not meet the inclusion criteria were deemed not relevant. Finally, six articles passed full text screening and were included in this review, Median age in all six studies was 60–71 years old and the majority of patients were male 73–81%), which is in line with other large heart failure studies 1%, which,37. In aTM algorithm would provide better insight into impeding decompensated heart failure episodes [The MultiSENSE study was the landmark trial that hypothesised that the use of multiple sensors computed into the HeartLogicepisodes . The stuTM index of ≥16 compared with a HeartLogicTM index <16 was associated with a 10.6-fold higher heart failure event ratio  compared with 0.08 events per patient year “out of alert” state) [TM index demonstrated only a modest event ratio of 0.16 events per patient year. In contrast, a low NT-Pro BNP and an “in alert” HeartLogicTM index demonstrated a 3-fold higher event ratio of 0.47 events per patient year and a 23.5 times increased risk of a heart failure event compared to the “out of alert” and low NT-Pro BNP levels group. The group of patients who were “in alert” and had elevated NT-Pro BNP levels at baseline had a 50-fold higher event rate compared with patients “out of alert” state and a low NT-Pro BNP [TM index did not show significant interactions [A post-hoc analysis of the MultiSENSE data by Gardner and colleagues showed that a HeartLogic” state) . Increas-Pro BNP . These dractions .Capucci and colleagues performed a retrospective analysis of a case series of 67 patients  . During The results of two large prospective multicentre registries were published in 2020 ,40. CalòTM alerts in 53 of the 104 patients  [In the second recently published prospective multicentre registry, Santini and colleagues reported 100 HeartLogicnt year) . Sixty oTM features during the period of February–April 2020 [TM index before (1 February 2020–19 February 2020) or during (23 March 2020–15 April 2020) the first peak of the COVID-19 pandemic were observed. A significant drop in patient activity levels, with a corresponding drop in mean heart rate, a small increase in thoracic impedance and a less frequent S3 were observed during the first peak of the COVID-19 pandemic [In the most recent study published in 2020, Mitter and colleagues performed a retrospective chart review of 38 New York patients with heart failure and active HeartLogicril 2020 . No diffpandemic . A decreTM algorithm and reported a sensitivity of 70% for detecting an upcoming heart failure episode [TM index ≥ 16 [TM index alerts 34–38 days prior to a heart failure event in need of hospitalisation and 12 days before a minor clinical heart failure event [TM index in predicting fluid retention and provided us with insights into the scope of functionalities of the algorithm. However, in order to further investigate the potential of the HeartLogicTM index in modulating clinical outcomes—i.e., prevention of (re-)hospitalisation and shortening of admission duration, it is essential that this CIED modality be well embedded in a clinical care path.To date, studies focused primarily on the validation of the HeartLogic episode . On averdex ≥ 16 ,33,40. Tdex ≥ 16 ,33,40. Tre event ,33. A core event . These sTM algorithm, it is important for this CIED-based index to be incorporated into a clinical care path with defined roles and responsibilities of the healthcare professionals involved and an overall course of action in the case of an “in alert” patient status. TM index can be embedded in clinical practice.To explore the full range of clinical applications of the HeartLogicTM features need to be activated by the device technician. After a CIED implantation, the HeartlogicTM algorithm is first calibrated during a consecutive 30-day period. Following this calibration period, the deviations in the input provided by the sensors will be reflected in the value of the HeartLogicTM index. The index value and the sensor input data will be monitored and stored in the CIED of the patient and transferred via the home monitoring system at regular intervals. These data can be accessed by the authorised healthcare providers using a secure web-based application. Data are typically initially reviewed by device technicians, who are supervised by a cardiologist-CIED specialist. In the case of a HeartLogicTM alert, the device technician will analyse the CIED interrogation data and will inform the heart failure caregiver of the “in alert” status of the patient. The heart failure caregiver will contact the patient to check for potential signs and symptoms of fluid retention. In the case of (suspicion of) decompensated heart failure, this will be managed accordingly with lifestyle advice, medication adjustments and clinical evaluation as deemed necessary. The effect of the above intervention will be evaluated by reassessment of the clinical condition of the patient and the HeartLogicTM index.After CIED implantation or a pulse generator exchange procedure, the HeartLogicTM index in our tertiary hospital.Three cases are discussed next to illustrate the implementation of the HeartLogicA 69-year-old male patient had an anterior wall infarction in 1986, and an ICD for primary prevention was implanted in 2005. He developed progressive heart failure despite optimal medical treatment. Coronary artery bypass grafting, mitral valve plasty, tricuspid valve plasty and aortic valve replacement were performed in September 2017. A surgical left ventricular lead was placed, and the pulse generator was upgraded to a CRT-D.TM feature was available for clinical use from January 2018, 2 and a pro-BNP level of 6474 ng/L. The HeartLogicTM index was 8, which is on the upper limit of normal (point A). On February the 5th, the HeartLogicTM alert was issued as the index crossed the programmed threshold of 16 (point B). A review of the remote data showed that the index had gradually increased to 17 over the last 2 weeks. We contacted the patient by phone: he reported no symptoms or signs of fluid retention. Re-evaluation by phone was performed 2 weeks later (point C). Despite a further increase in the HeartLogicTM index to 25, he still reported to be asymptomatic although he admitted to having a larger fluid and salt intake than advised. We recommended him to adjust his intake. Thereafter, the HeartLogicTM index stabilised, but did not decrease. Accordingly, an outpatient visit was scheduled (point D). At the outpatient clinic, the patient initially denied having symptoms. However, despite cardiac rehabilitation, his exercise capacity decreased over the last weeks and he experienced mild shortness of breath during exercise. Physical examination showed elevated jugular venous pressure and mild ankle oedema. Laboratory testing revealed a decrease in renal function with an eGFR of 33 mL/min/1.73 m2 and the pro-BNP level had increased to 9650 ng/L. The HeartLogicTM index was 22. Accordingly, we concluded that the patient had gradually developed signs of fluid retention and increased the dosage of bumetanide. After this, exercise capacity increased and he successfully completed the cardiac rehabilitation program. Simultaneously, the HeartLogicTM index declined to 0 (point E). At a follow-up visit in April, the patient had no signs of fluid retention. Laboratory testing revealed that the eGFR improved to 42 mL/min/1.73 m2 and that the pro-BNP level declined to 4173 ng/L. Currently, two and a half years after surgery, the patient is in a clinically stable condition  and no decompensated heart failure hospitalisations have occurred. This case illustrates how the HeartLogicTM index can successfully be incorporated into a structured heart failure care path and shows that the index may be of value in guiding ambulant medication adjustments.After calibration, the HeartLogicTM index was well below the threshold of 16. In April 2018, he was admitted with dyspnoea based on a symptomatic slow ventricular tachycardia, which was terminated by antitachycardia pacing. Interestingly, his HeartLogicTM index had not surpassed the threshold of 16, A 49-year-old male patient with heart failure due to a familial hypertrophic cardiomyopathy had an ICD implanted for secondary prevention. In January 2018, his device was upgraded to a CRT-D because of progressive heart failure and a worsening LV function. Initially, his HeartLogicTM index exceeded the threshold. Remote interrogation of the CRT-D revealed no arrhythmias. The heart failure nurse contacted the patient by phone. The patient denied having symptoms of fluid retention although his exercise capacity was modest, and his weight had increased by two kilograms in four days. He said he had adhered to the lifestyle advice. The bumetanide dose was increased for three days, after which his weight returned to target and his exercise capacity improved. After two weeks, the HeartLogicTM index decreased to 0. In this case, the HeartLogicTM index accurately reflected the fluid status and symptoms of decompensation but did not give alerts in the case of arrhythmia that did not disturb the fluid status.On 29 May, 7 weeks after discharge, his HeartLogicA 64-year-old female patient had heart failure due to an anthracycline medicated dilated cardiomyopathy. Despite optimal medical treatment and a mitral and tricuspid valve plasty in 2008, her left ventricular systolic function remained poor. Accordingly, an ICD for primary prevention was implanted in 2009. Since 2014, she had progressive heart failure and recurrent episodes of atrial fibrillation. Despite treatment with amiodarone, she developed permanent atrial fibrillation and dyspnoea NYHA class III. She was screened for a heart transplantation listing but was rejected due to stage 4 chronic kidney disease.TM index was 5, In April 2018, she developed a progressive cardiorenal syndrome with an admission because of decompensated heart failure. After recompensation with furosemide and dobutamine, an upgrade to a CRT-D device was performed because of intraventricular conduction disorder with a QRS duration of 140 ms. A few weeks later she was admitted to the surgical ward because of spontaneous bleeding from pseudoaneurysm of the arteria gastroduodenalis complicated by acute tubular necrosis and further renal deterioration. Although she retained residual diuresis, the renal function only partially recovered, and she was started on haemodialysis twice a week. During the outpatient clinic visit 1 month later, there were no signs of fluid overload and the HeartLogicTM index rapidly increased to 38. The patient denied experiencing symptoms of fluid retention and was compliant with the lifestyle advice. According to the care path, a re-evaluation by phone followed 2 weeks later. At that time, the HeartLogicTM index had increased to 50. She admitted having a higher salt intake and a slight increase in dyspnoea. She was in NYHA class III and physical examination revealed signs of fluid retention. The NT-proBNP had increased from 9500 ng/L to 22,000 ng/L. Despite an increase in the daily dosage of bumetanide to 15 mg/day, her fluid status could not be sufficiently optimised. Following a multidisciplinary consultation with the nephrologist, it was decided to extract extra fluid during each dialysis session. Subsequently, the HeartLogicTM index decreased, ultimately to 1 and heart failure symptoms improved. This case illustrates that HeartLogicTM can be used as a marker for fluid status in patients with complex haemodynamics, such as in cardiorenal syndrome.In July 2018, the HeartLogicTM algorithm was performed on 31 December 2020. To this aid, ClinicalTrials.gov, a database for clinical studies conducted around the world was used. The search was restricted to “HeartLogic” and “heart failure” patients. Two ongoing and one yet to be initiated study (n = 3) were extracted. Additionally, a recently conducted and not yet published study by Treskes et al. was retrieved from the Leiden University Medical Centre research registration. An overview of these four studies is provided in A review of ongoing registered studies on the HeartLogicTM algorithm has by now been well established in the literature and it is clear that the ongoing studies are going to shift the focus from surrogate markers to clinical outcomes—including mortality, heart failure related hospitalisations and re-admissions.The validation of the HeartLogicTM index in 2700 patients. The primary endpoint is all-cause mortality and secondary endpoint is heart failure related hospitalisations. The first results are expected in 2025.The MANAGE-HF study is a randomised open label trial that has been enrolling patients since 2017. It will evaluate the clinical efficacy of CIED remote monitoring of heart failure patients with and without the HeartLogicTM sensors and rehospitalisation within 30 days after an index heart-failure-related hospitalisation. The sensor value changes will be compared between the no readmission group and the readmission within 30 days group. It is expected that the HeartLogicTM feature will be further enhanced based on the results of this study so that such alerts can lead to earlier intervention and reduction in heart failure admissions. Over 2100 patients have been included and patient recruitment was preliminary terminated in June 2020. Follow-up and data analysis are currently ongoing.The PREEMPT-HF study is a prospective observational study that started enrolling patients in 2018. It will focus on association between HeartLogicTM pre-activation period of 365 days is compared with a 365 days post-activation period, primary endpoint consists of total number of hospitalisations for decompensated heart failure. Secondary endpoints are the number of patients hospitalised for heart failure, mean number of heart failure admissions per patient and mean length of hospital stay in days in the pre-activation period compared to the post-activation period.A third study by Treskes et al. is a prospective non-blinded single-arm cohort study that has recently been completed and is currently under review for publication. It included 74 patients from three participating centres in the Netherlands, Belgium and Switzerland. A HeartLogicTM France study is a prospective observational cohort study that was due to start enrolling patients in December 2020. Estimated enrolment consists of 300 patients. The study will focus on the annual heart failure hospitalisation rate as its primary endpoint. The secondary endpoints include: the annual cardiovascular and heart failure mortality rate, annual rate of unplanned hospitalisations due to ventricular and atrial arrythmias, annual rate of hospitalisation days related to heart failure, ventricular or atrial arrythmia, and patient quality of life. In addition, the study aims to perform weekly evaluation of the HeartLogicTM index in all its subjects for the duration of a yearThe HeartLogicTM algorithm has extensively been validated and its association with, and role in, the prediction of impeding fluid retention several weeks prior to symptoms have been confirmed by numerous international studies. However, ongoing and future trials still have to clarify the impact of the HeartLogicTM algorithm and timely HeartLogicTM index guided intervention on hard clinical outcomes—including (reduction in) mortality, heart failure related hospitalisations and re-admissions. Furthermore, constraints on logistical implementation have to be resolved.The HeartLogicTM index as a standalone technique to guide therapeutic actions. Patient care is not a “one size fits all”, and a HeartLogicTM index guided clinical care path seems essential in this matter. Ideally, a standardised protocol should be at hand in which the roles of the individual care providers and the (therapeutic) consequences of a HeartLogicTM alert are clearly defined. It still remains to be investigated whether mild symptoms or an alert by itself justifies therapeutic adjustments. In the MANAGE-HF trial [TM alert, regardless of symptoms. However, due to the false alert rate and the potential side effects of high doses of diuretics , it can be argued that therapeutic action should only be undertaken in the case of concomitant symptoms. The manufacturer aims to enhance the HeartLogicTM features based on the results of the PREEMPT study to optimise its role in guiding early therapeutic intervention in the prevention of heart failure readmissions [In order to move forward, several practical aspects have to be considered. None of the above-mentioned studies evaluated the HeartLogicHF trial , by desimissions .TM index is not released by Boston Scientific, it would be of interest to understand what the predictive values of the individual components are and correlate these to other remote monitoring strategies that are currently implemented in heart failure patients. In particular, implantable pulmonary artery pressure sensors, such as the CardioMEMSTM sensor, enable daily measurement of left ventricular filling pressures, which have been shown to increase several weeks before a period of decompensation becomes clinically apparent [Although the exact algorithm behind the cumulative HeartLogicapparent ,27. GiveTM features in specific patient groups—in particular, to guide care in those with advanced heart failure where conventional heart therapies and symptom management strategies are no longer effective, i.e., patients with a left ventricular assist device (LVAD) or those listed for a heart transplant or LVAD implantation; patients with (cardio-)renal failure requiring frequent fluid status optimisation by means of forced diuresis or dialysis and patients with pulmonary hypertension [Future studies are expected to focus on the efficacy of the HeartLogicrtension . An importension ,46.TM and telemonitoring guided care “close to home” are essential. The insurance companies and the healthcare ministry are key players in healthcare financing and highlight the importance of not only focusing on the efficacy, but also evaluating the cost effectiveness of HeartLogicTM guided care in various healthcare systems.To successfully implement a healthcare program, it is imperative to involve the different stakeholders. Regional collaborations with referring hospitals and general practitioners to be able to provide effective HeartLogicTM algorithm. Several limitations should therefore be taken into account. We reviewed three electronic databases in search of literature and might have overlooked potentially relevant (ongoing) studies and therefore we acknowledge the possibility of skewed presentation. Other interesting developments in future sensors, including flexible electronics and wearable devices, are beyond the scope of this review and therefore not discussed in detail. To date, limited literature on the HeartLogicTM algorithm is available; the majority of the studies are observational trials or case series with limited number of patients and relatively short duration of follow-up. In this review, a case series of three patients is shown to illustrate the implementation of the HeartLogicTM algorithm in clinical practice. These cases provide no causal evidence and are illustrative by nature. The weight of each individual sensor in the algorithm of the HeartLogicTM index is not released by the manufacturer. The potential impact of missing data collected by the CIED can therefore not be evaluated [This is a narrative review on the HeartLogicvaluated . Data onTM algorithm has been successfully validated for early detection of fluid retention in an upcoming heart failure event. The results are promising, and several studies are currently focusing on hard clinical outcomes, such as (reduction in) mortality, heart-failure-related hospitalisations and re-admissions. A dedicated and well-defined clinical care path incorporating the HeartLogicTM algorithm is required to maximise the benefit of “patient tailored care” and to limit the impact of clinically unexplained alerts. Further enhancement of the HeartLogicTM algorithm and better understanding of the predictive values of alerts, addressing the logistical and financial aspects, are expected to contribute to a better integrated care service for patients with a CIED.The HeartLogic


The risk of left ventricular (LV) and right ventricular (RV) maladaptation after surgery for isolated primary mitral regurgitation (PMR) is poorly defined. We aimed to evaluate LV and RV contractile function using speckle-tracking analysis alongside with quantification of exercise tolerance in patients with PMR after mitral valve surgery. All consecutive patients with symptomatic PMR undergoing mitral valve surgery between July 2015 and May 2017 were prospectively enrolled. Sequential echocardiographic studies along with clinical assessment were performed before and three months after surgery. Mean age in 138 patients was 65.8 ± 12.7 years, 48.2% (66) of whom were female. Mean LV ejection fraction decreased from 57 ± 12% to 50 ± 11% (p < 0.001), LV global longitudinal strain deteriorated from −19.2 ± 4.1% to −15.7 ± 3.8% (p < 0.001), and mechanical strain dispersion increased from 88 ± 12 to 117 ± 115 ms (p = 0.004). There was a reduction in tricuspid annulus plane systolic excursion from 22 ± 5 mm to 18 ± 4 mm (p < 0.001), as well as a slight deterioration of RV free wall mean longitudinal strain from −16.9 ± 5.6% to −15.7 ± 4.1% (p = 0.05). The rate of moderate to severe tricuspid regurgitation significantly decreased (p < 0.005). Regarding exercise tolerance, the New York Heart Association class improved (p < 0.001) and the walking distance increased (p < 0.001). During mid-term follow up after surgery for PMR, a deterioration of LV and RV contractile function measures could be observed. However, the clinical status, LV dimensions, and concomitant tricuspid regurgitation improved which in particular imply more effective RV contractile pattern. Primary mitral regurgitation (PMR) due to mitral valve degeneration is the most common etiology in patients undergoing mitral valve surgery . SurgicaYet, patients with mitral regurgitation are often referred too late for surgery due to alleged preserved left ventricular (LV) function in echocardiographic controls . Due to However, the risk of functional LV maladaptation, the reaction of right ventricular (RV) function, and the resulting clinical implications after mitral valve surgery for isolated mitral regurgitation are poorly defined . On the Speckle-tracking based myocardial deformation analysis has meanwhile become an established method to evaluate myocardial function. Speckle-tracking based assessment of longitudinal strain is independent of the insonation angle, and can be used retrospectively on digitally archived standard grey-scale images .Hence, we aimed to evaluate LV and RV contractile function using longitudinal strain by speckle-tracking analysis together with the clinical status of patients with isolated PMR before and 3 months after mitral valve surgery.www.clinicaltrials.gov (NCT02296710).Assessment of exercise tolerance by the New York Heart Association (NYHA) classification alongside, the 6-min walking test and echocardiographic examinations were prospectively performed before and 3 months after surgery in all consecutive patients with severe PMR who underwent isolated mitral valve surgery between July 2015 and May 2017. The decision for surgical treatment was made after heart team discussion for each case individually. The study was approved by local Ethics Committee of Ruhr University of Bochum and carried out in accordance with the Declaration of Helsinki. All data were included in a database, which is registered at All study participants underwent standard transthoracic echocardiography . The echo studies were performed by highly qualified medical staff and analysed by the same echocardiographer with long-time experience. The analyses and grading of the mitral regurgitation were performed according to the recommendations of the American and European Societies of Echocardiography , 10.In cases with irregular cardiac rhythm  at least five loops were recorded and the average values has been provided.LV ejection fraction was assessed using the Simpson´s method. LV stroke volume was calculated by subtraction of the LV end-systolic volume from the end-diastolic volume. The Nyquist-limit was placed around 50–60 cm/s in color Doppler settings.To characterize RV function, tricuspid annular plane systolic excursion (TAPSE) and RV fractional area change (RV-FAC) were measured alongside with RV free wall longitudinal strain analysis.LV global longitudinal strain (GLS) was assessed as previously described using the speckle-tracking algorithm provided within the QLAB system (QLAB Version 10.2) . ThroughRV free wall longitudinal strain assessment was performed using a RV focused view with optimized RV endocardial borders according to the recommendations of the European and American Societies of Echocardiography Fig. d 12]. T. T12]. TStatistical analysis was performed using the SPSS-Software . Continuous variables are reported as mean ± standard deviation. Categorical variables are presented as frequencies and percentages. Baseline data were validated for normal distribution using the Kolmogorov–Smirnov method. Student’s T-test for unpaired and paired parametric samples or their analogues for nonparametric samples (Mann–Whitney and Wilcoxon signed rank) or the chi-square test were performed for group comparisons. A p-value < 0.05 was considered significant for all comparisons.2, a regurgitant volume of 67 ± 7 ml and a mean biplane vena contracta of 7.3 ± 0.5 mm. Out of the entire group 95 patients (68.9%) underwent mitral valve repair and 43 (31.1%) valve replacement.A total of 156 consecutive patients with primary mitral regurgitation were admitted and evaluated for mitral valve repair between July 2015 and May 2017. Five of them also required myocardial revascularization and four patients presented with a combined valve disease which had to be addressed. eight patients refused participation in the study and one patient was found to suffer from mitral valve endocarditis. Finally, 138 patients were included in the analyses. The baseline characteristics including parameters for mitral regurgitation severity are shown in Tables Details of echocardiographic parameters before and after surgery are presented in Table LV end-diastolic volume markedly decreased from 157 ± 57 ml to 138 ± 51 ml (p < 0.001) following valve surgery, while the other morphological parameters such as end-systolic diameter, septal thickness and posterior wall thickness did not change.Compared to baseline examinations, LV ejection fraction decreased from 57 ± 12% to 50 ± 11% (p < 0.001) while LV GLS deteriorated from −19.2 ± 4.1% to −15.7 ± 3.8% (p < 0.001). Additionally, strain dispersion increased from 88 ± 12 ms to 117 ± 115 ms (p = 0.004).With respect to RV function, tricuspid annular plane systolic excursion (TAPSE) was reduced from 22 ± 5 mm to 18 ± 4 mm (p < 0.001). RV free wall mean strain also showed a slight although borderline significant deterioration . However, tricuspid regurgitation improved after mitral valve surgery  and walking distance in the 6-min walking test  improved significantly . In this study, LV-EF and LV GLS showed a similar deterioration of the contractile function (3). In a retrospectively analysed cohort of 506 patients with a wide range of cardiac comorbidities and a median follow-up of 3.5 years, Kim et al. postulated GLS to better predict cardiac events and all-cause mortality than standard echocardiographic parameters . The authors concluded this measure to be helpful to estimate the optimal timing for mitral valve surgery . InteresHowever, despite functional impairment of the left ventricle, the patients showed pronounced clinical improvement in NYHA class and 6-min walking distance Fig. a, c. MorMitral regurgitation leads to a volume overload of the LA . The LA In the absence of volume overload after surgery, the pressure in the pulmonary vascular bed and consecutively in the right ventricle decreases. Right ventricular dimensions and functional tricuspid regurgitation are consecutively reduced . HoweverAnother aspect is the reduced mobility of the septum due to the increased LV impairment. In addition, the incompletely understood cardioplegia effect may have played a role , 22–24. Our mid-term follow-up data on exercise tolerance demonstrate a clear clinical improvement, which implies an economization and higher effectiveness of RV myocardial performance. Accordingly, tricuspid regurgitation also improved after surgery probably because of improved hemodynamic and lack of volume overload which is also a sign of recovered clinical status , 26.The study is descriptive and not designed to explain the phenomena it observes and can therefore only generate hypotheses. In addition, further studies should investigate whether and to what extent the deteriorated function parameters persist during longer-term follow-up and whether this has a long-term impact on survival.During mid-term follow up after surgery for PMR, a deterioration of LV and RV contractile function measures could be observed. However, the clinical status, LV dimensions, and concomitant tricuspid regurgitation improved significantly which in particular imply more effective RV contractile pattern.


Trypanosoma cruzi vaccines could significantly contribute to the control of ChD. The aim of this study was to examine the usefulness of echocardiography in determining the prophylactic effect of the DNA vaccines on heart damage using T. cruzi genes cloned into an expression vector, which was intramuscularly injected to beagle dogs. Structural and functional changes in the chagasic heart were monitored easily by echocardiography, and it was determined that plasmid DNA vaccination with T. cruzi genes induced moderate protection in immunized dogs avoiding enlargement of cardiac chambers, poor contractibility, and heart failure, especially with pBCSP plasmid , as was reported previously.Chagas disease (ChD) has become one of the biggest public-health problems in Latin America due to its incapacitating effects and mortality rates. Therefore, it is important to detect cardiac involvement as early as possible in order to estimate the risk and prognosis before the patient becomes symptomatic. Development of anti-Trypanosoma cruzi genes encoding a trans-sialidase protein and an amastigote-specific glycoprotein were tested as vaccines in canine model. The aim for this study was determining the prophylactic effect of these genes in experimentally infected dogs by echocardiography evaluation to compare with our findings obtained by other techniques published previously. Low fractional-shortening values of non-vaccinated dogs suggested an impairment in general cardiac function. Low left ventricular ejection fraction values found in infected dogs suggested myocardial injury regardless of whether they were vaccinated. Low left ventricular diastolic/systolic diameters suggested that progressive heart damage or heart dilation could be prevented by DNA vaccination. Systolic peak time was higher in non-vaccinated groups, increasing vulnerability to malignant arrhythmias and sudden death. High left ventricular volume suggested a decrease in wall thickness that might lead to increased size of the heart cavity, except in the pBCSP plasmid-vaccinated dogs. There was an echocardiographic evidence of left ventricular dilation and reduction in systolic function in experimental chagasic dogs. Echocardiography allowed a more complete follow-up of the pathological process in the living patient than with other techniques like electrocardiography, anatomopathology, and histopathology, being the method of choice for characterizing the clinical stages of ChD.Chagas disease (ChD) is considered an emerging disease in the USA and Europe.  Trypanosoma cruzi, which infects humans and more than 100 species of domestic and sylvatic mammals and can be transmitted by over 150 species of hemiptera insects of the subfamily Triatominae (Reduviidae) [Chagas disease (ChD) is caused by the protozoan parasite uviidae) ,3,4. ChDuviidae) ,7. Accoruviidae) ,9.There are two successive stages in ChD: acute and chronic phases. In the acute phase, cardiac involvement may occur in up to 90% of cases. After six to eight weeks, most patients show recovery of the clinical manifestations . The maiThe diagnosis of ChD can be made by serology a few weeks after the primary infection. Large-scale epidemiological studies have consistently demonstrated that about three-quarters of seropositive patients remain asymptomatic throughout their entire life . It is tIn chronic Chagas heart disease, the electrocardiogram (EKG) has been the method of choice for detecting myocardial damage, especially in remote endemic areas, because of its low cost, portability. and simplicity. For noninvasive detection of early myocardial damage, other methods have been used, including Holter monitoring, echocardiography, nuclear scans, and stress tests . Two-dimTrypanosoma cruzi, acting as reservoirs, but they can also develop acute and chronic disease, similar to human infection; therefore, canine Chagas’ disease has become a major veterinarian concern in the Americas [Dogs play a major role in the domestic cycle of Americas ,17,18. IAmericas . In addiAmericas ,28,29,30T. cruzi vaccines could significantly contribute to the control of ChD. Immunological protection against experimental infection with T. cruzi has been studied since the second decade of the last century, testing many types of immunogens [TcSP  and TcSSP4 (encoding amastigote-specific protein) genes were evaluated prophylactically as DNA vaccines in both murine and canine model of ChD [Development of anti-munogens . In our l of ChD ,34,35,36T. cruzi genes cloned into an expression vector, which was intramuscularly injected to beagle dogs. To do so, we use this cardiac imaging method to measure hemodynamic parameters to determine whether echocardiography provides accurate data on the development of morphological changes in the heart of experimentally infected and immunized/infected chagasic dogs and if these data are consistent with those reported previously [The aim of this study was to examine the usefulness of echocardiography in determining the prophylactic effect of the DNA vaccines on heart damage using eviously ,35,36.ad libitum. All dogs had a completed schedule of preventive medicine. A standardized enzyme-linked immunosorbent assay (ELISA) [T. cruzi.Animal handling and experimental procedures were approved by the Bioethics Committee of the National Institute of Cardiology Ignacio Chávez and performed under the established guidelines of the International Guiding Principles for Biomedical Research involving Animals and the Norma Oficial Mexicana (NOM-062-ZOO-1999) Technical Specifications for the Care and Use of Laboratory Animals . Forty-s (ELISA)  used to T. cruzi genes encoding the TcSSP4 (amastigote-specific protein) and TcSP  antigens were cloned in the commercially available eukaryotic expression vector pBK-CMV (Stratagene) to generate two constructs, pBCSSP4 and pBCSP, respectively, as described previously [The eviously . The dog5 metacyclic trypomastigotes per animal, which were obtained from urine and feces of triatomes and resuspended in SS of a well-characterized Mexican T. cruzi Ninoa strain (MHOM/MX/1994/Ninoa (T. cruzi)) [n = 6) were infected with an inoculum size that ranged from 50 × 103 to 2 × 106 metacyclic trypomastigotes. The amount of T. cruzi Ninoa strain inoculum had no effect on the severity of the canine ChD [The dogs immunized with DNA or mock-immunized with SS as well as three animals belonging to positive control group were challenged intraperitoneally two weeks after the last immunization with 5 × 10 cruzi)) ,40. The nine ChD ,35,36,38® tablets) at light sedation dose of 1.25 mg/kg of body weight was used by oral administration. Image acquisition was done by means of a right parasternal long-axis view and right apical two- and four-chamber view in bidimensional mode according to Boon’s method [Transthoracic echocardiography (Phillips IE33) with a 2.5–3.5 MHz probe was performed in all dogs three times at 1-week intervals before start the study and during the chronic stage of infection  in order to detect and compare morphological changes in the dogs’ heart among basal and/or reference values. The animals were positioned in dorsal and right lateral decubitus without any chemical restriction during the study; this could be achieved with previous training through daily manipulation in examination tables in order to keep the dogs in the desired position to carry out the study. In those few cases which chemical restriction was necessary , acepromazine . The parametric statistical test of one-way ANOVA was used to examine the vaccination effect within each group for echocardiographic variables. When a significant difference was detected, the Tukey test was used to compare the means. Results were expressed as mean ± standard deviation. The level of significance in all tests was set at p ≤ 0.05.All data obtained  were analyzed with commercially available software IBMT. cruzi infection was confirmed microscopically (parasitemia) in all infected groups by examining freshly isolated blood samples collected from the brachiocephalic vein every third day, observing from 200 to 400 parasites/mL as limit of detection intermittently between day 22 and day 55 postinfection. T. cruzi infection was diagnosed by the ELISA method two months postinoculation and was confirmed by indirect immunofluorescence technique in all unimmunized/infected dogs. All animals were monitored clinically by general physical examinations and electrocardiographic studies [The experimental  studies .T. cruzi genes reported previously on the protection of heart damage with the reduction of the cardiac function alterations by hemodynamic parameters, echocardiography was performed. This noninvasive method provided the useful tool to evaluate both anatomy structure and function of the heart. The mean ± standard deviations values of some cardiovascular parameters recorded at each group (specified in To correlate the prophylactic effects of DNA vaccines with The infected dogs (B group) had fractional shortening (FS %) values significantly reduced, very similar to those obtained in mock-immunized (G group) and empty cloning vector-immunized (F group) dogs, suggesting an impairment in general cardiac function since their basal values showed percentages within the reported reference values  and simiT. cruzi DNA (G group)  . No signG group) , suggestp < 0.05) than those of dogs that did not receive either vaccination in which progressive heart damage or heart dilation was diagnosed , while the values observed in vaccinated dogs were slightly lower  and mock-vaccinated/infected (G group) dogs ; converse values , showingTcSP gene (D group) resemble those obtained in the healthy control (A group) and immunized/noninfected (C group) dogs  , suggestup) dogs .T. cruzi infection was to prevent splenomegaly and to avoid serious damage to the heart, in which lesions were limited to the subepicardial tissue [About the protection of the vaccine at the clinical level, it was observed that the hyperthermia of the acute phase was avoided, that lymphadenopathy was detected, that tachycardia was prevented in both acute and chronic stages, and that the severity and number of abnormalities on the EKG decreased  Table 3Table 3. l tissue  , in those which were immunized with pBK-CMV plasmid (F group), and in the SS-mock immunized (G group). This parameter assesses size of cardiac chambers; if the parameter is high, it reflects a volume increase inside the chamber and therefore heart dilation [T. cruzi gene encoding TcSP trans-sialidase protein is able to protect against heart dilation or to avoid progressive heart damage if it is used as a prophylactic measure. Also, the vaccination could be effective to avoid more severe disorders such as malignant arrhythmias and sudden death because, in accordance with Biolo et al. [Diastolic measurements were higher in the groups that were not immunized with any dilation . Howevero et al. , the LV LV systolic diameter high values in animals of B, F, and G groups in the present study, which did not receive DNA immunization as preventive action, showed a marked cardiac function damage demonstrated by a significant increase of LV systolic diameter as well as systolic peak time. The systolic measurements by echocardiography assess cardiac function as well as the increased LV chamber size during systole . Two-dimTcSP gene as DNA vaccine (D group), suggesting that pBCSP immunization may protect in developing an increase in ventricular mass and end-diastolic volume as adaption mechanism by a chronic volume overload [The LV volume remained in reference values in those animals receiving the overload  like hypoverload . In addioverload , which sThe overall evaluation of these echocardiographic parameters indicates that the hearts of nonimmunized/infected dogs had volume overload with FS % below (27.32–31.64%) the references values (33–46%)  and, togTrypanosoma cruzi, being a study limitation. Further research should consider using echocardiography at an earlier stage of the ChD in order to follow up the pathological process, to give a timely symptomatic treatment, or to even try the trypanocidal therapy because, although acute chagasic myocarditis is infrequent, appearing in only 1% to 5% of those having the acute phase , there are published echocardiographic series on ChD patients who had abnormal two-dimensional echocardiograms in 52% and pericardial effusion in 42%. In addition, mean-LVEF was normal (63%) in these patients. Apical or anterior dyskinesis was found in 21%, and only 6% had LV dilation. These findings demonstrate the need to perform echocardiograms to rule out other cardiac conditions to lead to HF and to evaluate LV dysfunctions during the acute phase of ChD [This study, using dogs as an experimental animal model suggests that more valuable clinical data could be obtained by echocardiography for the management of the patient than those found by electrocardiography or by evidence of cardiac damage observed postmortem at necropsy or by histopathology. However, our echocardiography recordings were performed from 12 months after the challenge with e of ChD .Echocardiography has been very useful in prognosis of some canine diseases. For example, heart disease is not well characterized in adult dogs with Duchenne muscular dystrophy, so Guo et al. defined the clinical course of cardiomyopathy by evaluating echocardiography and cardiac magnetic resonance imaging in 24 golden retriever dogs. The study showed that dogs with muscular dystrophy have a progressive cardiomyopathy characterized by LV systolic and diastolic dysfunction, LV chamber enlargement, myocardial tension abnormalities, and myocardial fibrosis similar to that seen in dilated cardiomyopathy (DCM) . The purThere is a growing literature demonstrating the potential of nonconventional echocardiography in clinical and subclinical cardiac conditions; speckle tracking echocardiography is capable to discriminate between different causes of LV hypertrophy by ultrasound deformation imaging . HoweverT. cruzi genes induces moderate protection in immunized dogs, avoiding enlargement of cardiac chambers, poor contractibility, and HF, especially with pBCSP plasmid. Using echocardiography, structural and functional changes in the chagasic heart were monitored easily and without pain or discomfort to the patient. Also, this method was a suitable tool to evaluate the protection of progressive heart damage or heart dilation provided by the prophylactic effect of the DNA vaccine. Transthoracic echocardiography should be the method of choice for characterizing the clinical stages of ChD, such as systolic dysfunction during the acute phase of ChD, and to rule out a rapidly treatable cause of HF .In conclusion, it has successfully demonstrated that ChD in experimental infected dogs resulted in cardiac dilation and that plasmid DNA vaccination with


Myocardial ischemia in hypertrophic cardiomyopathy (HCM) is associated with poor outcomes. Vasodilator stress cardiac magnetic resonance (CMR) can detect and quantitate inducible ischemia in HCM patients. We hypothesized that myocardial ischemia assessed by CMR is associated with myocardial fibrosis and reduced exercise capacity in HCM. In 105 consecutive HCM patients, we performed quantitative assessment of left ventricular volume and mass, wall thickness, segmental wall thickening percent, segmental late Gadolinium enhancement (LGE), and extracellular volume fraction (ECV). Time-signal intensity curves of first pass perfusion sequences were generated for each segment at stress and rest. A myocardial perfusion reserve index (MPRI) (stress/rest slope) was calculated. Patients who underwent an echocardiographic (n = 73) and cardiopulmonary exercise test (n = 37) within 30 days were included. The mean age was 53.2 ± 15.4 years; 60% were male, and 82 patients had asymmetric hypertrophy. Segments with end diastolic thickness ≥ 1.2 cm had a higher burden of LGE (4.1% vs 0.5% per segment), reduced MPRI (2.6 ± 1.5 vs 3.1 ± 1.8) and reduced thickening percent (48.9 ± 41.7% vs. 105.3 ± 59.5%), . Patients with ischemia (any segment with MPRI < 2) were more likely to have dynamic left ventricular outflow tract (LVOT) obstruction , to be smokers , and had a higher ECV . The total LGE burden was similar between the two groups (P = 0.47). Increasing ischemia burden (number of segments with MPRI < 2) was associated with worsened ventilatory efficiency (VE/VCO2) (P < 0.001) but not peak oxygen consumption or anerobic threshold (P > 0.2). In a patient-level multivariable logistic regression model, only LVOT obstruction remained a significant predictor of ischemia burden (P = 0.03). Myocardial ischemia by CMR is associated with myocardial segmental dysfunction and interstitial fibrosis, as assessed by ECV, in HCM patients, even in segments free of LGE. Conversely, quantitative ischemia burden was not associated with replacement fibrosis as assessed by total LGE burden. Patients with ischemia had greater prevalence of dynamic LVOT obstruction; and in a subset of patients with cardiopulmonary exercise testing, ischemia burden was associated with worsened ventilatory efficiency. The natural history of HCM varies from a benign asymptomatic course to symptoms of chest pain or dyspnea, and in advanced stages to heart failure and sudden death2. Myocardial ischemia is an important pathophysiologic process in HCM and is associated with left ventricular adverse remodeling and systolic dysfunction4. Potential mechanisms include increased oxygen requirements due to hypertrophy, diastolic dysfunction and elevated filling pressures, abnormalities of intramyocardial arterioles, abnormal coronary flow dynamics in part due to left ventricular outflow tract (LVOT) obstruction7.Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, with a prevalence recently estimated as high as 1 in 200 live births9. It is a validated non-invasive method for quantitation of myocardial replacement fibrosis using the late gadolinium enhancement (LGE) technique10, as well as myocardial interstitial fibrosis using extracellular volume fraction (ECV)12. Vasodilator stress CMR allows for detection and quantitation of myocardial ischemia, and the degree of ischemia assessed by CMR has recently been linked to progression of LGE13. Assessment of myocardial ischemia, however, is not part of routine clinical assessment of HCM patients by CMR, particularly those considered to be low-intermediate risk for SCD15. We hypothesized that myocardial ischemia assessed by vasodilator stress CMR will be associated with myocardial fibrosis and reduced exercise capacity. Our second objective was to assess the predictors of ischemia on CMR.Cardiovascular magnetic resonance (CMR) is an important imaging modality in diagnosing and risk stratifying HCM patients8. We excluded patients who had prior septal reduction therapy, epicardial coronary artery disease (CAD), prior myocardial infarction, late gadolinium enhancement (LGE) in a CAD pattern, implanted cardiac devices, claustrophobia, or glomerular filtration rate < 30 mL/min per 1.76 m2. Figure The study was approved by the institutional review board at Houston Methodist Hospital and informed written consent obtained from all patients. All studies were performed in accordance with relevant guidelines and regulations. We included 105 consecutive adult patients from the DEBAKEY CMR Registry (NCT04281823), a prospective institutional registry. The studies were performed between July 2011 and June 2017. We included patients > 18 years old confirmed to have HCM according to guidelines16. Regadenoson 0.4 mg  was injected over approximately 10 s into a peripheral vein followed by a 5 mL saline flush. The stress perfusion sequence was started within 30–60 s of Regadenoson injection. Gadolinium-based contrast (0.15 mmol/kg gadopentetate dimeglumine or gadoterate meglumine) was infused at 3.5–4.5 ml/s followed by a saline flush (50 ml) via an antecubital vein . Patients routinely received aminophylline 100 mg intravenously for reversal of hyperemia after stress images were acquired. Rest perfusion was performed ~ 10 min after reversal.Patients were asked to refrain from caffeine for 24 h before Regadenoson stress CMR. Most procedures were completed in approximately 45 min. Studies were performed on 3 T and 1.5 T CMR systems . Steady state free precession sequences were used to acquire a series of short axis cine images and standard long axis views  during single breath holds, using retrospective ECG gating with slice thickness of 6, 4 mm gap, echo time = 1.33 ms, temporal resolution per phase 35–40 ms, in-plane resolution ~ 1.5–2.0 × 1.5–2.0 mm/pixel, and flip angle of 45–75 degrees. The ECG triggered modified Look Locker inversion recovery (MOLLI) sequence was employed for assessment of myocardial T1 relaxation times in a mid-ventricular slice. Native myocardial T1 relaxation time was measured before administration of contrast16. Acquisition scans for post contrast T1 mapping were performed after the standard delayed enhancement acquisition protocol for a mid-ventricular matching slice, approximately 15–20 min after the infusion of the contrast agent. Parameters for MOLLI technique include slice thickness of 6 mm, voxel size 2.1 × 1.6 × 6 mm, TE = 1.09, TR = 675, flip angle = 35°, twofold parallel imaging. Precontrast 5(3)3 and post-contrast 4(1)3(1)2 heart beat sampling schemes were used on the 1.5-T scanner and pre-contrast 5(4)2 and post-contrast 4(1)2(2)2 heart beat sampling schemes on the 3.0-T scanner. Shimming and delta frequency adjustments were applied to minimize off-resonance artifacts16.LGE imaging was performed ~ 10 min after intravenous injection of the second dose of gadolinium contrast (rest perfusion imaging) using an ECG gated inversion recovery gradient echo sequence in identical locations to the cine images. Scanning parameters included slice thickness of 6 mm, gap 4 mm, voxel size 2.1 × 1.6 × 6 mm, TE = 1.15, and flip angle = 20°HCM phenotype was assessed by identifying the predominant location of hypertrophy . One experienced observer performed quantification of left and right ventricular ejection fraction and volumes on a series of short axis slices from the base to the apex of each ventricle. The endocardial borders were manually traced for end diastolic and end systolic images for all slices. Quantitative analysis of segmental thickness and segmental systolic function (thickening percent) was recorded according to the American Heart Association’s 16 segment model. Papillary muscles were excluded from ventricular volumes. LV mass was calculated by tracing LV epicardial and endocardial borders at end diastole and assuming myocardial density of 1.05 g/ml. CMR42 Version 5.6  was used for all analyses.17. Figure In semiquantitative perfusion analysis, time-signal intensity curves of motion corrected perfusion sequences were generated for each myocardial segment using semiautomated tracking of the endocardial and epicardial borders with manual correction to exclude artifacts. Corresponding time signal intensity curves were derived for each myocardial segment, and the maximal slope of these curves was reported for each of the 16 myocardial segments. This analysis was repeated for rest perfusion imaging and a myocardial perfusion reserve index (MPRI) (stress/rest slope) calculated for each segment. Baseline correction was applied on the rest perfusion sequences to account for remaining gadolinium contrast signal from the stress sequences performed first. An MPRI below 2 was considered abnormalManual endocardial and epicardial contour tracing was performed for all short-axis segmented LGE images and the full width half maximum technique signal threshold was used in LGE quantitation. Total LGE mass was expressed as a percentage of the LV. Percent LGE in each segment was also calculated similar to perfusion slopes and percent thickening.16. Extracellular volume (ECV) was calculated as: ECV = ∆R1 myocardium/∆R1 blood × (100 − HCT), where ∆R1 myocardium or change in relaxation rate is given by: 1/T1 myocardium post contrast injection—1/T1 myocardium pre-contrast injection, and ΔR1 blood = 1/T1 blood-post contrast—1/T1 blood-pre-contrast administration. HCT refers to hematocrit obtained at the time of CMR. By this technique an estimate of T1 is encoded in the intensity of each pixel. ECV, T1 pre-contrast and T1 post contrast values were calculated separately for each of the six segments in the midventricular slice before and after contrast administration. We applied the ECV analysis to the six segments at the mid-ventricular level similar to other investigators18. Measurements were calculated as an average of all 6 segments. An offset of 20% from epicardial and endocardial contours was applied in the perfusion and T1 sequences to reduce bias from partial volume effects.Analysis of T1 values was performed using manually contoured regions of interest, for both pre and post contrast midventricular slicesEach CMR imaging technique was blindly scored on separate days without knowledge of clinical data or echocardiographic findings, which were collected by other observers. Interobserver variability was assessed in 10 random patients by a blinded experienced CMR reader. First pass perfusion measurements, LGE, and ECV measures had excellent correlation .16. In patients who did not have an echocardiographic study available for analysis within 30 days of CMR, we used CMR findings or available echocardiographic studies outside of the 30 day window, to determine the presence of LVOT obstruction. This was done only for the purposes of ESC risk score.Patients who underwent an echocardiographic study within 30 days of the CMR study were included (n = 73). Echocardiographic measurements were performed by an independent observer without knowledge of CMR findings. The remainder of patients were referrals from other institutions thus echocardiographic studies were not available for analysis. Dynamic LVOT obstruction was quantified at rest, with the Valsalva maneuver, and with exercise if indicated A subgroup of patients (n = 37) underwent a symptom limited exercise treadmill testing for clinical indications. A modified Bruce protocol with measurement of peak oxygen consumption  was used. Respiratory gas analysis was done as breath by breath gas analysis. Continuous EKG monitoring was performed. Stress testing was terminated due to leg fatigue, shortness of breath, or chest pain. The cardiovascular and ventilatory responses to exercise evaluated included changes in heart rate, blood pressure, peak O2 consumption (PVO2), anerobic threshold (AT), and ventilatory efficiency (VE/VCO2) values. Testing was performed after cardiac medications were withheld for four half-lives to avoid their confounding effects on LV function.Patient characteristics were reported as proportions for categorical variables and as median / interquartile range (IQR) or mean/standardized deviation for continuous variables as applicable. Distribution of continuous variables was tested by The Kolmogorov–Smirnov test. Differences across groups were determined by Chi-square for categorical variables and Student t-test or Mann Whitney U tests for continuous variables as appropriate. Descriptive analyses of MPRI were performed both on a patient and segmental level. Univariate logistic regression analyses were used to determine the characteristics associated with MRPI < 2. Variables having a p-value of < 0.2 in the univariate analysis or considered as clinically important were investigated further by multivariable logistic regression modeling. All the analyses were performed on SPSS version 21 . A p value of < 0.05 was considered statistically significant.19. None of the patient had prior history of syncope or sudden death. Twenty-two (21%) patients had family history of sudden death. Nineteen patients (18%) had moderate mitral regurgitation (MR) quantified by CMR and three patients had severe MR. The remainder of patients had mild or no MR. One patient had an LVEF of < 50%. Most studies were performed on a 3 T scanner (78%) and the rest were performed on a 1.5 T scanner (22%). The median estimated European Society of Cardiology (ESC) Risk20 was 2.2% with IQR of 1.3. Only two patients had an ESC risk ≥ 6%. No adverse events were recorded after Regadenoson infusion. All stress perfusion studies were completed successfully.Baseline patient characteristics are shown in Table Segmental level analysis of all 105 patients included 1,680 segments. The mean end-diastolic wall thickness was 10.6 mm ± 3.9 mm) with 513 (30.5%) of segments having end diastolic wall thickness ≥ 1.2 cm. In comparison to normal thickness segments, segments with end diastolic thickness ≥ 1.2 cm had a higher burden of LGE (4.1% vs 0.5% per segment), reduced MPRI (2.6 ± 1.5 vs 3.1 ± 1.8) and reduced thickening percent (48.9 ± 41.7% vs 105.3 ± 59.5%), . On comparison of segments < 1.2 cm vs ≥ 1.2 cm, segmental ECV was similar . Consistent results for all comparisons were noted when comparing segments ≥ 1.5 cm  vs. segments < 1.5 cm and when comparing segments ≥ 1.3 cm  vs. segments < 1.3 cm  even after excluding segments with any LGE. Segments with LGE had a lower MPRI than segments without LGE   had at least one segment with MPRI < 2 and were considered the group with ischemia. The mean number of segments with MPRI < 2 was 6.7 ± 5.3 segments. Global ventricular measures are shown in Table In comparison to patients without ischemia, patients with ischemia were more likely to have dynamic LVOT obstruction , and have a higher resting LVOT gradient . There were more smokers in the ischemia group . There was a trend in the ischemia group to have family history of sudden death (P = 0.052). No significant differences in NYHA class were found. The total LGE burden was similar between the two groups (P = 0.4) but ECV was higher in the ischemic group .In patients who underwent exercise testing, no significant differences were noted in exercise duration in the ischemic vs non-ischemic group , peak VO2 consumption  vs or anaerobic threshold . But VE/VCO2 was higher in the group with ischemia (P = 0.05), and increasing ischemia burden (number of segments with MPRI < 2) was associated with worsened ventilatory efficiency VE/VCO2 (P < 0.001)  which may affect MRPI calculation, and importantly, that pathophysiologic mechanisms behind ischemia and LGE are not completely interlinked. Based on the association of CMR detected ischemia with interstitial fibrosis and reduced segmental function, we hypothesize that assessment of ischemia could aid in the detection of early features of decompensation towards heart failure in HCM patients. However, further longitudinal studies are needed to further explore this. Considering the association between ischemia burden and LVOT obstruction, intensification of therapy to alleviate LVOT obstruction may have an effect on reducing ischemic burden, although whether this impacts clinical outcomes requires further study. The complex and heterogenous etiologies of ischemia in HCM certainly warrant further investigation.The direct visualization and quantitation of replacement fibrosis by LGE techniques has become essential in risk-stratifying HCM patients. Vasodilator stress CMR can also detect and quantify perfusion abnormalities in HCM, which were recently linked to LGE progression24. However, we did not find significant differences in exercise duration, peak VO2 or the anaerobic threshold between the ischemic and non-ischemic groups, although the latter two were slightly lower in the group with ischemia. This may be due to the small number of patients with exercise data and confirmation is needed in larger studies.In our study, myocardial ischemia was associated with decreased ventilatory efficiency on CPET, which is known to be a poor prognostic marker both in HF and in HCM25. Semi-quantitative measures were also validated against microspheres albeit not in HCM26. We did not assess differences in MRPI in the subendocardium vs subepicardium in our study. However, studies by Tyan et al.22, Petersen et al.27, and others have established myocardial ischemia to predominate in the subendocardial zones. Data on exercise capacity was limited to a small subgroup which limited analysis; and Holter monitoring, genotyping, and clinical outcomes were not described. As this is a relatively low risk population, we observed only 3 deaths on follow up. Only a minority of patients enrolled underwent coronary angiography to rule out epicardial coronary disease. However, patients with LGE or ischemia in a coronary distribution were excluded; and clinical history and available diagnostic testing results were thoroughly evaluated to minimize confounding. No control population was used in this study because our primary aim was to compare HCM patients with and without ischemia and multiples studies have already established the differences between HCM patients and healthy controls.Our study has several limitations: this is a cohort from a tertiary referral center and selection bias limits the generalizability of the findings. However, the low-intermediate risk population is likely the group where stress CMR can influence management and frequency of monitoring. We used semi-quantitative measures of ischemia rather than absolute measures of myocardial blood flow, however, semi-quantitative measures were found to be more reproducible than quantitative methods and could be performed with commercially available softwareWe found that reduced myocardial perfusion reserve measured by vasodilator stress CMR was associated with myocardial segmental function and myocardial interstitial fibrosis, as assessed by ECV, in low-intermediate risk HCM patients. While segments with LGE had slightly lower MPRI, quantitative total ischemia burden was not associated with replacement fibrosis as total LGE burden. Reduced MRPI correlated with increased wall thickness, reduced segmental wall thickening, increased ECV, even in myocardial segments free of LGE. Patients with ischemia have greater prevalence of dynamic LVOT obstruction. In the subset of patients who underwent cardiopulmonary exercise testing, presence of ischemia was associated with worsened ventilatory efficiency but no significant difference in exercise duration or peak VO2.


Rationale: The prognosis of pulmonary arterial hypertension is poor, especially amongst patients with connective tissue disease related pulmonary arterial hypertension. Right ventricular contractility is known to be decreased in scleroderma related pulmonary arterial hypertension. However, it is not known whether intrinsic right ventricular dysfunction is seen in a general CTD population.Objectives: In this study of a large cohort of patients with pulmonary arterial hypertension with multi-year follow-up, we sought to examine the association of measurements of right ventricular function with survival in connective tissue disease associated pulmonary arterial hypertension.Methods: Clinical characteristics of a deidentified cohort of 845 patients with pulmonary arterial hypertension were compared between patients with and without connective tissue disease. The Kaplan-Meier method was used to examine the survival of patients over more than 4 years. The association between right ventricular stroke work index and mortality was examined in patients with connective tissue disease associated pulmonary arterial hypertension.Measurements and Main Results: Significant differences in the 6-min walk distance, Borg dyspnea index, right ventricular stroke work index, and pulmonary artery pulsatility index were identified between patients with and without connective tissue disease associated pulmonary arterial hypertension. Patients with connective tissue disease had a lower right ventricular stroke work index, which was associated with decreased survival in this group; this association approached significance when adjusting for age and renal function.Conclusions: Right ventricular dysfunction as measured by right ventricular stroke work index is associated with decreased survival in patients with connective tissue disease associated pulmonary arterial hypertension despite similar pulmonary vascular resistance. These findings are suggestive of intrinsic right ventricular function in connective tissue disease associated pulmonary arterial hypertension that has a negative impact on the long-term survival of these individuals. Pulmonary arterial hypertension (PAH) is a progressive and ultimately life-limiting disease, resulting in right ventricular failure and death. The prognosis of PAH is poor; the REVEAL registry of over 3,500 PAH patients demonstrates a 5-year survival of 57% . Of the In particular, systemic sclerosis associated PAH (SSc-PAH) is associated with a poor prognosis –5, and sWhile several studies indicate that intrinsic right ventricular dysfunction is a feature associated with worse prognosis in subjects with SSc-PAH, it is not well-studied whether this is true of the CTD-PAH population outside of SSc-PAH and may account for the poorer outcomes in this group. In this study, we seek to examine the hemodynamics and measures of right ventricular function in a large cohort of PAH patients with several years of vital status follow-up in order to understand factors that influence the survival differences between CTD-PAH and non-CTD-PAH. We hypothesize that hemodynamic measurements indicate a decreased right ventricular function in individuals with CTD-PAH compared with those with non-CTD PAH, and that these measurements are associated with a poorer prognosis.Using a previously described de-identified cohort of 847 PAH subjects, of whom 845 had the variables of interest available for study , we compFor the purposes of our study, inclusion criteria included individuals from this cohort who were ≥18 years old with World Health Organization (WHO) group 1 PAH. Right ventricular stroke work index (RVSWI) was calculated by the following equation: RVSWI = (stroke volume/body surface area) ×  × 0.0136 . Of notet-tests were used to compare continuous variables between different groups  vs. non-SSc- CTD-PAH patients). The Kaplan-Meier method was used to examine the survival of patients with CTD-PAH and non-CTD-PAH over more than 4 years. The Cox proportional hazards model was used to examine the univariable and multivariable associations between RVSWI and mortality, and PAPi and mortality, in CTD-PAH subjects separately, adjusting for age and glomerular filtration rate (GFR). All investigators had the ability to query any aspect of the data.Student A total of 845 subjects were included in this analysis , 177 of p < 0.001, p = 0.02, A greater proportion of subjects with CTD-PAH were female and older in age . The CTDp < 0.0001). RVSWI was significantly associated with mortality (p = 0.02) in the CTD-PAH group, and this finding was still valid even when adjusting for age (p = 0.02); the association approached significance after adjusting for age and GFR (p = 0.055) . PAPi was not found to be associated with mortality in the CTD-PAH group (p = 0.49); after adjusting for age and GFR the association remained non-significant (p = 0.68)  . Althoug = 0.68) .p-value of 0.055; likely reflective of limitations due to sample size. Although the decreased RVSWI is observed in this group despite lower pulmonary artery pressure and similar pulmonary vascular resistance to non-CTD-PAH subjects, RVSWI is a load-dependent measure and therefore further assessment with pressure volume loops or myocardial biopsies with sarcomere analysis is needed to investigate this finding further.Using a large PAH database with multi-year follow-up, this study raises the hypothesis that there is intrinsic RV dysfunction in CTD-PAH subjects associated with decreased long-term survival. The association of RVSWI with mortality in the CTD-PAH group approached but did not meet significance after adjusting for age and GFR with a Our findings add to an important body of literature describing the unique characteristics of the CTD-PAH population. Rhee et al., previously showed that subjects with CTD-PAH have poorer response to PAH therapy as measured by 6MWD, despite having baseline hemodynamics that were less severely perturbed than in their non-CTD-PAH group . This fiIn summary, evidence from prior studies suggests that right ventricular contractility is decreased in individuals with SSc-PAH, perhaps due to depressed sarcomere function, and furthermore, SVI is predictive of mortality in this group. Our results are consistent with these findings from prior studies, and also demonstrate a relationship between a surrogate measure of RV contractility, the RVSWI, and mortality in the general CTD-PAH population.RVSWI is a measurement of work, or energy, required for the right ventricle to eject blood during one cardiac cycle indexed for body surface area (BSA), and has been determined to be a powerful predictor of right heart failure post LVAD, as well as mortality post lung transplant , 25. WhiIt is worth noting that our finding may be driven by the large percentage of subjects with SSc-PAH in our CTD population. Though there was no significant difference noted in measurements of RV function between the CTD patients with and without SSc, this may not have been detected due to the size of our study. Additionally, MCTD and overlap syndrome were not included in the Ssc-PAH group, and thus a difference between Ssc and non-Ssc PAH may be obscured by not including these scleroderma spectrum disorders. An additional limitation of the study is that the rheumatologic diagnosis of individuals was indicated by the treating provider, who was not a rheumatologist.Since the subjects included in this study were originally enrolled in trials at a time when PAH therapies were limited, they were not on combination PAH therapies. We believe that served to minimize potential confounders. However, combination therapy is the mainstay of PAH therapy, and it remains unclear how combination therapy may impact the identified association.In summary, this study of a large number of PAH subjects with multiyear follow-up demonstrates that there is reduced RV function as measured by RVSWI in CTD-PAH patients despite a lower pulmonary artery pressure and similar pulmonary vascular resistance, and that this RV dysfunction is associated with decreased survival. Understanding whether RVSWI is decreased in this group due to intrinsic right ventricular dysfunction will require further analysis with additional, load independent measurements. Continued investigation into the molecular mechanisms driving RV dysfunction in PAH will provide important insights into this life-threatening disease.ISS@unither.com).The dataset utilized for this analysis is proprietary to United Therapeutics Corporation. Qualified investigators may submit research requests to United Therapeutics Corporation (An Institutional Review Board waiver was granted from the Yale Human Investigation Committee for analysis of deidentified patient data.KC, KH, and WF designed the study. YR performed the statistical analyses. KC and WF wrote the first draft of the manuscript. All authors contributed to the manuscript writing and editing.KH has received either grants/contracts, consulting or speaking honoraria from Actelion Pharmaceuticals, Bayer Healthcare, Eiger Pharmaceuticals, Gilead Sciences, Reata Pharmaceuticals and United Therapeutics Corporation. WF is currently a full-time employee of Actelion Clinical Research and had previously received research support/funding from Actelion, and United Therapeutics Corporation, and personal fees for consulting and/or speakers bureau from Actelion, United Therapeutics, Bayer, and Gilead, outside the submitted work. WF affiliation is listed as Yale University as the majority of the work for the study was performed during his employment at Yale. YR is an employee of United Therapeutics. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Constrictive pericarditis arises as a result of the fibrous thickening of the pericardium due to chronic inflammatory changes from various injuries. Increased pulmonary and systemic venous pressures manifest clinical features of left and right heart failure. Idiopathic or post-viral pericarditis is the most common cause followed by postpericardiotomy, radiation-induced causes. Right-sided heart failure symptoms predominate over left-sided heart failure symptoms due to the equalization of pressures. No single diagnostic test can provide a definitive diagnosis or evidence of constrictive pericarditis. Medical management is difficult for constrictive pericarditis. The treatment of choice for constrictive pericarditis is pericardiectomy. Chronic inflammation leads to pericardial scarring and fibrous thickening, which causes constrictive pericarditis -2. The oEtiologyChronic pericardial inflammation can result in constrictive pericarditis. Tuberculosis is the most common cause of constrictive pericarditis in developing regions of the world ,7-9. ThePathophysiologyThickening and fibrous scarring with adhesions of the two pericardial layers leads to obliteration of the pericardial cavity and makes the pericardium rigid and thickened ,12,14. TClinical presentationClinical features of constrictive pericarditis are due to left and right-sided heart failure and elevated filling pressures. Early symptoms include nonspecific features such as fatigue, malaise, and decreased exercise tolerance -17,19. AKussmaul’s sign  is commonly noted. Kussmaul’s sign is sensitive but lacks specificity. Increased jugular venous pulsation with a prominent y descent is produced by rapid early diastolic ventricular filling. Cardiac auscultation made muffled heart sounds, a soft first heart sound, and an occasional pericardial knock. A pericardial knock is heard in early diastole, 0.06 to 0.1 seconds after the second heart sound and it indicates abrupt cessation of diastolic filling ,22,25. PDiagnostic testingNo single diagnostic test can provide a definitive diagnosis or evidence of constrictive pericarditis. Several different diagnostic tests may be sometimes obtained when there is a high clinical suspicion -24,26. AThe evaluation of the diastolic flow pattern with Doppler and the respiratory changes in the Doppler diastolic flow patterns may assist in providing significant evidence of constrictive pericarditis -25,27. GCardiac computed tomography (CT) and magnetic resonance imaging (MRI) are supportive and nondiagnostic for constrictive pericarditis. A thickened pericardium of more than 4 mm on cardiac CT is supportive of the diagnosis and the best modality for the evaluation of pericardial calcification. Cardiac MRI may show ventricular interdependence and septal bounce and is the best modality to evaluate pericardial inflammation. Cardiac CT and/or MRI are useful to evaluate the extent of pericardial thickening and plan for pericardiectomy ,29,31. RTherapyMedical TherapyMedical management is difficult for constrictive pericarditis. Patients with New York Heart Association class I symptoms can be initially started on diuretics and a low sodium diet. Nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and steroids may be beneficial in constrictive pericarditis, however, the majority of these patients usually require pericardiectomy ,30-33. MSurgical TherapyThe treatment of choice for constrictive pericarditis is pericardiectomy  with symptomatic improvement in over 90% of patients after the procedure -30,32. TThe clinical features of constrictive pericarditis are due to left and right-sided heart failure. Right-sided heart failure symptoms predominate over left-sided heart failure symptoms due to the equalization of pressures in all four cardiac chambers. It is often challenging to make a definitive diagnosis of constrictive pericarditis, as no gold standard diagnostic test exists. As a result, the diagnosis of constrictive pericarditis is commonly missed. The treatment of choice for constrictive pericarditis is pericardiectomy, which leads to symptomatic improvement in over 90% of patients after the procedure. It is imperative to recognize the varied presenting features of constrictive pericarditis early in the disease course in order to ensure timely management for preventing the progression of the disease and obtaining improved outcomes.