Prediction of interactions between cell surface proteins by machine learning.

Cells detect changes in their external environments or communicate with each other through proteins on their surfaces. These cell surface proteins form a complicated network of interactions in order to fulfill their functions. The interactions between cell surface proteins are highly dynamic and, thus, challenging to detect using traditional experimental techniques. Here, we tackle this challenge using a computational framework. The primary focus of the framework is to develop new tools to identify interactions between domains in the immunoglobulin (Ig) fold, which is the most abundant domain family in cell surface proteins. These interactions could be formed between ligands and receptors from different cells or between proteins on the same cell surface. In practice, we collected all structural data on Ig domain interactions and transformed them into an interface fragment pair library. A high-dimensional profile can then be constructed from the library for a given pair of query protein sequences. Multiple machine learning models were used to read this profile so that the probability of interaction between the query proteins could be predicted. We tested our models on an experimentally derived dataset that contains 564 cell surface proteins in humans. The cross-validation results show that we can achieve higher than 70% accuracy in identifying the PPIs within this dataset. We then applied this method to a group of 46 cell surface proteins in Caenorhabditis elegans. We screened every possible interaction between these proteins. Many interactions recognized by our machine learning classifiers have been experimentally confirmed in the literature. In conclusion, our computational platform serves as a useful tool to help identify potential new interactions between cell surface proteins in addition to current state-of-the-art experimental techniques. The tool is freely accessible for use by the scientific community. Moreover, the general framework of the machine learning classification can also be extended to study the interactions of proteins in other domain superfamilies.

Incidence, Predictors, and Outcomes of Venous and Arterial Thrombosis in COVID-19: A Nationwide Inpatient Analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is known to increase the risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE). However, the incidence, predictors, and outcomes of clinical thrombosis for inpatients with COVID-19 are not well known. This study aimed to enhance our understanding of clinical thrombosis in COVID-19, its associated factors, and mortality outcomes. METHOD: Hospitalised adult (≥18 years of age) patients with COVID-19 in 2020 were retrospectively identified from the US National Inpatient Sample database. Clinical characteristics, incident VTE, ATE, and in-hospital mortality outcomes were recorded. Multivariable logistic regression was performed to identify clinical factors associated with thrombosis and in-hospital mortality in COVID-19 inpatients. RESULTS: A total of 1,583,135 adult patients with COVID-19 in the year 2020 were identified from the National Inpatient Sample database; patients with thrombosis were 41% females with a mean age of 65.4 (65.1-65.6) years. The incidence of thrombosis was 6.1% (97,185), including VTE at 4.8% (76,125), ATE at 3.0% (47,790), and the in-hospital mortality rate was 13.4% (212,785). Patients with thrombosis were more likely to have respiratory symptoms of COVID-19 (76.7% vs 75%, p<0.001) compared with patients without thrombosis. The main factors associated with overall thrombosis, VTE, and ATE were paralysis, ventilation, solid tumours without metastasis, metastatic cancer, and acute liver failure. Although all thrombosis categories were associated with higher in-hospital mortality for COVID-19 inpatients in univariable analyses (p<0.001), they were not in multivariable analyses-thrombosis (odds ratio [OR] 1.24; 95% confidence interval [CI] 0.90-1.70; p=0.19), VTE (OR 0.70; 95% CI 0.52-1.00; p=0.05), and ATE (OR 1.07; 95% CI 0.92-1.25; p=0.36). CONCLUSIONS: The association of COVID-19 with thrombosis and VTE increases with increasing severity of the COVID-19 disease. Risk stratification of thrombosis is crucial in COVID-19 patients to determine the necessity of thromboprophylaxis.

Prognostic impact of left ventricular systolic dysfunction in patients with mixed aortic valve disease undergoing aortic valve replacement.

BACKGROUND: The implications of left ventricular remodeling and dysfunction before and after aortic valve replacement (AVR) for mixed aortic valve disease (MAVD) are not well understood. This study aims to evaluate the impact of AVR on left ventricular (LV) systolic function in MAVD, and determine the prognostic value of postoperative LV global longitudinal strain (LV-GLS) and LV ejection fraction (LVEF). METHODS: We retrospectively assessed 489 consecutive patients with MAVD (defined as at least moderate aortic stenosis and at least moderate aortic regurgitation) and baseline LVEF ≥50%, who underwent AVR between February 2003 and August 2018. All patients had baseline echocardiography, whereas 192 patients underwent postoperative echocardiography between 3 and 18 months after AVR. The primary endpoint was all-cause mortality. RESULTS: Mean age was 65 ± 15 years, and 65% were male. AVR in MAVD patients has a neutral effect on LV systolic function quantitated by LVEF and LV-GLS. During a median follow-up period of 5.8 years, 65 patients (34%) of 192 patients with follow-up echocardiography died. The patients with postoperative LVEF ≥50% had better survival than those with postoperative LVEF <50% (P < .001). Furthermore, among patients with postoperative LVEF ≥50%, mortality differed between patients with postoperative LV-GLS worse than -15% and those with postoperative LV-GLS better than -15% (P < .001). CONCLUSIONS: In patients with MAVD who underwent AVR, the mean postoperative LV-GLS and LVEF remain at a similar value to baseline. However, worse postoperative LV-GLS and LVEF were both independently associated with higher mortality in this population.

Physical and physiological effects of dobutamine stress echocardiography in low-gradient aortic stenosis.

Dobutamine stress echocardiography (DSE) is a useful tool for assessing low-gradient significant aortic stenosis (AS) and contractile reserve (CR), but its prognostic utility has become controversial in recent studies. We evaluated the impact of DSE on aortic valve physiological, structural, and left ventricular parameters in low-gradient AS. Consecutive patients undergoing DSE for low-gradient AS evaluation from September 2010 to July 2016 were retrospectively studied, and DSE findings were divided into four groups: with and without severe AS and/or CR. Relationships between left ventricular chamber quantification, CR, aortic valve Doppler during DSE, and calcium score [by computerized tomography (CT)] were analyzed. There were 258 DSE studies performed on 243 patients, mean age 77.6 ± 10.8 yr and 183 (70.1%) were males. With increasing dobutamine dose, apart from systolic blood pressure, left ventricular ejection fraction, flow, cardiac power output, and longitudinal strain magnitude, along with aortic valve area and mean aortic gradient were all significantly increased (P < 0.05). Flow and mean gradient increased in both the presence and absence of CR, whereas stroke volume and aortic valve area increased mainly in those with CR only. The aortic valve area increased in both patients with low and high calcium scores; however, the baseline area was lower in those with a higher calcium score. During DSE, aortic valve area increases with increase in aortic valve gradient. Higher calcium score is associated with lower baseline aortic valve area, but the aortic valve area still increases with dobutamine even in presence of a high calcium score.NEW & NOTEWORTHY We show that even in most severe aortic stenosis, there is some residual valve pliability. This suggests that a complete loss of pliability is not compatible with survival.

Sex-based differences in left ventricular remodeling in patients with chronic aortic regurgitation: a multi-modality study.

BACKGROUND: Significant aortic regurgitation (AR) leads to left ventricular (LV) remodeling; however, little data exist regarding sex-based differences in LV remodeling in this setting. We sought to compare LV remodeling and AR severity, assessed by echocardiography and cardiovascular magnetic resonance (CMR), to discern sex-based differences. METHODS: Patients with ≥ moderate chronic AR by echocardiography who underwent CMR within 90 days between December 2005 and October 2015 were included. Nonlinear regression models were built to assess the effect of AR regurgitant fraction (RF) on LV remodeling. A generalized linear model and Bland Altman analyses were constructed to evaluate differences between CMR and echocardiography. Referral for surgical intervention based on symptoms and LV remodeling was evaluated. RESULTS: Of the 243 patients (48.3 ± 16.6 years, 58 (24%) female), 119 (49%) underwent surgical intervention with a primary indication of severe AR, 97 (82%) men, 22 (18%) women. Significant sex differences in LV remodeling emerged on CMR. Women demonstrated significantly smaller LV end-diastolic volume index (LVEDVI) (96.8 ml/m2 vs 125.6 ml/m2, p < 0.001), LV end-systolic volume index (LVESVI) (41.1 vs 54.5 ml/m2, p < 0.001), blunted LV dilation in the setting of increasing AR severity (LVEDVI p value < 0.001, LVESVI p value 0.011), and LV length indexed (8.32 vs 9.69 cm, p < 0.001). On Bland Altman analysis, a significant interaction with sex and LV diameters was evident, demonstrating a significant increase in the difference between CMR and echocardiography measurements as the LV enlarged in women: LVEDVI (p = 0.006), LVESVI (p < 0.001), such that echocardiographic measurements increasingly underestimated LV diameters in women as the LV enlarged. LV length was higher for males with a linear effect from RF (p < 0.001), with LV length increasing at a higher rate with increasing RF for males compared to females (two-way interaction with sex p = 0.005). Sphericity volume index was higher for men after adjusting for a relative wall thickness (p = 0.033). CONCLUSIONS: CMR assessment of chronic AR revealed significant sex differences in LV remodeling and significant echocardiographic underestimation of LV dilation, particularly in women. Defining optimal sex-based CMR thresholds for surgical referral should be further developed. TRIAL REGISTRATION: NA.

Comparison of risk scores for predicting outcomes after isolated tricuspid valve surgery.

BACKGROUND: Risk models play important roles in stratification and decision-making towards cardiac surgery. Isolated tricuspid valve surgery is a high risk but increasingly performed the operation, however, the performance of risk models has not been externally evaluated in these patients. We compared the prognostic utility of contemporary risk scores for isolated tricuspid valve surgery. METHODS: Consecutive patients undergoing isolated tricuspid valve surgery at Cleveland Clinic during 2004-2018 were evaluated in this cohort study. EuroSCORE II, Society of Thoracic Surgeon's tricuspid (STS-TVS) score, and the Model for End-stage Liver Disease (MELD) score were retrospectively calculated, and their performance for predicting operative mortality, postoperative complications, and mortality during follow-up was assessed. RESULTS: Amongst 207 patients studied, the mean age was 54.1 ± 17.9 years, 116 (56.0%) were female, 92 (44.4%) had secondary tricuspid regurgitation, and 151 (72.9%) had a surgical repair. Mean EuroSCORE II, STS-TVS, and MELD scores were 6.3 ± 6.6%, 5.5 ± 6.2%, and 9.8 ± 4.7, respectively. C-statistics (95% confidence intervals) for operative mortality were 0.83 (0.74-0.93) for EuroSCORE II, 0.60 (0.45-0.75) for STS-TVS score, and 0.74 (0.58-0.89) for MELD score, while observed/expected ratios were 0.78 and 0.89 for the first two scores. All three scores were associated with mortality during follow-up and discriminated most postoperative complications. CONCLUSION: EuroSCORE II was superior to STS-tricuspid score for isolated TVS risk assessment. Although surgical risk scores traditionally underestimated operative mortality after isolated tricuspid valve surgery, they did not in our cohort, reflecting the excellent surgical results. The simple MELD score performed similarly to the EuroSCORE II, especially for discriminating morbidities.

Clinical and Echocardiographic Characteristics of Bartonella Infective Endocarditis: An 8-Year Single-Centre Experience in the United States.

BACKGROUND: Infective endocarditis due to Bartonella species is rare. The clinical and echocardiographic characteristics are not well defined. We aimed to investigate the clinical and echocardiographic findings of Bartonella endocarditis in the contemporary era. METHODS: The infective endocarditis (IE) registry and echocardiographic database at our institution were retrospectively analysed to evaluate the clinical and echocardiographic features of Bartonella endocarditis. RESULTS: Between January 2008 and December 2015, there were 11 patients with Bartonella IE (0.84% among a total of 1,308 cases of definite IE): median age 54 (30-69) years, all male, 9 Caucasian, 10 had a history of cat exposure, 10 had a pre-existing valvulopathy including 6 patients with a prosthetic valve with prosthesis age range between 3 to 5 years and 1 patient with implantable cardioverter defibrillator (ICD). Bartonella henselae was responsible for all the cases. Echocardiographic evidence of IE was found in 6 of 11 patients on transthoracic echocardiography (TTE), and 6 of 8 on transoesophageal echocardiography (TEE). Bartonella IE was associated with significant valvular destruction and dysfunction on echocardiography. Nine (9) patients were managed surgically with excellent outcomes, including two patients who failed initial medical therapy. Two (2) patients who were managed medically had progression of valvular dysfunction. At a median follow-up of 6 months, there were no deaths attributable to IE or other cardiovascular causes. CONCLUSION: In a contemporary single-centre cohort in the United States, Bartonella IE remains rare, but should be considered when pathogen could not be identified in patients with suspected IE, especially those with prosthetic valves or bicuspid aortic valve (BAV). The vast majority of patients with Bartonella IE were managed surgically with excellent outcomes.

Incremental Value of Global Longitudinal Strain to Michigan Risk Score and Pulmonary Artery Pulsatility Index in Predicting Right Ventricular Failure Following Left Ventricular Assist Devices.

BACKGROUND: The incremental utility of right ventricular (RV) strain on predicting right ventricular failure (RVF) following left ventricular assist device (LVAD) implantation, beyond clinical and haemodynamic indices, is not clear. METHODS: Two hundred and forty-six (246) patients undergoing LVAD implantation, who had transthoracic echocardiograms pre and post LVAD, pulmonary artery pulsatility index (PAPI) measurements and Michigan risk score, were included. We analysed RV global longitudinal strain (GLS) using speckle tracking echocardiography. RVF following LVAD implantation was defined as the need for medical support for >14 days, or unplanned RV assist device insertion after LVAD implantation. RESULTS: Mean preoperative RV-GLS was -7.8±2.8%. Among all, 27% developed postoperative RVF. A classification and regression tree analysis identified preoperative Michigan risk score, PAPI and RV-GLS as important parameters in predicting postoperative RVF. Eighty per cent (80%) of patients with PAPI <2.1 developed postoperative RVF, while only 4% of patients with PAPI >6.8 developed RVF. For patients with a PAPI of 2.1-3.2, having baseline Michigan risk score >2 points conferred an 81% probability of subsequent RVF. For patients with a PAPI of 3.3-6.8, having baseline RV-GLS of -4.9% or better conferred an 86% probability of no subsequent RVF. The sensitivity and specificity of this algorithm for predicting postoperative RVF were 67% and 93%, respectively, with an area under the curve of 0.87. CONCLUSION: RV-GLS has an incremental role in predicting the development of RVF post-LVAD implantation, even after controlling for clinical and haemodynamic parameters.

Cardiac risk stratification in cancer patients: A longitudinal patient-patient network analysis.

BACKGROUND: Cardiovascular disease is a leading cause of death in general population and the second leading cause of mortality and morbidity in cancer survivors after recurrent malignancy in the United States. The growing awareness of cancer therapy-related cardiac dysfunction (CTRCD) has led to an emerging field of cardio-oncology; yet, there is limited knowledge on how to predict which patients will experience adverse cardiac outcomes. We aimed to perform unbiased cardiac risk stratification for cancer patients using our large-scale, institutional electronic medical records. METHODS AND FINDINGS: We built a large longitudinal (up to 22 years' follow-up from March 1997 to January 2019) cardio-oncology cohort having 4,632 cancer patients in Cleveland Clinic with 5 diagnosed cardiac outcomes: atrial fibrillation, coronary artery disease, heart failure, myocardial infarction, and stroke. The entire population includes 84% white Americans and 11% black Americans, and 59% females versus 41% males, with median age of 63 (interquartile range [IQR]: 54 to 71) years old. We utilized a topology-based K-means clustering approach for unbiased patient-patient network analyses of data from general demographics, echocardiogram (over 25,000), lab testing, and cardiac factors (cardiac). We performed hazard ratio (HR) and Kaplan-Meier analyses to identify clinically actionable variables. All confounding factors were adjusted by Cox regression models. We performed random-split and time-split training-test validation for our model. We identified 4 clinically relevant subgroups that are significantly correlated with incidence of cardiac outcomes and mortality. Among the 4 subgroups, subgroup I (n = 625) has the highest risk of de novo CTRCD (28%) with an HR of 3.05 (95% confidence interval (CI) 2.51 to 3.72). Patients in subgroup IV (n = 1,250) had the worst survival probability (HR 4.32, 95% CI 3.82 to 4.88). From longitudinal patient-patient network analyses, the patients in subgroup I had a higher percentage of de novo CTRCD and a worse mortality within 5 years after the initiation of cancer therapies compared to long-time exposure (6 to 20 years). Using clinical variable network analyses, we identified that serum levels of NT-proB-type Natriuretic Peptide (NT-proBNP) and Troponin T are significantly correlated with patient's mortality (NT-proBNP > 900 pg/mL versus NT-proBNP = 0 to 125 pg/mL, HR = 2.95, 95% CI 2.28 to 3.82, p < 0.001; Troponin T > 0.05 µg/L versus Troponin T ≤ 0.01 µg/L, HR = 2.08, 95% CI 1.83 to 2.34, p < 0.001). Study limitations include lack of independent cardio-oncology cohorts from different healthcare systems to evaluate the generalizability of the models. Meanwhile, the confounding factors, such as multiple medication usages, may influence the findings. CONCLUSIONS: In this study, we demonstrated that the patient-patient network clustering methodology is clinically intuitive, and it allows more rapid identification of cancer survivors that are at greater risk of cardiac dysfunction. We believed that this study holds great promise for identifying novel cardiac risk subgroups and clinically actionable variables for the development of precision cardio-oncology.

Reference Ranges, Diagnostic and Prognostic Utility of Native T1 Mapping and Extracellular Volume for Cardiac Amyloidosis: A Meta-Analysis.

BACKGROUND: Cardiac MRI is central to the evaluation of cardiac amyloidosis (CA). Native T1 mapping and extracellular volume (ECV) are novel MR techniques with evolving utility in cardiovascular diseases, including CA. PURPOSE: To perform a meta-analysis of the diagnostic and prognostic data of native T1 mapping and ECV techniques for assessing CA. STUDY TYPE: Systematic review and meta-analysis. POPULATION: In all, 3520 patients including 1539 with CA from 22 studies retrieved following systematic search of Pubmed, Cochrane, and Embase. FIELD STRENGTH/SEQUENCE: 1.5T or 3.0T/modified Look-Locker inversion recovery (MOLLI) or shortened MOLLI (shMOLLI) sequences. ASSESSMENT: Meta-analysis was performed for all CA and for light-chain (AL) and transthyretin (ATTR) subtypes. Thresholds were calculated to classify native T1 and ECV values as not suggestive, indeterminate, or suggestive of CA. STATISTICAL ANALYSIS: Area under the receiver-operating characteristic curves (AUCs) and hazards ratios (HRs) with 95% confidence intervals (95% CI) were pooled using random-effects models and Open-Meta(Analyst) software. RESULTS: Six studies were diagnostic, 16 studies reported T1 and ECV values to determine reference range, and six were prognostic. Pooled AUCs (95% CI) for diagnosing CA were 0.92 (0.89-0.96) for native T1 mapping and 0.96 (0.93-1.00) for ECV, with similarly high detection rates for AL- and ATTR-CA. Based on the pooled values of native T1 and ECV in CA and control subjects, the thresholds that suggested the absence, indeterminate, or presence of CA were identified as <994 msec, 994-1073 msec, and >1073 msec, respectively, for native T1 at 1.5T. Pooled HRs (95% CI) for predicting all-cause mortality were 1.15 (1.08-1.22) for native T1 mapping as a continuous parameter, 1.19 (1.01-1.40) for ECV as a continuous parameter, and 4.93 (2.64-9.20) for ECV as a binary threshold. DATA CONCLUSION: Native T1 mapping and ECV had high diagnostic performance and predicted all-cause mortality in CA. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Defining the Reference Range for Left Ventricular Strain in Healthy Patients by Cardiac MRI Measurement Techniques: Systematic Review and Meta-Analysis.

BACKGROUND. Echocardiography is the primary noninvasive technique for left ventricular (LV) strain measurement. MRI has potential advantages, although reference ranges and thresholds to differentiate normal from abnormal left ventricular global longitudinal strain (LVGLS), left ventricular global circumferential strain (LVGCS), and left ventricular global radial strain (LVGRS) are not yet established. OBJECTIVE. The purpose of our study was to determine the mean and lower limit of normal (LLN) of MRI-derived LV strain measurements in healthy patients and explore factors potentially influencing these measurements. EVIDENCE ACQUISITION. PubMed, Embase, and Cochrane Library databases were searched for studies published through January 1, 2020, that reported MRI-derived LV strain measurements in at least 30 healthy individuals. Mean and LLN measurements of LV strain were pooled using random-effects models overall and for studies stratified by measurement method (feature tracking [FT] or tagging). Additional subgroup and meta-regression analyses were performed. EVIDENCE SYNTHESIS. Twenty-three studies with a total of 1782 healthy subjects were included. Pooled means and LLNs for all studies were -18.6% (95% CI, -19.5% to -17.6%) and -13.3% (-13.9% to 12.7%) for LVGLS, -21.0% (-22.4% to -19.6%) and -15.6% (-17.0% to -14.3%) for LVGCS, and 38.7% (30.5-46.9%) and 20.6% (15.1-26.1%) for LVGRS. Pooled means and LLNs for LVGLS by strain measurement method were -19.4% (95% CI, -20.6% to -18.1%) and -13.1% (-14.2% to -12.0%) for FT and -15.6% (-16.2% to -15.1%) and -13.1% (-14.1% to -12.2%) for tagging. A later year of study publication, increasing patient age, and increasing body mass index were associated with more negative mean LVGLS values. An increasing LV end-diastolic volume index was associated with less negative mean LVGLS values. No factor was associated with LLN of LVGLS. CONCLUSION. We determined the pooled means and LLNs, with associated 95% CIs, for LV strain by cardiac MRI to define thresholds for normal, abnormal, and borderline strain in healthy patients. The method of strain measurement by MRI affected the mean LVGLS. No factor affected the LLN of LVGLS. CLINICAL IMPACT. This meta-analysis lays a foundation for clinical adoption of MRI-derived LV strain measurements, with management implications in both healthy patients and patients with various disease states.

Diagnostic Utility of CT and MRI for Mycotic Aneurysms: A Meta-Analysis.

OBJECTIVE. The purpose of this meta-analysis was to assess the diagnostic performance of CT and MRI in detecting mycotic aneurysm, an infection of high mortality and morbidity. MATERIALS AND METHODS. The PubMed, Cochrane, and Embase databases were searched from January 1, 1980, through June 30, 2019, for diagnostic studies assessing both sensitivity and specificity of CT or MRI for detecting mycotic aneurysms, and studies were pooled by use of random-effects models and freely available meta-analysis software. RESULTS. Among 1507 articles searched, 15 studies of CT (13 studies) or MRI (five studies) for aortic and cerebral mycotic aneurysms were included. The studies evaluated 622 imaging examinations for 249 mycotic aneurysms. The pooled sensitivities and specificities of CT for all mycotic aneurysms were 0.82 (95% CI, 0.77-0.87) and 0.93 (95% CI, 0.89-0.95) and of MRI were 0.79 (95% CI, 0.61-0.91) and 0.89 (95% CI, 0.81-0.95). CT and MRI had pooled sensitivities and specificities of 0.84 (95% CI, 0.78-0.89) and 0.92 (95% CI, 0.89-0.95) for aortic and 0.71 (95% CI, 0.54-0.85) and 0.90 (95% CI, 0.83-0.95) for cerebral mycotic aneurysms. Heterogeneity and publication bias were observed in some pooled analyses. CONCLUSION. CT and MRI had moderately high sensitivities and specificities for mycotic aneurysms. Study heterogeneity, publication bias, and modest sample size were important limitations, warranting larger and higher-quality studies.

Relationships between mitral annular calcification and cardiovascular events: A meta-analysis.

BACKGROUND: Mitral annular calcification (MAC) is prevalent in the aging population, with recent renewed interest regarding its associations with cardiovascular risk factors, outcomes, and influence on valvular heart disease and interventions. This meta-analysis aimed to report the relationships between MAC and cardiovascular mortality and morbidity events. METHODS: Relevant studies were searched from PubMed, Cochrane, and Embase databases until November 30, 2019. Associations between MAC as a binary variable with death and cardiovascular events were pooled using random-effects models. The main outcomes of interest were all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, atrial fibrillation, and procedural outcomes. RESULTS: Among 799 article abstracts and 122 full-text articles screened, 26 (16 prospective and 10 retrospective) studies totaling 35 070 subjects were analyzed. MAC was associated with higher all-cause death, hazard ratio (95% confidence interval) 1.76 (1.43-2.22), and cardiovascular mortality 1.85 (1.45-23.5). It also positively correlated with myocardial infarction 1.48 (1.22-1.79), stroke 1.51 (1.22-2.05), incidental heart failure 1.55 (1.30-1.84), atrial fibrillation 1.75 (1.43-2.15), and their composite, major adverse cardiovascular events (MACE). Finally, conversion to mitral valve replacement at time of cardiac surgery was more in patients with MAC than without MAC, with odds ratio (95% confidence interval) 2.82 (1.28-6.18). CONCLUSION: Mitral annular calcification was overall associated with higher rates of death, and both individual and composite cardiovascular events. The presence of increasingly encountered MAC has significant clinical implications for cardiovascular risk assessment and valvular interventions.

A novel machine learning-derived radiotranscriptomic signature of perivascular fat improves cardiac risk prediction using coronary CT angiography.

BACKGROUND: Coronary inflammation induces dynamic changes in the balance between water and lipid content in perivascular adipose tissue (PVAT), as captured by perivascular Fat Attenuation Index (FAI) in standard coronary CT angiography (CCTA). However, inflammation is not the only process involved in atherogenesis and we hypothesized that additional radiomic signatures of adverse fibrotic and microvascular PVAT remodelling, may further improve cardiac risk prediction. METHODS AND RESULTS: We present a new artificial intelligence-powered method to predict cardiac risk by analysing the radiomic profile of coronary PVAT, developed and validated in patient cohorts acquired in three different studies. In Study 1, adipose tissue biopsies were obtained from 167 patients undergoing cardiac surgery, and the expression of genes representing inflammation, fibrosis and vascularity was linked with the radiomic features extracted from tissue CT images. Adipose tissue wavelet-transformed mean attenuation (captured by FAI) was the most sensitive radiomic feature in describing tissue inflammation (TNFA expression), while features of radiomic texture were related to adipose tissue fibrosis (COL1A1 expression) and vascularity (CD31 expression). In Study 2, we analysed 1391 coronary PVAT radiomic features in 101 patients who experienced major adverse cardiac events (MACE) within 5 years of having a CCTA and 101 matched controls, training and validating a machine learning (random forest) algorithm (fat radiomic profile, FRP) to discriminate cases from controls (C-statistic 0.77 [95%CI: 0.62-0.93] in the external validation set). The coronary FRP signature was then tested in 1575 consecutive eligible participants in the SCOT-HEART trial, where it significantly improved MACE prediction beyond traditional risk stratification that included risk factors, coronary calcium score, coronary stenosis, and high-risk plaque features on CCTA (Δ[C-statistic] = 0.126, P < 0.001). In Study 3, FRP was significantly higher in 44 patients presenting with acute myocardial infarction compared with 44 matched controls, but unlike FAI, remained unchanged 6 months after the index event, confirming that FRP detects persistent PVAT changes not captured by FAI. CONCLUSION: The CCTA-based radiomic profiling of coronary artery PVAT detects perivascular structural remodelling associated with coronary artery disease, beyond inflammation. A new artificial intelligence (AI)-powered imaging biomarker (FRP) leads to a striking improvement of cardiac risk prediction over and above the current state-of-the-art.

Contemporary Outcomes of Pulmonary Valve Endocarditis: A 16-Year Single Centre Experience.

BACKGROUND: Limited data exist regarding the clinical characteristics and contemporary outcomes of patients with pulmonary valve (PoV) infective endocarditis (IE). METHODS: This is a retrospective cohort study of patients with a confirmed diagnosis of IE affecting the PoV at our centre between January 2002 and October 2018. Electronic medical records were reviewed to gather the clinical and echocardiographic variables. The population was subdivided according to risk factor profiles: group 1: miscellaneous risk factors; group 2: patients with congenital heart disease (CHD); and group 3: patients who inject drugs (PWID). The primary outcome was all-cause mortality. RESULTS: Out of 2,124 cases of IE during the study period, 24 (1.1%) patients had PoV IE. The majority of cases of PoV IE occurred in patients with prosthetic valves (54.2%). Coagulase-negative Staphylococci species were the most common micro-organisms. Seventy-five per cent (75%) of the patients required surgical management. The median follow-up was 2.8 years (interquartile range: 0.2-5.3 years). Patients with miscellaneous risk factors were older (p<0.01), and had higher rates of hypertension (p=0.01) and hyperlipidaemia (p=0.04). There was a statistically significant difference in survival between the groups (p=0.03), mainly driven by better outcomes of patients with CHD, compared to those with miscellaneous risk factors. CONCLUSIONS: In a contemporary 16-year series, a high proportion of patients with PoV IE required surgical management. Patients with PoV IE and CHD had better survival, compared to patients with miscellaneous risk factors at a median follow-up of 2.8 years.

Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of prospective outcome data.

BACKGROUND: Coronary artery inflammation inhibits adipogenesis in adjacent perivascular fat. A novel imaging biomarker-the perivascular fat attenuation index (FAI)-captures coronary inflammation by mapping spatial changes of perivascular fat attenuation on coronary computed tomography angiography (CTA). However, the ability of the perivascular FAI to predict clinical outcomes is unknown. METHODS: In the Cardiovascular RISk Prediction using Computed Tomography (CRISP-CT) study, we did a post-hoc analysis of outcome data gathered prospectively from two independent cohorts of consecutive patients undergoing coronary CTA in Erlangen, Germany (derivation cohort) and Cleveland, OH, USA (validation cohort). Perivascular fat attenuation mapping was done around the three major coronary arteries-the proximal right coronary artery, the left anterior descending artery, and the left circumflex artery. We assessed the prognostic value of perivascular fat attenuation mapping for all-cause and cardiac mortality in Cox regression models, adjusted for age, sex, cardiovascular risk factors, tube voltage, modified Duke coronary artery disease index, and number of coronary CTA-derived high-risk plaque features. FINDINGS: Between 2005 and 2009, 1872 participants in the derivation cohort underwent coronary CTA (median age 62 years [range 17-89]). Between 2008 and 2016, 2040 patients in the validation cohort had coronary CTA (median age 53 years [range 19-87]). Median follow-up was 72 months (range 51-109) in the derivation cohort and 54 months (range 4-105) in the validation cohort. In both cohorts, high perivascular FAI values around the proximal right coronary artery and left anterior descending artery (but not around the left circumflex artery) were predictive of all-cause and cardiac mortality and correlated strongly with each other. Therefore, the perivascular FAI measured around the right coronary artery was used as a representative biomarker of global coronary inflammation (for prediction of cardiac mortality, hazard ratio [HR] 2·15, 95% CI 1·33-3·48; p=0·0017 in the derivation cohort, and 2·06, 1·50-2·83; p<0·0001 in the validation cohort). The optimum cutoff for the perivascular FAI, above which there is a steep increase in cardiac mortality, was ascertained as -70·1 Hounsfield units (HU) or higher in the derivation cohort (HR 9·04, 95% CI 3·35-24·40; p<0·0001 for cardiac mortality; 2·55, 1·65-3·92; p<0·0001 for all-cause mortality). This cutoff was confirmed in the validation cohort (HR 5·62, 95% CI 2·90-10·88; p<0·0001 for cardiac mortality; 3·69, 2·26-6·02; p<0·0001 for all-cause mortality). Perivascular FAI improved risk discrimination in both cohorts, leading to significant reclassification for all-cause and cardiac mortality. INTERPRETATION: The perivascular FAI enhances cardiac risk prediction and restratification over and above current state-of-the-art assessment in coronary CTA by providing a quantitative measure of coronary inflammation. High perivascular FAI values (cutoff ≥-70·1 HU) are an indicator of increased cardiac mortality and, therefore, could guide early targeted primary prevention and intensive secondary prevention in patients. FUNDING: British Heart Foundation, and the National Institute of Health Research Oxford Biomedical Research Centre.

Angiographic predictors of adverse outcomes after percutaneous coronary intervention in patients with radiation associated coronary artery disease.

OBJECTIVES: To determine procedural predictors of long-term outcomes for patients with radiation associated coronary artery disease (CAD) treated with percutaneous coronary intervention (PCI). BACKGROUND: Patients who develop CAD after external beam radiation therapy (XRT) for cancer are at high-risk for adverse events following PCI. It is unknown if specific angiographic features can predict outcomes in this population. METHODS: This is an observational study of 157 patients with malignancy who received XRT prior to PCI. Rates of major adverse cardiovascular and cerebrovascular events (MACCEs; all-cause mortality, myocardial infarction, repeat revascularization, or stroke) were compared across patient characteristics over time with the Cox proportional hazards and Kaplan-Meier's analyses. RESULTS: During follow-up of 5.4 ± 4.5 years, 91 (58%) patients had MACCE. On Kaplan-Meier's analysis of angiographic characteristics, MACCE was more frequent in patients with at least moderate target vessel calcification (P = 0.023), ostial stenosis (P = 0.049), target vessel diameter ≥ 3.0 mm (P = 0.018), a SYNTAX score ≥ the median of 11 (P = 0.014), or bare metal stenting (BMS)/balloon angioplasty (BA) compared to drug-eluting stenting (DES) (P = 0.006). Cardiac death was more frequent in patients with SYNTAX score ≥ 11 (P = 0.028) or BMS (P = 0.043). After multivariable adjustment for both angiographic and clinical characteristics, independent predictors of MACCE were BMS placement (P = 0.013), chronic kidney disease ≥ stage 3 (P = 0.019), New York Heart Association (NYHA) heart failure class ≥3 (P = 0.034), and SYNTAX score ≥ 11 (P = 0.041). CONCLUSIONS: In patients previously exposed to XRT treated with PCI, independent angiographic predictors of MACCE include SYNTAX score ≥ 11 and BMS placement, suggestive that DES should be preferred in this population.

Unrecognized Cardiac Amyloidosis at the Time of Mitral Valve Surgery: Incidence and Outcomes.

OBJECTIVE: It is increasingly recognized that cardiac amyloidosis can occur in patients with severe aortic stenosis undergoing both surgical and transcatheter valve replacements. We aimed to investigate whether unrecognized cardiac amyloidosis may also occur in patients with severe mitral valve disease undergoing surgery. METHODS: The pathology department database at our center was retrospectively analyzed over a 10-year period for cases in which the mitral valve or another type of cardiac tissue removed at the time of mitral surgery demonstrated incidental amyloidosis. Clinical and echocardiographic variables were collected from the electronic medical record and the echocardiographic database. RESULTS: Between 2007 and 2016, a total of 7,733 mitral valve surgical specimens were received. Of these, there were 15 cases in which the mitral valve, or another type of cardiac tissue removed at surgery, demonstrated incidentally detected amyloidosis. The most frequent comorbidities were hypertension (87%) and atrial fibrillation (80%); 13 patients (87%) underwent bioprosthetic mitral valve replacement, and 2 patients (13%) underwent mitral valve repair. Sites of amyloid deposition were the mitral valve (80%), left atrial appendage (33%), and subaortic tissue (7%); 14 patients (93%) had wild-type transthyretin amyloid. The mean duration of follow-up was 1,023 days (range: 29-2,811 days). There were no surgical complications in the follow-up period. CONCLUSIONS: Over a 10-year period, incidentally detected cardiac amyloidosis occurred in 0.2% of the mitral valve surgical cases. The outcomes for these patients undergoing mitral valve surgery were excellent, with no complications or deaths attributable to surgery at a mean follow-up of 1,023 days.

Management and outcomes in mitral valve prolapse with ventricular arrhythmias undergoing ablation and/or implantation of ICDs.

BACKGROUND: While there is an association between isolated mitral valve prolapse (MVP) and sudden cardiac arrest (SCA), the baseline characteristics and outcomes of patients with isolated MVP who experience ventricular arrhythmias (VAs) and then subsequently undergo catheter ablation and/or implantable cardioverter defibrillator (ICD) implantation are unknown. METHODS: We performed a retrospective review of all patients at the Cleveland Clinic with isolated MVP between 1997 and 2016 who underwent VA catheter ablation or secondary prevention ICD implantation. RESULTS: Of 617 screened patients, we identified 43 patients with isolated MVP and significant VA who underwent ICD placement (n = 13, 30%) or catheter ablation (n = 30, 70%). Both leaflets were most commonly involved (n = 22, 52%) with posterior MVP being next most common (n = 15, 36%). The most common foci of VA origin was the left ventricular papillary muscle (n = 9, 27%). Ablation was successful in the majority of cases (n = 20, 65%). At a mean follow-up of 2.5 years, 11 patients (26%) had recurrent VT. CONCLUSIONS: Patients with isolated MVP and VA were more likely to have bileaflet prolapse and at least moderate mitral regurgitation. VA originated more commonly from left-sided foci. While ablation was acutely successful in the majority of cases, there was still a moderate rate of VA recurrence. There is still more study needed on factors that will predict malignant VAs and management of these VAs in the MVP population.

Predictors and Prognostic Significance of Right Ventricular Ejection Fraction in Patients With Ischemic Cardiomyopathy.

BACKGROUND: Decreased right ventricular (RV) ejection fraction (RVEF) portends poor prognosis in patients with ischemic cardiomyopathy, and previous studies have suggested an association between mitral regurgitation (MR) and RVEF. We sought to evaluate this association and whether mitral valve repair or replacement affects the relationship between RV function and mortality. METHODS: We included 588 patients (mean age, 63±11 years; 75% male) with ischemic cardiomyopathy who underwent cardiac magnetic resonance imaging between 2002 and 2008. Baseline characteristics, left ventricular ejection fraction, MR severity, treatment modality, scar burden, and RVEF were assessed. Multivariable linear regression and Cox proportional hazards models were used to assess the association between MR and RVEF and between RVEF and mortality, respectively. RESULTS: After adjustment for age, sex, left ventricular ejection fraction, right bundle-branch block, and RV scar, MR severity was found to be associated independently with RVEF. There were a total of 240 deaths during a median follow-up time of 5.7 years. After multivariable adjustment, every 10% decrease in RVEF was associated with a 17% increased risk of death (P=0.008). Although decreasing RVEF was associated with a poor prognosis in the nonrepair group (hazard ratio, 1.28; 95% confidence interval, 1.12-1.47; P<0.001), it was not associated with death in the mitral valve repair or replacement group (P for interaction=0.046). CONCLUSIONS: MR severity was found to be an independent predictor of RVEF, as were right bundle-branch block, left ventricular ejection fraction, and the presence of RV scar. Decreasing RVEF is associated with increased mortality in patients with ischemic cardiomyopathy; however, this association may be mitigated in patients who undergo mitral valve repair or replacement.