ELRL-MD: a deep learning approach for myocarditis diagnosis using cardiac magnetic resonance images with ensemble and reinforcement learning integration.

Objective.Myocarditis poses a significant health risk, often precipitated by viral infections like coronavirus disease, and can lead to fatal cardiac complications. As a less invasive alternative to the standard diagnostic practice of endomyocardial biopsy, which is highly invasive and thus limited to severe cases, cardiac magnetic resonance (CMR) imaging offers a promising solution for detecting myocardial abnormalities.Approach.This study introduces a deep model called ELRL-MD that combines ensemble learning and reinforcement learning (RL) for effective myocarditis diagnosis from CMR images. The model begins with pre-training via the artificial bee colony (ABC) algorithm to enhance the starting point for learning. An array of convolutional neural networks (CNNs) then works in concert to extract and integrate features from CMR images for accurate diagnosis. Leveraging the Z-Alizadeh Sani myocarditis CMR dataset, the model employs RL to navigate the dataset's imbalance by conceptualizing diagnosis as a decision-making process.Main results.ELRL-DM demonstrates remarkable efficacy, surpassing other deep learning, conventional machine learning, and transfer learning models, achieving an F-measure of 88.2% and a geometric mean of 90.6%. Extensive experimentation helped pinpoint the optimal reward function settings and the perfect count of CNNs.Significance.The study addresses the primary technical challenge of inherent data imbalance in CMR imaging datasets and the risk of models converging on local optima due to suboptimal initial weight settings. Further analysis, leaving out ABC and RL components, confirmed their contributions to the model's overall performance, underscoring the effectiveness of addressing these critical technical challenges.

Current frailty knowledge, awareness, and practices among physicians following the 2022 European consensus document on Frailty in Cardiology.

Aims: Aging-related cardiovascular disease and frailty burdens are anticipated to rise with global aging. In response to directions from major cardiovascular societies, we investigated frailty knowledge, awareness, and practices among cardiologists as key stakeholders in this emerging paradigm a year after the European Frailty in Cardiology consensus document was published. Methods and results: We launched a prospective multinational web-based survey via social networks to broad cardiology communities representing multiple World Health Organization regions, including Western Pacific and Southeast Asia regions. Overall, 578 respondents [38.2% female; ages 35-49 years (55.2%) and 50-64 years (34.4%)] across subspecialties, including interventionists (43.3%), general cardiologists (30.6%), and heart failure specialists (HFSs) (10.9%), were surveyed. Nearly half had read the consensus document (38.9%). Non-interventionists had better perceived knowledge of frailty assessment instruments (fully or vaguely aware, 57.2% vs. 45%, adj. P = 0.0002), exercise programmes (well aware, 12.9% vs. 6.0%, adj. P = 0.001), and engaged more in multidisciplinary team care (frequently or occasionally, 52.6% vs. 41%, adj. P = 0.002) than interventionists. Heart failure specialists more often addressed pre-procedural frailty (frequently or occasionally, 43.5% vs. 28.2%, P = 0.004) and polypharmacy (frequently or occasionally, 85.5% vs. 71%, adj. P = 0.014) and had consistently better composite knowledge (39.3% vs. 21.6%, adj. P = 0.001) and practice responses (21% vs. 11.1%, adj. P = 0.018) than non-HFSs. Respondents with better knowledge responses also had better frailty practices (40.3% vs. 3.6%, adj. P < 0.001). Conclusion: Distinct response differences suggest that future strategies strengthening frailty principles should address practices peculiar to subspecialties, such as pre-procedural frailty strategies for interventionists and rehabilitation interventions for HFSs.

Application of artificial intelligence techniques for non-alcoholic fatty liver disease diagnosis: A systematic review (2005-2023).

BACKGROUND AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease with a rapidly growing incidence worldwide. For prognostication and therapeutic decisions, it is important to distinguish the pathological stages of NAFLD: steatosis, steatohepatitis, and liver fibrosis, which are definitively diagnosed on invasive biopsy. Non-invasive ultrasound (US) imaging, including US elastography technique, and clinical parameters can be used to diagnose and grade NAFLD and its complications. Artificial intelligence (AI) is increasingly being harnessed for developing NAFLD diagnostic models based on clinical, biomarker, or imaging data. In this work, we systemically reviewed the literature for AI-enabled NAFLD diagnostic models based on US (including elastography) and clinical (including serological) data. METHODS: We performed a comprehensive search on Google Scholar, Scopus, and PubMed search engines for articles published between January 2005 and June 2023 related to AI models for NAFLD diagnosis based on US and/or clinical parameters using the following search terms: "non-alcoholic fatty liver disease", "non-alcoholic steatohepatitis", "deep learning", "machine learning", "artificial intelligence", "ultrasound imaging", "sonography", "clinical information". RESULTS: We reviewed 64 published models that used either US (including elastography) or clinical data input to detect the presence of NAFLD, non-alcoholic steatohepatitis, and/or fibrosis, and in some cases, the severity of steatosis, inflammation, and/or fibrosis as well. The performances of the published models were summarized, and stratified by data input and algorithms used, which could be broadly divided into machine and deep learning approaches. CONCLUSION: AI models based on US imaging and clinical data can reliably detect NAFLD and its complications, thereby reducing diagnostic costs and the need for invasive liver biopsy. The models offer advantages of efficiency, accuracy, and accessibility, and serve as virtual assistants for specialists to accelerate disease diagnosis and reduce treatment costs for patients and healthcare systems.

Stress Perfusion Cardiac Magnetic Resonance vs SPECT Imaging for Detection of Coronary Artery Disease.

BACKGROUND: GadaCAD2 was 1 of 2 international, multicenter, prospective, Phase 3 clinical trials that led to U.S. Food and Drug Administration approval of gadobutrol to assess myocardial perfusion and late gadolinium enhancement (LGE) in adults with known or suspected coronary artery disease (CAD). OBJECTIVES: A prespecified secondary objective was to determine if stress perfusion cardiovascular magnetic resonance (CMR) was noninferior to single-photon emission computed tomography (SPECT) for detecting significant CAD and for excluding significant CAD. METHODS: Participants with known or suspected CAD underwent a research rest and stress perfusion CMR that was compared with a gated SPECT performed using standard clinical protocols. For CMR, adenosine or regadenoson served as vasodilators. The total dose of gadobutrol was 0.1 mmol/kg body weight. The standard of reference was a 70% stenosis defined by quantitative coronary angiography (QCA). A negative coronary computed tomography angiography could exclude CAD. Analysis was per patient. CMR, SPECT, and QCA were evaluated by independent central core lab readers blinded to clinical information. RESULTS: Participants were predominantly male (61.4% male; mean age 58.9 ± 10.2 years) and were recruited from the United States (75.0%), Australia (14.7%), Singapore (5.7%), and Canada (4.6%). The prevalence of significant CAD was 24.5% (n = 72 of 294). Stress perfusion CMR was statistically superior to gated SPECT for specificity (P = 0.002), area under the receiver operating characteristic curve (P < 0.001), accuracy (P = 0.003), positive predictive value (P < 0.001), and negative predictive value (P = 0.041). The sensitivity of CMR for a 70% QCA stenosis was noninferior and nonsuperior to gated SPECT. CONCLUSIONS: Vasodilator stress perfusion CMR, as performed with gadobutrol 0.1 mmol/kg body weight, had superior diagnostic accuracy for diagnosis and exclusion of significant CAD vs gated SPECT.

Pluripotent stem cell-derived committed cardiac progenitors remuscularize damaged ischemic hearts and improve their function in pigs.

Ischemic heart disease, which is often associated with irreversibly damaged heart muscle, is a major global health burden. Here, we report the potential of stem cell-derived committed cardiac progenitors (CCPs) have in regenerative cardiology. Human pluripotent embryonic stem cells were differentiated to CCPs on a laminin 521 + 221 matrix, characterized with bulk and single-cell RNA sequencing, and transplanted into infarcted pig hearts. CCPs differentiated for eleven days expressed a set of genes showing higher expression than cells differentiated for seven days. Functional heart studies revealed significant improvement in left ventricular ejection fraction at four and twelve weeks following transplantation. We also observed significant improvements in ventricular wall thickness and a reduction in infarction size after CCP transplantation (p-value < 0.05). Immunohistology analyses revealed in vivo maturation of the CCPs into cardiomyocytes (CM). We observed temporary episodes of ventricular tachyarrhythmia (VT) in four pigs and persistent VT in one pig, but the remaining five pigs exhibited normal sinus rhythm. Importantly, all pigs survived without the formation of any tumors or VT-related abnormalities. We conclude that pluripotent stem cell-derived CCPs constitute a promising possibility for myocardial infarction treatment and that they may positively impact regenerative cardiology.

Automated Adrenal Gland Disease Classes Using Patch-Based Center Symmetric Local Binary Pattern Technique with CT Images.

Incidental adrenal masses are seen in 5% of abdominal computed tomography (CT) examinations. Accurate discrimination of the possible differential diagnoses has important therapeutic and prognostic significance. A new handcrafted machine learning method has been developed for the automated and accurate classification of adrenal gland CT images. A new dataset comprising 759 adrenal gland CT image slices from 96 subjects were analyzed. Experts had labeled the collected images into four classes: normal, pheochromocytoma, lipid-poor adenoma, and metastasis. The images were preprocessed, resized, and the image features were extracted using the center symmetric local binary pattern (CS-LBP) method. CT images were next divided into 16 × 16 fixed-size patches, and further feature extraction using CS-LBP was performed on these patches. Next, extracted features were selected using neighborhood component analysis (NCA) to obtain the most meaningful ones for downstream classification. Finally, the selected features were classified using k-nearest neighbor (kNN), support vector machine (SVM), and neural network (NN) classifiers to obtain the optimum performing model. Our proposed method obtained an accuracy of 99.87%, 99.21%, and 98.81% with kNN, SVM, and NN classifiers, respectively. Hence, the kNN classifier yielded the highest classification results with no pathological image misclassified as normal. Our developed fixed patch CS-LBP-based automatic classification of adrenal gland pathologies on CT images is highly accurate and has low time complexity [Formula: see text]. It has the potential to be used for screening of adrenal gland disease classes with CT images.

Adverse cardiovascular and metabolic perturbations among older women: 'fat-craving' hearts.

BACKGROUND: Despite known sex-based differences in cardiovascular aging, differences in aging biology are poorly understood. We hypothesize that circulating metabolites studied cross-sectionally with cardiac aging may be associated with cardiovascular changes that distinguish cardiac aging in women. METHODS: A population-based cohort of community men and women without cardiovascular disease from Singapore underwent detailed clinical and echocardiography examinations. Cross-sectional associations between cardiac functional characteristics and metabolomics profiles were examined. RESULTS: Five hundred sixty-seven adults (48.9% women) participated. Women were younger (72 ± 4.4 years vs 73 ± 4.3 years, p = 0.022), had lower diastolic blood pressures (71 ± 11.0 mmHg vs 76 ± 11.2 mmHg, p < 0.0001, and less likely to have diabetes mellitus (18.0% vs 27.6%, p = 0.013) and smoking (3.8% vs 34.5%, p < 0.001). Body mass indices were similar (24 ± 3.8 kg/m2 vs 24 ± 3.4 kg/m2, p = 0.29), but women had smaller waist circumferences (81 ± 10.1 cm vs 85 ± 9.2 cm, p < 0.001). Women had a significantly higher E/e' ratios (10.9 ± 3.4 vs 9.9 ± 3.3, p = 0.007) and mitral A peak (0.86 ± 0.2 m/s vs 0.79 ± 0.2 m/s, p < 0.001) than men. Among women, lower E/e' ratio was associated with higher levels of C16 (OR 1.019, 95%CI 1.002-1.036, p = 0.029), C16:1 (OR 1.06, 95%CI 1.006-1.118, p = 0.028), serine (OR 1.019, 95%CI 1.002-1.036, p = 0.025), and histidine (OR 1.045, 95%CI 1.013-1.078, p = 0.006). Lower mitral A peak was associated with higher levels of histidine (OR 1.039, 95%CI 1.009-1.070, p = 0.011), isoleucine (OR 1.013, 95%CI 1.004-1.021, p = 0.004), and C20 (OR 1.341, 95%CI 1.067-1.684, p = 0.012). CONCLUSION: Impairments in diastolic functions were more frequent among older women compared to men, despite lower prevalence of vascular risk factors and preserved cardiac structure. Cardiac aging in women correlated with metabolites involved in fatty acid oxidation and tricyclic acid cycle fuelling.

Automated detection of pain levels using deep feature extraction from shutter blinds-based dynamic-sized horizontal patches with facial images.

Pain intensity classification using facial images is a challenging problem in computer vision research. This work proposed a patch and transfer learning-based model to classify various pain intensities using facial images. The input facial images were segmented into dynamic-sized horizontal patches or "shutter blinds". A lightweight deep network DarkNet19 pre-trained on ImageNet1K was used to generate deep features from the shutter blinds and the undivided resized segmented input facial image. The most discriminative features were selected from these deep features using iterative neighborhood component analysis, which were then fed to a standard shallow fine k-nearest neighbor classifier for classification using tenfold cross-validation. The proposed shutter blinds-based model was trained and tested on datasets derived from two public databases-University of Northern British Columbia-McMaster Shoulder Pain Expression Archive Database and Denver Intensity of Spontaneous Facial Action Database-which both comprised four pain intensity classes that had been labeled by human experts using validated facial action coding system methodology. Our shutter blinds-based classification model attained more than 95% overall accuracy rates on both datasets. The excellent performance suggests that the automated pain intensity classification model can be deployed to assist doctors in the non-verbal detection of pain using facial images in various situations (e.g., non-communicative patients or during surgery). This system can facilitate timely detection and management of pain.

Automated BI-RADS classification of lesions using pyramid triple deep feature generator technique on breast ultrasound images.

Ultrasound (US) is an important imaging modality used to assess breast lesions for malignant features. In the past decade, many machine learning models have been developed for automated discrimination of breast cancer versus normal on US images, but few have classified the images based on the Breast Imaging Reporting and Data System (BI-RADS) classes. This work aimed to develop a model for classifying US breast lesions using a BI-RADS classification framework with a new multi-class US image dataset. We proposed a deep model that combined a novel pyramid triple deep feature generator (PTDFG) with transfer learning based on three pre-trained networks for creating deep features. Bilinear interpolation was applied to decompose the input image into four images of successively smaller dimensions, constituting a four-level pyramid for downstream feature generation with the pre-trained networks. Neighborhood component analysis was applied to the generated features to select each network's 1,000 most informative features, which were fed to support vector machine classifier for automated classification using a ten-fold cross-validation strategy. Our proposed model was validated using a new US image dataset containing 1,038 images divided into eight BI-RADS classes and histopathological results. We defined three classification schemes: Case 1 involved the classification of all images into eight categories; Case 2, classification of breast US images into five BI-RADS classes; and Case 3, classification of BI-RADS 4 lesions into benign versus malignant classes. Our PTDFG-based transfer learning model attained accuracy rates of 79.29%, 80.42%, and 88.67% for Case 1, Case 2, and Case 3, respectively.

The mechanistic pathways of oxidative stress in aortic stenosis and clinical implications.

Despite the elucidation of the pathways behind the development of aortic stenosis (AS), there remains no effective medical treatment to slow or reverse its progress. Instead, the gold standard of care in severe or symptomatic AS is replacement of the aortic valve. Oxidative stress is implicated, both directly as well as indirectly, in lipid infiltration, inflammation and fibro-calcification, all of which are key processes underlying the pathophysiology of degenerative AS. This culminates in the breakdown of the extracellular matrix, differentiation of the valvular interstitial cells into an osteogenic phenotype, and finally, calcium deposition as well as thickening of the aortic valve. Oxidative stress is thus a promising and potential therapeutic target for the treatment of AS. Several studies focusing on the mitigation of oxidative stress in the context of AS have shown some success in animal and in vitro models, however similar benefits have yet to be seen in clinical trials. Statin therapy, once thought to be the key to the treatment of AS, has yielded disappointing results, however newer lipid lowering therapies may hold some promise. Other potential therapies, such as manipulation of microRNAs, blockade of the renin-angiotensin-aldosterone system and the use of dipeptidylpeptidase-4 inhibitors will also be reviewed.

Sex differences in proteomic correlates of coronary microvascular dysfunction among patients with heart failure and preserved ejection fraction.

AIMS: Little information is available on sex differences in coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF). We investigated sex-specific proteomic profiles associated with CMD in patients with HFpEF. METHODS AND RESULTS: Using the prospective multinational PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in HFpEF; n = 182; 54.6% women), we compared clinical and biomarker correlates of CMD (defined as coronary flow reserve [CFR] <2.5) between men and women with HFpEF. We used lasso penalized regression to analyse 242 biomarkers from high-throughput proximity extension assays, adjusting for age, body mass index, creatinine, smoking and study site. The prevalence of CMD was similarly high in men and women with HFpEF (77% vs. 70%; p = 0.27). Proteomic correlates of CFR differed by sex, with 10 versus 16 non-overlapping biomarkers independently associated with CFR in men versus women, respectively. In men, proteomic correlates of CFR included chemokine ligand 20, brain natriuretic peptide, proteinase 3, transglutaminase 2, pregnancy-associated plasma protein A and tumour necrosis factor receptor superfamily member 14. Among women, the strongest proteomic correlates with CFR were insulin-like growth factor-binding protein 1, phage shock protein D, CUB domain-containing protein 1, prostasin, decorin, FMS-like tyrosine kinase 3, ligand growth differentiation factor 15, spondin-1, delta/notch-like epidermal growth factor-related receptor and tumour necrosis factor receptor superfamily member 13B. Pathway analyses suggested that CMD was related to the inflammation-mediated chemokine and cytokine signalling pathway among men with HFpEF, and the P13-kinase and transforming growth factor-beta signalling pathway among women with HFpEF. CONCLUSION: While the prevalence of CMD among men and women with HFpEF is similar, the drivers of microvascular dysfunction may differ by sex. The current inflammatory paradigm of CMD in HFpEF potentially predominates in men, while derangement in ventricular remodelling and fibrosis may play a more important role in women.

Thymosin ß4 increases cardiac cell proliferation, cell engraftment, and the reparative potency of human induced-pluripotent stem cell-derived cardiomyocytes in a porcine model of acute myocardial infarction.

Rationale: Previous studies have shown that human embryonic stem cell-derived cardiomyocytes improved myocardial recovery when administered to infarcted pig and non-human primate hearts. However, the engraftment of intramyocardially delivered cells is poor and the effectiveness of clinically relevant doses of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in large animal models of myocardial injury remains unknown. Here, we determined whether thymosin ß4 (Tb4) could improve the engraftment and reparative potency of transplanted hiPSC-CMs in a porcine model of myocardial infarction (MI). Methods: Tb4 was delivered from injected gelatin microspheres, which extended the duration of Tb4 administration for up to two weeks in vitro. After MI induction, pigs were randomly distributed into 4 treatment groups: the MI Group was injected with basal medium; the Tb4 Group received gelatin microspheres carrying Tb4; the CM Group was treated with 1.2 × 108 hiPSC-CMs; and the Tb4+CM Group received both the Tb4 microspheres and hiPSC-CMs. Myocardial recovery was assessed by cardiac magnetic resonance imaging (MRI), arrhythmogenesis was monitored with implanted loop recorders, and tumorigenesis was evaluated via whole-body MRI. Results: In vitro, 600 ng/mL of Tb4 protected cultured hiPSC-CMs from hypoxic damage by upregulating AKT activity and BcL-XL and promoted hiPSC-CM and hiPSC-EC proliferation. In infarcted pig hearts, hiPSC-CM transplantation alone had a minimal effect on myocardial recovery, but co-treatment with Tb4 significantly enhanced hiPSC-CM engraftment, induced vasculogenesis and the proliferation of cardiomyocytes and endothelial cells, improved left ventricular systolic function, and reduced infarct size. hiPSC-CM implantation did not increase incidence of ventricular arrhythmia and did not induce tumorigenesis in the immunosuppressed pigs. Conclusions: Co-treatment with Tb4-microspheres and hiPSC-CMs was safe and enhanced the reparative potency of hiPSC-CMs for myocardial repair in a large-animal model of MI.

Infective Endocarditis in Patients on Chronic Hemodialysis.

BACKGROUND: Infective endocarditis (IE) is a common and serious complication in patients receiving chronic hemodialysis (HD). OBJECTIVES: This study sought to investigate whether there are significant differences in complications, cardiac surgery, relapses, and mortality between IE cases in HD and non-HD patients. METHODS: Prospective cohort study (International Collaboration on Endocarditis databases, encompassing 7,715 IE episodes from 2000 to 2006 and from 2008 to 2012). Descriptive analysis of baseline characteristics, epidemiological and etiological features, complications and outcomes, and their comparison between HD and non-HD patients was performed. Risk factors for major embolic events, cardiac surgery, relapses, and in-hospital and 6-month mortality were investigated in HD-patients using multivariable logistic regression. RESULTS: A total of 6,691 patients were included and 553 (8.3%) received HD. North America had a higher HD-IE proportion than the other regions. The predominant microorganism was Staphylococcus aureus (47.8%), followed by enterococci (15.4%). Both in-hospital and 6-month mortality were significantly higher in HD versus non-HD-IE patients (30.4% vs. 17% and 39.8% vs. 20.7%, respectively; p < 0.001). Cardiac surgery was less frequently performed among HD patients (30.6% vs. 46.2%; p < 0.001), whereas relapses were higher (9.4% vs. 2.7%; p < 0.001). Risk factors for 6-month mortality included Charlson score (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 1.11 to 1.44; p = 0.001), CNS emboli and other emboli (HR: 3.11; 95% CI: 1.84 to 5.27; p < 0.001; and HR: 1.73; 95% CI: 1.02 to 2.93; p = 0.04, respectively), persistent bacteremia (HR: 1.79; 95% CI: 1.11 to 2.88; p = 0.02), and acute onset heart failure (HR: 2.37; 95% CI: 1.49 to 3.78; p < 0.001). CONCLUSIONS: HD-IE is a health care-associated infection chiefly caused by S. aureus, with increasing rates of enterococcal IE. Mortality and relapses are very high and significantly larger than in non-HD-IE patients, whereas cardiac surgery is less frequently performed.

Familial Hypercholesterolemia in Asia Pacific: A Review of Epidemiology, Diagnosis, and Management in the Region.

Familial hypercholesterolemia (FH) is a common genetic disease that is estimated to affect at least 15 million people in the Asia Pacific region. Affected individuals are at significantly increased risk of premature atherosclerotic cardiovascular disease. A literature review was undertaken to provide an overview of the epidemiology, diagnosis, and management of FH across the region.Currently, epidemiological data relating to FH are lacking across the Asia Pacific. Of the 15 countries and regions considered, locally conducted studies to determine FH prevalence were only identified for Australia, China, India, and Japan. Although practically all national clinical guidelines for dyslipidemia include some commentary on FH, specific guidelines on the management of FH are available for only one third of the countries and regions evaluated. Estimates of current FH diagnosis rates suggest that most affected individuals remain undiagnosed and untreated. Although innovative medications such as proprotein convertase subtilisin/kexin type 9 inhibitors have been approved and are available in most countries and regions considered, they are currently reimbursed in only one quarter.Despite these shortcomings, there is cause for optimism. Early experience with cascade screening in Hong Kong, India, and Vietnam has proven an effective means of identifying family members of probands, as has a reverse screening of family members of children with FH in China. FH registries are gaining momentum across the region, with registries now established in almost half of the countries and regions evaluated. This review concludes with a Call to Action on FH for Asia Pacific to engage healthcare professionals, improve public awareness, and form national FH alliances, comprising all relevant healthcare professional organizations, as a platform to expedite national quality improvement programs in the management of FH.

Proteomic Evaluation of the Comorbidity-Inflammation Paradigm in Heart Failure With Preserved Ejection Fraction: Results From the PROMIS-HFpEF Study.

BACKGROUND: A systemic proinflammatory state has been hypothesized to mediate the association between comorbidities and abnormal cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). We conducted a proteomic analysis to investigate this paradigm. METHODS: In 228 patients with HFpEF from the multicenter PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction), 248 unique circulating proteins were quantified by a multiplex immunoassay (Olink) and used to recapitulate systemic inflammation. In a deductive approach, we performed principal component analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted coexpression network analyses of all 248 proteins to identify clusters of proteins that overrepresented inflammatory pathways. We defined comorbidity burden as the sum of 8 common HFpEF comorbidities. We used multivariable linear regression and statistical mediation analyses to determine whether and to what extent inflammation mediates the association of comorbidity burden with abnormal cardiac structure/function in HFpEF. We also externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without heart failure. RESULTS: Comorbidity burden was associated with abnormal cardiac structure/function and with principal components/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e' ratio, and tricuspid regurgitation velocity; and worse right ventricular function (tricuspid annular plane systolic excursion and right ventricular free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19%-35%), E/e' ratio (18%-29%), tricuspid regurgitation velocity (27%-41%), and tricuspid annular plane systolic excursion (13%) (P<0.05 for all), but not right ventricular free wall strain. TNFR1 (tumor necrosis factor receptor 1), UPAR (urokinase plasminogen activator receptor), IGFBP7 (insulin-like growth factor binding protein 7), and GDF-15 (growth differentiation factor-15) were the top individual proteins that mediated the relationship between comorbidity burden and echocardiographic parameters. In the validation cohort, inflammation was upregulated in HFpEF cases versus controls, and the most prominent inflammation protein cluster identified in PROMIS-HFpEF was also present in HFpEF cases (but not controls) in the validation cohort. CONCLUSIONS: Proteins involved in inflammation form a conserved network in HFpEF across 2 independent cohorts and may mediate the association between comorbidity burden and echocardiographic indicators of worse hemodynamics and right ventricular dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.

Myocardial Viability and Long-Term Outcomes in Ischemic Cardiomyopathy.

BACKGROUND: The role of assessment of myocardial viability in identifying patients with ischemic cardiomyopathy who might benefit from surgical revascularization remains controversial. Furthermore, although improvement in left ventricular function is one of the goals of revascularization, its relationship to subsequent outcomes is unclear. METHODS: Among 601 patients who had coronary artery disease that was amenable to coronary-artery bypass grafting (CABG) and who had a left ventricular ejection fraction of 35% or lower, we prospectively assessed myocardial viability using single-photon-emission computed tomography, dobutamine echocardiography, or both. Patients were randomly assigned to undergo CABG and receive medical therapy or to receive medical therapy alone. Left ventricular ejection fraction was measured at baseline and after 4 months of follow-up in 318 patients. The primary end point was death from any cause. The median duration of follow-up was 10.4 years. RESULTS: CABG plus medical therapy was associated with a lower incidence of death from any cause than medical therapy alone (182 deaths among 298 patients in the CABG group vs. 209 deaths among 303 patients in the medical-therapy group; adjusted hazard ratio, 0.73; 95% confidence interval, 0.60 to 0.90). However, no significant interaction was observed between the presence or absence of myocardial viability and the beneficial effect of CABG plus medical therapy over medical therapy alone (P = 0.34 for interaction). An increase in left ventricular ejection fraction was observed only among patients with myocardial viability, irrespective of treatment assignment. There was no association between changes in left ventricular ejection fraction and subsequent death. CONCLUSIONS: The findings of this study do not support the concept that myocardial viability is associated with a long-term benefit of CABG in patients with ischemic cardiomyopathy. The presence of viable myocardium was associated with improvement in left ventricular systolic function, irrespective of treatment, but such improvement was not related to long-term survival. (Funded by the National Institutes of Health; STICH ClinicalTrials.gov number, NCT00023595.).

A Population-wide study of electrocardiographic (ECG) norms and the effect of demographic and anthropometric factors on selected ECG characteristics in young, Southeast Asian males-results from the Singapore Armed Forces ECG (SAFE) study.

BACKGROUND: Routine use of pre-participation electrocardiograms (ECGs) has been used by the Singapore Armed Forces, targeting early detection of significant cardiac diseases. We aim to describe the impact of demographic and anthropometric factors on ECG variables and establish a set of electrocardiographic reference ranges specific to a young male multiethnic Southeast Asian cohort. METHODS AND RESULTS: Between November 1, 2009, and December 31, 2014, 144,346 young male conscripts underwent pre-participation screening that included a 12-lead ECG, demographic and anthropometric measurements. The Chinese population had the longest PR interval (146.7 ± 19.7 vs. 145.21 ± 19.2 in Malays vs. 141.2 ± 18.8 ms in Indians), QRS duration (94.5 ± 9.8 vs. 92.6 ± 9.7 in Malays vs. 92.5 ± 9.4 ms in Indians) and QTcB interval (408.3 ± 21.3 vs. 403.5 ± 21.6 in Malays vs. 401.2 ± 21.4 ms in Indians) (all p < 0.001). Body mass index (BMI) >25 kg/m2 and body fat >25% were independently associated with lower prevalence of increased QRS voltage on ECG. Systolic blood pressure of >140 mmHg or diastolic blood pressure of >90 mmHg independently increased the prevalence of increased QRS voltage on ECG. CONCLUSIONS: Electrocardiographic parameters vary across different ethnicities and in comparison with international norms. In our population, diagnosis of increased QRS voltage by ECG is less prevalent with obesity and increased body fat. Further analysis of gold standard measurements for the diagnosis of LVH in our population is ongoing, to improve the accuracy of the ECG screening process.

The association between blood pressure and long-term outcomes of patients with ischaemic cardiomyopathy with and without surgical revascularization: an analysis of the STICH trial.

Aims: Hypertension (HTN) is a well-known contributor to cardiovascular disease, including heart failure (HF) and coronary artery disease, and is the leading risk factor for premature death world-wide. A J- or U-shaped relationship has been suggested between blood pressure (BP) and clinical outcomes in different studies. However, there is little information about the significance of BP on the outcomes of patients with coronary artery disease and left ventricular dysfunction. This study aimed to determine the relationship between BP and mortality outcomes in patients with ischaemic cardiomyopathy. Methods and results: The influence of BP during a median follow-up of 9.8 years was studied in a total of 1212 patients with ejection fraction ≤35% and coronary disease amenable to coronary artery bypass grafting (CABG) who were randomized to CABG or medical therapy alone (MED) in the STICH (Surgical Treatment for Ischaemic Heart Failure) trial. Landmark analyses were performed starting at 1, 2, 3, 4, and 5 years after randomization, in which previous systolic BP values were averaged and related to subsequent mortality through the end of follow-up with a median of 9.8 years. Neither a previous history of HTN nor baseline BP had any significant influence on long-term mortality outcomes, nor did they have a significant interaction with MED or CABG treatment. The landmark analyses showed a progressive U-shaped relationship that became strongest at 5 years (χ2 and P-values: 7.08, P = 0.069; 8.72, P = 0.033; 9.86; P = 0.020; 8.31, P = 0.040; 14.52, P = 0.002; at 1, 2, 3, 4, and 5-year landmark analyses, respectively). The relationship between diastolic BP (DBP) and outcomes was similar. The most favourable outcomes were observed in the SBP range 120-130, and DBP 75-85 mmHg, whereas lower and higher BP were associated with worse outcomes. There were no differences in BP-lowering medications between groups. Conclusion: A strong U-shaped relationship between BP and mortality outcomes was evident in ischaemic HF patients. The results imply that the optimal SBP might be in the range 120-130 mmHg after intervention, and possibly be subject to pharmacologic action regarding high BP. Further, low BP was a marker of poor outcomes that might require other interactions and treatment strategies. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00023595.

Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF.

Aims: To date, clinical evidence of microvascular dysfunction in patients with heart failure (HF) with preserved ejection fraction (HFpEF) has been limited. We aimed to investigate the prevalence of coronary microvascular dysfunction (CMD) and its association with systemic endothelial dysfunction, HF severity, and myocardial dysfunction in a well defined, multi-centre HFpEF population. Methods and results: This prospective multinational multi-centre observational study enrolled patients fulfilling strict criteria for HFpEF according to current guidelines. Those with known unrevascularized macrovascular coronary artery disease (CAD) were excluded. Coronary flow reserve (CFR) was measured with adenosine stress transthoracic Doppler echocardiography. Systemic endothelial function [reactive hyperaemia index (RHI)] was measured by peripheral arterial tonometry. Among 202 patients with HFpEF, 151 [75% (95% confidence interval 69-81%)] had CMD (defined as CFR <2.5). Patients with CMD had a higher prevalence of current or prior smoking (70% vs. 43%; P = 0.0006) and atrial fibrillation (58% vs. 25%; P = 0.004) compared with those without CMD. Worse CFR was associated with higher urinary albumin-to-creatinine ratio (UACR) and NTproBNP, and lower RHI, tricuspid annular plane systolic excursion, and right ventricular (RV) free wall strain after adjustment for age, sex, body mass index, atrial fibrillation, diabetes, revascularized CAD, smoking, left ventricular mass, and study site (P < 0.05 for all associations). Conclusions: PROMIS-HFpEF is the first prospective multi-centre, multinational study to demonstrate a high prevalence of CMD in HFpEF in the absence of unrevascularized macrovascular CAD, and to show its association with systemic endothelial dysfunction (RHI, UACR) as well as markers of HF severity (NTproBNP and RV dysfunction). Microvascular dysfunction may be a promising therapeutic target in HFpEF.