Prediction of coronary artery calcium scoring from surface electrocardiogram in atherosclerotic cardiovascular disease: a pilot study.

Aims: Coronary artery calcium (CAC) scoring is an established tool for cardiovascular risk stratification. However, the lack of widespread availability and concerns about radiation exposure have limited the universal clinical utilization of CAC. In this study, we sought to explore whether machine learning (ML) approaches can aid cardiovascular risk stratification by predicting guideline recommended CAC score categories from clinical features and surface electrocardiograms. Methods and results: In this substudy of a prospective, multicentre trial, a total of 534 subjects referred for CAC scores and electrocardiographic data were split into 80% training and 20% testing sets. Two binary outcome ML logistic regression models were developed for prediction of CAC scores equal to 0 and ≥400. Both CAC = 0 and CAC ≥400 models yielded values for the area under the curve, sensitivity, specificity, and accuracy of 84%, 92%, 70%, and 75%, and 87%, 91%, 75%, and 81%, respectively. We further tested the CAC ≥400 model to risk stratify a cohort of 87 subjects referred for invasive coronary angiography. Using an intermediate or higher pretest probability (≥15%) to predict CAC ≥400, the model predicted the presence of significant coronary artery stenosis (P = 0.025), the need for revascularization (P < 0.001), notably bypass surgery (P = 0.021), and major adverse cardiovascular events (P = 0.023) during a median follow-up period of 2 years. Conclusion: ML techniques can extract information from electrocardiographic data and clinical variables to predict CAC score categories and similarly risk-stratify patients with suspected coronary artery disease.

Targeting senescent cells alleviates obesity-induced metabolic dysfunction.

Adipose tissue inflammation and dysfunction are associated with obesity-related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug-inducible "suicide" genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra-abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity-related metabolic dysfunction and its complications.

17α-Estradiol Alleviates Age-related Metabolic and Inflammatory Dysfunction in Male Mice Without Inducing Feminization.

Aging is associated with visceral adiposity, metabolic disorders, and chronic low-grade inflammation. 17α-estradiol (17α-E2), a naturally occurring enantiomer of 17ß-estradiol (17ß-E2), extends life span in male mice through unresolved mechanisms. We tested whether 17α-E2 could alleviate age-related metabolic dysfunction and inflammation. 17α-E2 reduced body mass, visceral adiposity, and ectopic lipid deposition without decreasing lean mass. These declines were associated with reductions in energy intake due to the activation of hypothalamic anorexigenic pathways and direct effects of 17α-E2 on nutrient-sensing pathways in visceral adipose tissue. 17α-E2 did not alter energy expenditure or excretion. Fasting glucose, insulin, and glycosylated hemoglobin were also reduced by 17α-E2, and hyperinsulinemic-euglycemic clamps revealed improvements in peripheral glucose disposal and hepatic glucose production. Inflammatory mediators in visceral adipose tissue and the circulation were reduced by 17α-E2. 17α-E2 increased AMPKα and reduced mTOR complex 1 activity in visceral adipose tissue but not in liver or quadriceps muscle, which is in contrast to the generalized systemic effects of caloric restriction. These beneficial phenotypic changes occurred in the absence of feminization or cardiac dysfunction, two commonly observed deleterious effects of exogenous estrogen administration. Thus, 17α-E2 holds potential as a novel therapeutic for alleviating age-related metabolic dysfunction through tissue-specific effects.

Nonbiased Molecular Screening Identifies Novel Molecular Regulators of Fibrogenic and Proliferative Signaling in Myxomatous Mitral Valve Disease.

BACKGROUND: Pathological processes underlying myxomatous mitral valve degeneration (MMVD) remain poorly understood. We sought to identify novel mechanisms contributing to the development of this condition. METHODS AND RESULTS: Microarrays were used to measure gene expression in 11 myxomatous and 11 nonmyxomatous human mitral valves. Differential gene expression (thresholds P<0.05; fold-change >1.5) and pathway activation (Ingenuity) were confirmed using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Contributions of bone morphogenetic protein 4 and transforming growth factor (TGF)-ß2 to differential gene expression were evaluated in vitro. Contributions of angiotensin II to differential pathway activation were examined in mice in vivo. A total of 2602 genes were differentially expressed between myxomatous and nonmyxomatous valves. Canonical TGF-ß signaling was increased in MMVD because of increased ligand expression and derepression of SMA mothers against decapentaplegic 2/3 signaling and was confirmed with quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Myxomatous valves demonstrated activation of canonical bone morphogenetic protein and Wnt/ß-catenin signaling and upregulation of their common target runt-related transcription factor 2. Our data set provided transcriptional and immunohistochemical evidence for activated immune cell infiltration. In vitro treatment of mitral valve interstitial cells with TGF-ß2 increased ß-catenin signaling at mRNA and protein levels, suggesting interactions between TGF-ß2 and Wnt signaling. In vivo infusion of mice with angiotensin II recaptured several changes in signaling pathways characteristic of human MMVD. CONCLUSIONS: These data support a new disease framework whereby activation of TGF-ß2, bone morphogenetic protein 4, Wnt/ß-catenin, or immune signaling plays major roles in the pathogenesis of MMVD. We propose these pathways act in a context-dependent manner to drive phenotypic changes that fundamentally differ from those observed in aortic valve disease and open novel avenues guiding future research into the pathogenesis of MMVD.

Infiltrative cardiovascular diseases: cardiomyopathies that look alike.

Infiltrative cardiomyopathies are characterized by the deposition of abnormal substances that cause the ventricular walls to become progressively rigid, thereby impeding ventricular filling. Some infiltrative cardiac diseases increase ventricular wall thickness, while others cause chamber enlargement with secondary wall thinning. Increased wall thickness, small ventricular volume, and occasional dynamic left ventricular outflow obstruction (e.g., amyloidosis) can outwardly appear similar to conditions with true myocyte hypertrophy (e.g., hypertrophic cardiomyopathy, hypertensive heart disease). Likewise, infiltrative disease that presents with a dilated left ventricle with global or regional wall motion abnormalities and aneurysm formation (e.g., sarcoidosis) may mimic ischemic cardiomyopathy. Low-voltage QRS complex was the sine qua non of infiltrative cardiomyopathy (i.e., cardiac amyloid). However, low-voltage QRS complex is not a uniform finding with the infiltrative cardiomyopathies. The clinical presentation, along with functional and morphologic features, often provides enough insight to establish a working diagnosis. In most circumstances, however, tissue or serologic evaluation is needed to validate or clarify the cardiac diagnosis and institute appropriate therapy.

Does left atrial size predict mortality in asymptomatic patients with severe aortic stenosis?

BACKGROUND: We assessed the hypothesis that diastolic function represented by left atrial size determines the rate of development of symptoms and the risk of all-cause mortality in asymptomatic patients with severe aortic stenosis (AS). METHODS: From a database of 622 asymptomatic patients with isolated severe AS (velocity by Doppler >or= 4 m/sec) followed for 5.4 +/- 4 years, we reviewed the echocardiograms and evaluated Doppler echocardiographic indices of diastolic function. Prediction of symptom development and mortality by left atrial diameter with and without adjusting for clinical and echocardiographic parameters was performed using Cox proportional-hazards regression analysis. RESULTS: The age was 71 +/- 11 years and 317 (62%) patients were males. The aortic valve mean gradient was 46 +/- 11 mmHg, and the Doppler-derived aortic valve area was 0.9 +/- 0.2 cm(2). During follow-up, symptoms developed in 233 (45%), valve surgery was performed in 290 (57%) and 138 (27%) died. Left atrial enlargement was significantly correlated with symptom development (P < 0.05) but the association diminished after adjusting for aortic valve area and peak velocity (P = 0.2). However, atrial diameter predicted death independent of age and gender (P = 0.007), comorbid conditions (P = 0.03), and AS severity and Doppler parameters of diastolic function (P = 0.002). CONCLUSION: Diastolic function, represented as left atrial diameter, is related to mortality in asymptomatic patients with severe AS.

Effects of pulmonary thromboendarterectomy on right-sided echocardiographic parameters in patients with chronic thromboembolic pulmonary hypertension.

OBJECTIVE: To determine the echocardiographic changes in the heart at 3 months and 1 year after pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). PATIENTS AND METHODS: Thirty-two adult patients who underwent PTE for CTEPH at the Mayo Clinic in Rochester, Minn, from 1997 to 2003 were included in the study. All underwent transthoracic echocardiography before surgery. Follow-up echocardiography was performed within 3 months of surgery in 28 patients and 1 year postoperatively in 17 patients. The results were compared with baseline data. RESULTS: Within 3 months after PTE, the right ventricular end-diastolic area decreased from 38.4 +/- 12.8 cm2 to 32.5 +/- 10.4 cm2 (mean difference, 5.8 +/- 10.4 cm2; P = .02). The right ventricular end-systolic area decreased from 30.4 +/- 12.1 cm2 to 24.1 +/- 8.6 cm2 (mean difference, 6.3 +/- 10.1 cm2; P = .008). The right ventricular systolic pressure decreased significantly from 92.6 +/- 22.0 mm Hg to 55.0 +/- 19.8 mm Hg (mean difference, 40.0 +/- 24.8 mm Hg; P < .001). Tricuspid regurgitation (TR) improved from a mean grade of 2.5 +/- 1.2 to 1.2 +/- 1.1 (mean difference, 1.5 +/- 1.0; P < .001). At 12 months, the right ventricular end-diastolic area, right ventricular end-systolic area, right ventricular systolic pressure, and TR also were significantly lower than baseline values. CONCLUSION: In patients with CTEPH who undergo PTE, echocardiographic measurements of right ventricular size, systolic pressure, and TR show significant improvement immediately after surgery, which is sustained for up to 1 year after surgery.