MicroRNAs are associated with cardiac biomarkers, cardiac structure and function and incident outcomes in heart failure.

AIMS: The association between microRNAs (miRNAs) and established cardiac biomarkers is largely unknown. We aimed to measure the association between plasma miRNAs and N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin I, soluble urokinase-type plasminogen activator receptor (suPAR), and galectin-3 with cardiac structure and function and clinical outcomes. METHODS AND RESULTS: We quantified 32 plasma miRNAs using the FirePlex miRNA assay and measured biomarkers in 139 individuals with symptomatic heart failure (HF). We used principal component (PC) analysis and linear regression to evaluate the association between miRNAs and biomarkers with ventricular size and function by echocardiography and Cox modelling for the incidence of a first composite event of HF hospitalization, heart transplant, left ventricular assist device implant, or death. The mean (standard deviation) age at baseline was 64.3 (12.4) years, 33 (24%) were female, and 122 (88%) were White. A total of 45 events occurred over a median follow-up of 368 (interquartile range 234, 494) days. Baseline NT-proBNP (ß = -2.0; P = 0.001) and miRNA PC2 (ß = 2.6; P = 0.002) were associated with baseline left ventricular ejection fraction. NT-proBNP (ß = 20.6; P = 0.0004), suPAR (ß = -39.6; P = 0.005), and PC4 (ß = 21.1; P = 0.02) were associated with baseline left ventricular end-diastolic volumes. NT-proBNP [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.28-2.18, P = 0.0002], galectin-3 (HR 2.02, 95% CI 1.05-3.91, P = 0.036), PC3 (HR 1.75, 95% CI 1.23-2.49, P = 0.002), and PC4 (HR 1.67, 95% CI 1.1-2.52, P = 0.016) were independently associated with incident events. CONCLUSIONS: Biomarkers and miRNA PCs are associated with cardiac structure and function and incident cardiovascular outcomes. Combining information from miRNAs provides prognostic information beyond biomarkers in HF.

Cost-Effectiveness of Quadruple Therapy in Management of Heart Failure With Reduced Ejection Fraction in the United States.

BACKGROUND: The 2022 clinical guidelines for management of heart failure with reduced ejection fraction call for quadruple therapy. Quadruple therapy consists of an angiotensin receptor-neprilysin inhibitor (ARNi), sodium-glucose cotransporter-2 inhibitor (SGLT2i), mineralocorticoid receptor antagonist, and beta blocker. The ARNi and sodium-glucose cotransporter-2 inhibitor are newer additions to standard of care with the ARNi replacing ACE (angiotensin-converting enzyme) inhibitors and angiotensin II receptor blockers. METHODS: We investigate the cost-effectiveness of sequentially adding the SGLT2i and ARNi to form quadruple therapy as compared with the previous standard of care with ACE inhibitor/mineralocorticoid receptor antagonist/beta blocker. Using a 2-stage Markov model, we projected the expected lifetime discounted costs and quality-adjusted life years (QALYs) of a simulated cohort of US patients who underwent each treatment option and calculated incremental cost-effectiveness ratios. We assessed incremental cost-effectiveness ratios using criteria for health care value (<$50 000/quality-adjusted life year [QALY] indicating high-value, $50 000-150 000/QALY indicating intermediate value, and >$150 000/QALY indicating low-value) and a standard $100 000/QALY cost-effectiveness threshold. RESULTS: Compared with the previous standard of care, the SGLT2i addition had an incremental cost-effectiveness ratio of $73 000/QALY and weakly dominated the ARNi addition. The addition of both the ARNi and SGLT2i for quadruple therapy offered 0.68 additional discounted QALYs over the SGLT2i addition alone at a lifetime discounted cost of $66 700, resulting in an incremental cost-effectiveness ratio of $98 500/QALY. In sensitivity analysis varying drug prices, the incremental cost-effectiveness ratio for quadruple therapy ranged from $73 500/QALY using prices available to the US Department of Veterans Affairs to $110 000/QALY using drug list prices. CONCLUSIONS: While quadruple therapy offers intermediate value, it is borderline cost effective compared with adding the SGLT2i alone to previous standard of care. Thus, its cost-effectiveness is sensitive to a payer's ability to negotiate discounts off the increasing list prices for ARNI and SGLT2is. The demonstrated benefits of ARNi and SGLT2is should be weighed against their high prices in payer and policy considerations.

The Prediction of Cardiac Events Using Contemporary Risk Prediction Models after Radiation Therapy for Head and Neck Cancer.

This study aims to evaluate the efficacy of the Pooled Cohort Equation (PCE), U.S. Preventative Services Task Force (USPSTF), and Framingham Risk Score (FRS) models in predicting ASCVD events among patients receiving radiation therapy (RT) for head and neck cancer (HNCA). From a large cohort of HNCA patients treated with RT, ASCVD events were adjudicated. Observed vs. predicted ASCVD events were compared. We compared rates by statin eligibility status. Regression models and survival analysis were used to identify the relationship between predicted risk and post-RT outcomes. Among the 723 identified patients, 274 (38%) were statin-eligible based on USPSTF criteria, 359 (49%) based on PCE, and 234 (32%) based on FRS. During follow-up, 17% developed an ASCVD, with an event rate of 27 per 1000 person-years, 68% higher than predicted (RR 1.68 (95% CI: 1.02, 2.12), p < 0.001). In multivariable regression, there was no difference in event rates by statin eligibility status (p > 0.05). Post-RT, the observed event rate was higher than the predicted ASCVD risk across all grades of predicted risk (p < 0.05) and the observed risk of an ASCVD event was high even among patients predicted to have a low risk of ASCVD. In conclusion, current ASCVD risk calculators significantly underestimate the risk for ASCVD among patients receiving RT for HNCA.

Accelerated in Vivo Cardiac Diffusion-Tensor MRI Using Residual Deep Learning-based Denoising in Participants with Obesity.

PURPOSE: To develop and assess a residual deep learning algorithm to accelerate in vivo cardiac diffusion-tensor MRI (DT-MRI) by reducing the number of averages while preserving image quality and DT-MRI parameters. MATERIALS AND METHODS: In this prospective study, a denoising convolutional neural network (DnCNN) for DT-MRI was developed; a total of 26 participants, including 20 without obesity (body mass index [BMI] < 30 kg/m2; mean age, 28 years ± 3 [standard deviation]; 11 women) and six with obesity (BMI ≥ 30 kg/m2; mean age, 48 years ± 11; five women), were recruited from June 19, 2019, to July 29, 2020. DT-MRI data were constructed at four averages (4Av), two averages (2Av), and one average (1Av) without and with the application of the DnCNN (4AvDnCNN, 2AvDnCNN, 1AvDnCNN). All data were compared against the reference DT-MRI data constructed at eight averages (8Av). Image quality, characterized by using the signal-to-noise ratio (SNR) and structural similarity index (SSIM), and the DT-MRI parameters of mean diffusivity (MD), fractional anisotropy (FA), and helix angle transmurality (HAT) were quantified. RESULTS: No differences were found in image quality or DT-MRI parameters between the accelerated 4AvDnCNN DT-MRI and the reference 8Av DT-MRI data for the SNR (29.1 ± 2.7 vs 30.5 ± 2.9), SSIM (0.97 ± 0.01), MD (1.3 µm2/msec ± 0.1 vs 1.31 µm2/msec ± 0.11), FA (0.32 ± 0.05 vs 0.30 ± 0.04), or HAT (1.10°/% ± 0.13 vs 1.11°/% ± 0.09). The relationship of a higher MD and lower FA and HAT in individuals with obesity compared with individuals without obesity in reference 8Av DT-MRI measurements was retained in 4AvDnCNN and 2AvDnCNN DT-MRI measurements but was not retained in 4Av or 2Av DT-MRI measurements. CONCLUSION: Cardiac DT-MRI can be performed at an at least twofold-accelerated rate by using DnCNN to preserve image quality and DT-MRI parameter quantification.Keywords: Adults, Cardiac, Obesity, Technology Assessment, MR-Diffusion Tensor Imaging, Heart, Tissue CharacterizationSupplemental material is available for this article.© RSNA, 2021.

The Dynamic Platelet Transcriptome in Obesity and Weight Loss.

OBJECTIVE: Adiposity is associated with oxidative stress, inflammation, and glucose intolerance. Previous data suggest that platelet gene expression is associated with key cardiometabolic phenotypes, including body mass index but stable in healthy individuals over time. However, modulation of gene expression in platelets in response to metabolic shifts (eg, weight reduction) is unknown and may be important to defining mechanism. Approach and Results: Platelet RNA sequencing and aggregation were performed from 21 individuals with massive weight loss (>45 kg) following bariatric surgery. Based on RNA sequencing data, we measured the expression of 67 genes from isolated platelet RNA using high-throughput quantitative reverse transcription quantitative PCR in 1864 FHS (Framingham Heart Study) participants. Many transcripts not previously studied in platelets were differentially expressed with bariatric surgical weight loss, appeared specific to platelets (eg, not differentially expressed in leukocytes), and were enriched for a nonalcoholic fatty liver disease pathway. Platelet aggregation studies did not detect alteration in platelet function after significant weight loss. Linear regression models demonstrated several platelet genes modestly associated with cross-sectional cardiometabolic phenotypes, including body mass index. There were no associations between studied transcripts and incident diabetes or cardiovascular end points. CONCLUSIONS: In summary, while there is no change in platelet aggregation function after significant weight loss, the human platelet experiences a dramatic transcriptional shift that implicates pathways potentially relevant to improved cardiometabolic risk postweight loss (eg, nonalcoholic fatty liver disease). Further studies are needed to determine the mechanistic importance of these observations.

Anatomic and Flow Characteristics of Left Anterior Descending Coronary Artery Angiographic Stenoses Predisposing to Myocardial Infarction.

The impact of the anatomic characteristics of coronary stenoses on the development of future coronary thrombosis has been controversial. This study aimed at identifying the anatomic and flow characteristics of left anterior descending (LAD) coronary artery stenoses that predispose to myocardial infarction, by examining angiograms obtained before the index event. We identified 90 patients with anterior ST-elevation myocardial infarction (STEMI) for whom coronary angiograms and their reconstruction in the three-dimensional space were available at 6 to 12 months before the STEMI, and at the revascularization procedure. The majority of culprit lesions responsible for STEMI occurred between 20 and 40 mm from the LAD ostium, whereas the majority of stable lesions not associated with STEMI were found in distances >60 mm (p < 0.001). Culprit lesions were significantly more stenosed (diameter stenosis 68.6 ± 14.2% vs 44.0 ± 10.4%, p < 0.001), and significantly longer than stable ones (15.3 ± 5.4 mm vs 9.2 ± 2.5 mm, p < 0.001). Bifurcations at culprit lesions were significantly more frequent (88.8%) compared with stable lesions (34.4%, p < 0.001). Computational fluid dynamics simulations demonstrated that hemodynamic conditions in the vicinity of culprit lesions promote coronary thrombosis due to flow recirculation. A multiple logistic regression model with diameter stenosis, lesion length, distance from the LAD ostium, distance from bifurcation, and lesion symmetry, showed excellent accuracy in predicting the development of a culprit lesion (AUC: 0.993 [95% CI: 0.969 to 1.000], p < 0.0001). In conclusion, specific anatomic and hemodynamic characteristics of LAD stenoses identified on coronary angiograms may assist risk stratification of patients by predicting sites of future myocardial infarction.

Cost-effectiveness of Contemporary Statin Use Guidelines With or Without Coronary Artery Calcium Assessment in African American Individuals.

Importance: Clinical and economic consequences of statin treatment guidelines supplemented by targeted coronary artery calcium (CAC) assessment have not been evaluated in African American individuals, who are at increased risk for atherosclerotic cardiovascular disease and less likely than non-African American individuals to receive statin therapy. Objective: To evaluate the cost-effectiveness of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline without a recommendation for CAC assessment vs the 2018 ACC/AHA guideline recommendation for use of a non-0 CAC score measured on one occasion to target generic-formulation, moderate-intensity statin treatment in African American individuals at risk for atherosclerotic cardiovascular disease. Design, Setting, and Participants: A microsimulation model was designed to estimate life expectancy, quality of life, costs, and health outcomes over a lifetime horizon. African American-specific data from 472 participants in the Jackson Heart Study (JHS) at intermediate risk for atherosclerotic cardiovascular disease and other US population-specific data on individuals from published sources were used. Data analysis was conducted from November 11, 2018, to November 1, 2019. Main Outcomes and Measures: Lifetime costs and quality-adjusted life-years (QALYs), discounted at 3% annually. Results: In a model-based economic evaluation informed in part by follow-up data, the analysis was focused on 472 individuals in the JHS at intermediate risk for atherosclerotic cardiovascular disease; mean (SD) age was 63 (6.7) years. The sample included 243 women (51.5%) and 229 men (48.5%). Of these, 178 of 304 participants (58.6%) who underwent CAC assessment had a non-0 CAC score. In the base-case scenario, implementation of 2013 ACC/AHA guidelines without CAC assessment provided a greater quality-adjusted life expectancy (0.0027 QALY) at a higher cost ($428.97) compared with the 2018 ACC/AHA guideline strategy with CAC assessment, yielding an incremental cost-effectiveness ratio of $158 325/QALY, which is considered to represent low-value care by the ACC/AHA definition. The 2018 ACC/AHA guideline strategy with CAC assessment provided greater quality-adjusted life expectancy at a lower cost compared with the 2013 ACC/AHA guidelines without CAC assessment when there was a strong patient preference to avoid use of daily medication therapy. In probability sensitivity analyses, the 2018 ACC/AHA guideline strategy with CAC assessment was cost-effective compared with the 2013 ACC/AHA guidelines without CAC assessment in 76% of simulations at a willingness-to-pay value of $100 000/QALY when there was a preference to lose 2 weeks of perfect health to avoid 1 decade of daily therapy. Conclusions and Relevance: A CAC assessment-guided strategy for statin therapy appears to be cost-effective compared with initiating statin therapy in all African American individuals at intermediate risk for atherosclerotic cardiovascular disease and may provide greater quality-adjusted life expectancy at a lower cost than a non-CAC assessment-guided strategy when there is a strong patient preference to avoid the need for daily medication. Coronary artery calcium testing may play a role in shared decision-making regarding statin use.

On-call transthoracic echocardiographic interpretation by first year cardiology fellows: comparison with attending cardiologists.

BACKGROUND: Transthoracic echocardiograms (TTE) performed and interpreted by cardiology fellows during off-duty hours are critical to patient care, however limited data exist on their interpretive accuracy. Our aims were to determine the discordance rate between TTEs performed and interpreted by cardiology fellows and National Board of Echocardiography certified attending cardiologists and to identify factors associated with discordance. METHODS: Consecutive on-call TTEs acquired and interpreted by 1st year cardiology fellows over 4.6 years at an academic center were prospectively evaluated by attending cardiologists. Fellow interpretations were classified as concordant or discordant with the attending interpretation. We assessed the association of patient, imaging and fellow characteristics with discordance. RESULTS: A total of 777 TTE interpretations (730 patients) were performed/interpreted by 40 first year fellows and overread by 13 attendings. The most common indications were assessment of left ventricular function (40.9%) and pericardial effusion (37.3%). There was a major or minor discordance in 4.1 and 17.4% of studies, respectively with 42.1% of disagreements occurring in assessment of left ventricular size and function. The indication to assess left ventricular function [OR 2.19, 95% CI (1.32, 3.62), P = 0.002 vs. pericardial effusion] and greater duration of echocardiographic image acquisition (OR 1.02, 95% CI 1.01, 1.03, P = 0.004) were independently associated with overall discordance. CONCLUSIONS: In this large prospective study we found that attending cardiologists disagreed with 1 in 5 fellow TTE interpretations. Standardized tools for evaluation of echocardiograms performed by fellows are needed to ensure quality of training and patient safety.

Subclinical Atherosclerosis, Statin Eligibility, and Outcomes in African American Individuals: The Jackson Heart Study.

Importance: Modern prevention guidelines substantially increase the number of individuals who are eligible for treatment with statins. Efforts to refine statin eligibility via coronary calcification have been studied in white populations but not, to our knowledge, in large African American populations. Objective: To compare the relative accuracy of US Preventive Services Task Force (USPSTF) and American College of Cardiology/American Heart Association (ACC/AHA) recommendations in identifying African American individuals with subclinical and clinical atherosclerotic cardiovascular disease (ASCVD). Design, Setting, and Participants: In this prospective, community-based study, 2812 African American individuals aged 40 to 75 years without prevalent ASCVD underwent assessment of ASCVD risk. Of these, 1743 participants completed computed tomography. Main Outcomes and Measures: Nonzero coronary artery calcium (CAC) score, abdominal aortic calcium score, and incident ASCVD (ie, myocardial infarction, ischemic stroke, or fatal coronary heart disease). Results: Of the 2812 included participants, the mean (SD) age at baseline was 55.4 (9.4) years, and 1837 (65.3%) were female. The USPSTF guidelines captured 404 of 732 African American individuals (55.2%) with a CAC score greater than 0; the ACC/AHA guidelines identified 507 individuals (69.3%) (risk difference, 14.1%; 95% CI, 11.2-17.0; P < .001). Statin recommendation under both guidelines was associated with a CAC score greater than 0 (odds ratio, 5.1; 95% CI, 4.1-6.3; P < .001). While individuals indicated for statins under both guidelines experienced 9.6 cardiovascular events per 1000 patient-years, those indicated under only ACC/AHA guidelines were at low to intermediate risk (4.1 events per 1000 patient-years). Among individuals who were statin eligible by ACC/AHA guidelines, the 10-year ASCVD incidence per 1000 person-years was 8.1 (95% CI, 5.9-11.1) in the presence of CAC and 3.1 (95% CI, 1.6-5.9) without CAC (P = .02). While statin-eligible individuals by USPSTF guidelines did not have a significantly higher 10-year ASCVD event rate in the presence of CAC, African American individuals not eligible for statins by USPSTF guidelines had a higher ASCVD event rate in the presence of CAC (2.8 per 1000 person-years; 95% CI, 1.5-5.4) relative to without CAC (0.8 per 1000 person-years; 95%, CI 0.3-1.7) (P = .03). Conclusions and Relevance: The USPSTF guidelines focus treatment recommendations on 38% of high-risk African American individuals at the expense of not recommending treatment in nearly 25% of African American individuals eligible for statins by ACC/AHA guidelines with vascular calcification and at low to intermediate ASCVD risk.

Ideal Cardiovascular Health, Cardiovascular Remodeling, and Heart Failure in Blacks: The Jackson Heart Study.

BACKGROUND: The lifetime risk of heart failure (HF) is higher in the black population than in other racial groups in the United States. METHODS AND RESULTS: We measured the Life's Simple 7 ideal cardiovascular health metrics in 4195 blacks in the JHS (Jackson Heart Study; 2000-2004). We evaluated the association of Simple 7 metrics with incident HF and left ventricular structure and function by cardiac magnetic resonance (n=1188). Mean age at baseline was 54.4 years (65% women). Relative to 0 to 2 Simple 7 factors, blacks with 3 factors had 47% lower incident HF risk (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.39-0.73; P<0.0001); and those with ≥4 factors had 61% lower HF risk (HR, 0.39; 95% CI, 0.24-0.64; P=0.0002). Higher blood pressure (HR, 2.32; 95% CI, 1.28-4.20; P=0.005), physical inactivity (HR, 1.65; 95% CI, 1.07-2.55; P=0.02), smoking (HR, 2.04; 95% CI, 1.43-2.91; P<0.0001), and impaired glucose control (HR, 1.76; 95% CI, 1.34-2.29; P<0.0001) were associated with incident HF. The age-/sex-adjusted population attributable risk for these Simple 7 metrics combined was 37.1%. Achievement of ideal blood pressure, ideal body mass index, ideal glucose control, and nonsmoking was associated with less likelihood of adverse cardiac remodeling by cardiac magnetic resonance. CONCLUSIONS: Cardiovascular risk factors in midlife (specifically elevated blood pressure, physical inactivity, smoking, and poor glucose control) are associated with incident HF in blacks and represent targets for intensified HF prevention.

Hepatic steatosis is associated with cardiometabolic risk in a rural Indian population: A prospective cohort study.

BACKGROUND/OBJECTIVES: While adiposity and hepatic steatosis are linked to cardiovascular risk in developed countries, their prevalence and impact in low-income countries are poorly understood. We investigated the association of anthropomorphic variables and hepatic steatosis with cardiometabolic risk profiles and subclinical cardiovascular disease (CVD) in a large rural Indian cohort. METHODS: In 4691 individuals in the Birbhum Population Project in West Bengal, India, we performed liver ultrasonography, carotid ultrasound and biochemical and clinical profiling. We assessed the association of hepatic steatosis and anthropomorphic indices (BMI, waist circumference) with CVD risk factors (dysglycemia, dyslipidemia, hypertension) and subclinical CVD (by carotid intimal-medial thickness). RESULTS: Rural Indians exhibited a higher visceral adiposity index and pro-atherogenic dyslipidemia at a lower BMI than Americans. Individuals with any degree of hepatic steatosis by ultrasound had a greater probability of dysglycemia (adjusted odds ratio, OR=1.67, 95% CI 1.31-2.12, P<0.0001) and pro-atherogenic dyslipidemia (OR=1.33, 95% CI 1.07-1.63, P=0.009). We observed a positive association between liver fat, adiposity and carotid intimal-medial thickness (CIMT) in an unadjusted model (ß=0.02, P=0.0001); the former was extinguished after adjustment for cardiometabolic risk factors. CONCLUSIONS: In a large population of rural Indians, hepatic steatosis and waist circumference were associated with prevalent cardiometabolic risk and subclinical CVD at lower BMI relative to multi-ethnic Americans, though the association of the former with subclinical CVD was extinguished after adjustment. These results underscore the emerging relevance of hepatic steatosis and adiposity in the developing world, and suggest efforts to target these accessible phenotypes for cardiometabolic risk prevention.

Serum cystatin C- versus creatinine-based definitions of acute kidney injury following cardiac surgery: a prospective cohort study.

BACKGROUND: The primary aim of this study was to compare the sensitivity and rapidity of acute kidney injury (AKI) detection by cystatin C level relative to creatinine level after cardiac surgery. STUDY DESIGN: Prospective cohort study. SETTINGS & PARTICIPANTS: 1,150 high-risk adult cardiac surgery patients in the TRIBE-AKI (Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury) Consortium. PREDICTOR: Changes in serum creatinine and cystatin C levels. OUTCOME: Postsurgical incidence of AKI. MEASUREMENTS: Serum creatinine and cystatin C were measured at the preoperative visit and daily on postoperative days 1-5. To allow comparisons between changes in creatinine and cystatin C levels, AKI end points were defined by the relative increases in each marker from baseline (25%, 50%, and 100%) and the incidence of AKI was compared based on each marker. Secondary aims were to compare clinical outcomes among patients defined as having AKI by cystatin C and/or creatinine levels. RESULTS: Overall, serum creatinine level detected more cases of AKI than cystatin C level: 35% developed a ≥25% increase in serum creatinine level, whereas only 23% had a ≥25% increase in cystatin C level (P < 0.001). Creatinine level also had higher proportions meeting the 50% (14% and 8%; P < 0.001) and 100% (4% and 2%; P = 0.005) thresholds for AKI diagnosis. Clinical outcomes generally were not statistically different for AKI cases detected by creatinine or cystatin C level. However, for each AKI threshold, patients with AKI confirmed by both markers had a significantly higher risk of the combined mortality/dialysis outcome compared with patients with AKI detected by creatinine level alone (P = 0.002). LIMITATIONS: There were few adverse clinical outcomes, limiting our ability to detect differences in outcomes between subgroups of patients based on their definitions of AKI. CONCLUSIONS: In this large multicenter study, we found that cystatin C level was less sensitive for AKI detection than creatinine level. However, confirmation by cystatin C level appeared to identify a subset of patients with AKI with a substantially higher risk of adverse outcomes.