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Background: Quantitative pupillometry is a new tool in multimodal neuroprognostication of comatose patients after out-of-hospital cardiac arrest, but the reliability and precision of quantitative pupillometry is not fully understood. Methods: We conducted a prospective blinded validation study with repeated patient assessment at our cardiac intensive care unit. To investigate intra- and interobserver variability of pupil size (mm), each assessment was performed on the same patient by two staff nurses within 2 minutes. The sequence consisted of a series of measurements with quantitative-, and manual pupillometry, performed subsequently to each other. Bland-Altman analysis with 95% limits of agreement (LoA) was used. Results: We included 14 sedated, comatose patients (6 females) with a mean age of 70 ± 12 years, resulting in 28 individual assessments. Quantitative pupillometry presented intraobserver variability with mean difference for maximum pupil size of 0.04 ± 0.13 with LoA of -0.21 to 0.28, and interobserver variability with mean difference of 0.03 ± 0.17 and of -0.31 to 0.36. For comparison, manual pupillometry revealed a mean difference of -0.02 ± 0.31 with LoA of -0.58 to 0.63, and -0.14 ± 0.44 with LoA of -1.00 to 0.71 for intra-, and interobserver variability, respectively. When comparing pupil size for left and right eyes, quantitative pupillometry resulted in LoA at -0.19, 0.25 (left) and -0.23, 0.32 (right), and LoA at -0.33, 0.39 (left) and -0.30, 0.34 (right) for intra-, and interobserver variability, respectively. Manual pupillometry presented LoA at -0.59, 0.63 (for both left and right), and LoA at -1.10, 0.79 (left) and -0.95, 0.83 (right) for intra-, and interobserver variability, respectively. Conclusion: Results from quantitative pupillometry are significantly more reproducible than manual measurements, suggesting it can be safely implemented in clinical practice for multimodal neuroprognostication of post-cardiac arrest patients.

Introduction: Cardiogenic shock (CS) is a critical complication to acute myocardial infarction (AMI), with short-term mortality rates exceeding 40%. However, the definition of CS varies between trials, which may comprise interstudy comparability. Aim: The aim of the current study was to review differences and similarities of CS definitions used in randomized clinical trials (RCT) assessing patients with AMI-related CS. Methods: From the electronic databases MEDLINE and EMBASE we identified 19 AMI-related CS trials comprising a total of 2674 unique patients with CS. Results: Seven trials investigated left ventricular assist devices, eight investigated medical treatments, three percutaneous coronary interventions, and one trial investigated targeted temperature management. The inclusion criteria, baseline hemodynamics, endpoints and mortality varied markedly between trials. Hypotension was the most frequent inclusion criterion (17 (90%) trials), with a systolic blood pressure value Conclusions: RCTs of AMI-related CS show marked heterogeneity in inclusion criteria and outcomes potentially hampering interstudy comparability. Consensus criteria for CS appear needed for future selection of patients.

Introduction: Growth differentiation factor 15 (GDF-15) is considered as a biomarker of inflammatory and myocardial tissue injury. However, metformin increases plasma GDF-15, and may be responsible for the metabolic benefits (e.g. weight loss, decrease in Hemoglobin A1c and systolic blood pressure, and improvement in insulin resistance) effects in type 2 diabetes (T2D). Recently, sodium-glucose cotransporter-2 inhibitors (SGLT2i) demonstrated increment in GDF-15 in a proteomic analysis in T2D patients. Hypothesis: To examine SGLT2i’s effect on GDF-15 in HFrEF patients. Methods: This multicenter, randomized, double-blind, placebo-controlled exploratory sub-study enrolled 190 stable HFrEF patients with an ejection fraction of 40% or below. Patients were randomized (1:1) to empagliflozin 10 mg once daily or matching placebo for 12 weeks. Outcome measures were changes from baseline in GDF-15, high sensitive C-reactive protein (hsCRP), and high sensitive troponin T (hsTNT) adjusted for age, sex, BMI, T2D. Results: Mean age was 64 (SD, 11) years; 85% male, 13% with T2D, mean ejection fraction 29 (SD, 8)). Empagliflozin significantly increased GDF-15 compared to placebo [Empagliflozin: baseline, median (interquartile range (IQR)) 1177 (899-1720) pg/mL, follow-up, 1394 (970-1942) pg/mL: Placebo: baseline 1299 (915-1849) pg/mL, follow-up, 1276 (879-1924) pg/mL, adjusted ratio of change (1.10 [95% confidence interval (CI), 1.04-1.17]: p=0.002). There was no significant change in hsCRP (1.13 [95%CI, 0.89-1.43]: p=0.31), nor in hsTNT (1.09 [95%CI, 0.98-1.20]: p=0.12) (Figure 1). Conclusions: Empagliflozin significantly increased GDF-15 in predominantly non-diabetic HFrEF patients regardless of HF etiology, without a concomitant increase in hsCRP, or hsTNT compared to placebo. These results might explain the link between empagliflozin and the metabolic benefits seen in this population.

Introduction: In refractory out-of-hospital cardiac arrest (OHCA), prolonged whole-body ischemia with global tissue injury proceeds even after achievement of reperfusion with extracorporeal cardiopulmonary resuscitation (eCPR). Hypothesis: Biomarkers reflecting ischemia and inflammation may be used for prognostication of refractory OHCA managed with eCPR. Methods: This nationwide retrospective study included patients (≥18 years) with refractory OHCA managed with eCPR in Denmark (2011 to 2020). Biomarker levels at admission, at 24 hours (lactate, leukocytes, and platelets), and repeated measures of lactate after eCPR initiation were analyzed. Lactate clearance was calculated as (admission lactate - post eCPR lactate) / admission lactate x100%. Results: Two hundred eighteen patients (80% male; age 52±12yrs) were included. Primary cause of OHCA was acute myocardial infarction (63%), 69% had shockable primary rhythm and 86% witnessed OHCA with a median low-flow time of 105 minutes (Q1-Q3: 86-124 min.). Fifty-three (24%) survived to hospital discharge. Survivors had a significantly lower lactate level at admission (13.1 vs. 15.4 mmol/l, p=0.004) and after 24 hours (2.8 vs. 5.0, p=0.001), and a significantly higher admission platelet level (181 vs. 153 x10 9 /l, p=0.03). No difference in admission levels of leukocytes nor leukocytes and platelets after 24 hours were found between survivors and non-survivors. Lactate clearance was available for 68% and 79% of patients alive after 8 and 24 hours, respectively. All survivors had a lactate level less than admission lactate at 8 hours (lactate clearance >0%) and had cleared >25% of admission lactate at 24 hours after eCPR initiation. There was a significant difference in survival between quartiles of lactate clearance at 8 hours after eCPR initiation (Figure 1). Conclusion: In conclusion, early lactate clearance after eCPR initiation was associated with survival to discharge in refractory OHCA-patients.

Background: The relationship between blood volume and pressure in the vascular system can be described in terms of unstressed and stressed blood volume. Stressed blood volume determines venous pressure and provides preload back to the heart, which regulates the generation of cardiac output (CO) via the Frank-starling mechanism. Whether sodium-glucose cotransporter-2 (SGLT2i) favorably modifies stressed blood volume is not known. Hypothesis: To investigate the effect of SGLT2i (empagliflozin) on the hemodynamic estimated stressed blood volume (eSBV) in HFrEF patients compared to placebo. Methods: A post hoc analysis of investigator-initiated, double-blinded, placebo-controlled, randomized trial. Seventy patients were assigned to empagliflozin of 10 mg or matching placebo once daily for 12 weeks. Patients underwent right heart catheterization at rest and during exercise at baseline and follow-up. Outcome was change in eSBV after 12 weeks of empagliflozin treatment at each level of exercise. We conducted computer-modelling simulations based on invasive hemodynamic assessment to measure eSBV. Results: HFrEF patients with mean age was 57 years, mean ejection fraction 27%, 47 (71%) on diuretics were randomized. After 12 weeks treatment exercise eSBV was significantly reduced at 0 watt, 25 watt and 25 % of maximal exercise watt, compared to placebo [(0 watt; –258 mL, 95% CI –476 to –39, p=0.021); (25 watt; –301 mL, 95% CI –561 to –40, p=0.024); and (25% of peak exercise watt; –262 mL, 95% CI –490 to –34, p=0.024)]. There was no effect on rest, or at peak exercise eSBV [(Rest; –75 ml, 95% confidence interval [CI] –279 to 130; p=0.47); and (Peak; –96 mL, 95% CI –444 to 251, p=0.59)]. This was consistent among patients with and without type 2 diabetes, etiology of HFrEF, and diuretic usage (Figure 1). Conclusion: Empagliflozin may contribute to shift blood from the effective circulatory beds to the venous reservoir in reducing filling pressure and eSBV, but maintaining CO.

Background— A low cardiovascular disease risk profile (untreated cholesterol Methods and Results— The Coronary Artery Risk Development in (Young) Adults (CARDIA) study sample consisted of 3154 black and white participants 18 to 30 years of age at year 0 (1985–1986) who attended the year 0, 7, and 20 examinations. Healthy lifestyle factors defined at years 0, 7, and 20 included average body mass index 2 , no or moderate alcohol intake, higher healthy diet score, higher physical activity score, and never smoking. Mean age (25 years) and percentage of women (56%) were comparable across groups defined by number of healthy lifestyle factors. The age-, sex-, and race-adjusted prevalences of low cardiovascular disease risk profile at year 20 were 3.0%, 14.6%, 29.5%, 39.2%, and 60.7% for people with 0 or 1, 2, 3, 4, and 5 healthy lifestyle factors, respectively ( P for trend P for trend Conclusions— Maintaining a healthy lifestyle throughout young adulthood is strongly associated with a low cardiovascular disease risk profile in middle age. Public health and individual efforts are needed to improve the adoption and maintenance of healthy lifestyles in young adults.

Over the last several years, substantial progress has been achieved in defining the molecular basis for several genetically transmitted, nonatherosclerotic cardiovascular diseases. These advances in molecular biology have enhanced our understanding of the primary defects and basic mechanisms responsible for the pathogenesis of these conditions and their phenotypic expression, and in the process, new perspectives on cardiac diagnosis have been formulated. In the course of this scientific evolution, a certain measure of uncertainty has also arisen regarding the implications of genetic analysis for clinical diagnostic criteria. New subgroups of genetically affected individuals without conventional clinical diagnostic findings have been identified solely by virtue of access to molecular laboratory techniques, creating a number of medical and ethical concerns regarding the possible clinical implications. Indeed, the extent to which such individuals should receive sequential evaluations and/or therapy or be subjected to employment or insurance discrimination, psychological harm, loss of privacy, or unnecessary withdrawal from competitive athletics is uncertain but remains a legitimate source of concern. It is therefore particularly timely and appropriate to analyze these issues in detail, specifically the extent to which molecular biology has revised traditional diagnostic criteria. The role of genetic testing in assessing prognosis and identifying high-risk subgroups or in defining basic disease mechanisms and pathophysiology is, however, largely beyond the scope of this scientific statement. As models for the present critique, we selected the 3 most common familial cardiovascular diseases for which gene defects have been identified, each of which is associated with autosomal dominant inheritance and a risk for sudden cardiac death: hypertrophic cardiomyopathy (HCM), long-QT syndrome (LQTS), and Marfan syndrome (MFS).

Background: While individual health risk behaviors are independently associated with CVD and mortality, these behaviors frequently co-occur. Less is known about combinations of behaviors and their relationship to subclinical atherosclerosis. Objective: To identify patterns of behavior from young adulthood through middle age and whether these patterns are associated with developing coronary artery calcification (CAC) and carotid intima-media thickening (IMT) over 20 years Methods: Our sample consists of all participants in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study who completed the Year 20 exam (n = 3538). We assessed five healthy lifestyle factors at Years 0, 7, and 20: BMI (2 ), alcohol intake (women: ≤ 15 g/day; men: ≤ 30 g/day), diet (best 40% of cohort by race and sex: high in potassium, calcium, & fiber; low in saturated fatty acids), physical activity (> 300 exercise units), not a cigarette smoker (Yes/No). We applied Latent class analysis (LCA) to these 15 binary variables in order to identify a discrete set of participant groups characterized by the presence or absence of behaviors. We then regressed CAC and IMT thickening on our identified groups to determine those behavioral patterns that are associated with subclinical atherosclerosis. Regression models controlled for age, race, and gender. Missing values were replaced prior to analyses using imputation. Results: We identified six distinct behavioral patterns primarily characterized by combinations of the presence or absence of being overweight, smoking, and/or healthy diet and physical activity (HDiet&PA; see table). Odds of CAC and IMT thickening were highest among the two smoking groups. Normal-weight non-smokers had the lowest odds of CAC and the least IMT thickening. Conclusions: We identified combinations of behaviors through young adulthood associated with varying burden of subclinical atherosclerosis in middle age. These data may suggest potential targets for primordial and primary prevention.

More than 600,000 children in the United States have a congenital or acquired cardiac abnormality, and millions more are at risk of developing atherosclerotic disease in adulthood, a risk made particularly evident by the prevalence of cardiovascular risk factors in the young. There are barriers to optimum prevention and treatment of these conditions in children and youth. The AHA's Task Force on Children and Youth has described these barriers and outlined a series of recommendations and strategies to meet the challenges they impose. More research is needed, and research initiatives will be developed at scientific conferences designed to review critical areas of cardiac development and etiology of disease in children. Financial support for such research initiatives must be increased. Educational programs on cardiovascular risk factors will be extended to children and their families. When these programs are coordinated with efforts in the community and in schools, they will reduce the prevalence of cardiovascular risk factors. The task force recommends that various departments and committees of the AHA use their resources for the benefit of children: for example, by developing more research initiatives for funding by the AHA or NHLBI and increasing legislative and regulatory efforts in the areas such as mandatory school health programs and tobacco advertising. It is hoped that in the next decade, through research and educational efforts, many advances in the prevention and treatment of cardiovascular diseases in the young will be realized.

Building healthier lives, free of cardiovascular diseases and stroke” is the mission of the American Heart Association (AHA). The AHA realizes that the current healthcare crisis in the United States threatens this mission. Thus, we have prepared this statement regarding healthcare reform with particular emphasis on cardiovascular diseases and stroke. We intend to promote and actively engage in a dialogue within the country that addresses these critical issues. There is an urgent need to reform our healthcare system to improve the lives of individuals who have (or who are at risk for developing) cardiovascular diseases and stroke. Nearly 15 years have passed since healthcare reform became a prominent national policy issue. In 1993 and 1994, a series of articles appeared in Circulation describing the principles, recommendations and concerns of the AHA regarding healthcare reform.1–6 Tremendous accomplishments have been made over the intervening years in the biological and clinical sciences, resulting in significant improvements in the prevention, diagnosis and treatment of cardiovascular diseases and stroke. Unfortunately, new challenges threaten to reverse these gains, including the aging of the population and unwise lifestyle choices related to smoking, diet and physical activity. Children with congenital heart disease, who formerly would have died, now survive to confront these challenges. Barriers—often arising from the cost of care in the current healthcare system—make the delivery of patient-centered health care increasingly difficult. Many patients cannot readily access high-quality, evidence-based healthcare services, and healthcare providers face similar difficulties when trying to deliver these services. With over 46 million uninsured individuals in the United States and continued increases in the cost of both health insurance and health care, the need for meaningful healthcare reform is much greater today than it was 15 years ago. Unfortunately, the 46 million uninsured individuals include over 8 million children who have limited …

Background— Early outcomes after tricuspid valve replacement in young children are ill defined. The experience of the Pediatric Cardiac Care Consortium (45 centers, 1984 to 2002) was reviewed to evaluate the results of tricuspid valve replacement in children Methods and Results— Ninety-seven patients who underwent initial tricuspid valve replacement are included in the present analysis. The most frequent cardiac diagnoses were Ebstein’s anomaly (40%), pulmonary atresia (11%), and tetralogy of Fallot (8%). Age at tricuspid valve replacement was 2.9±1.7 years (mean±SD). Mean patient weight was 12.7±6.1 kg. The major outcome was survival to discharge. Associations among age, diagnosis, valve type/size, and outcome were evaluated through the use of χ 2 analysis and logistic regression model fitting approaches. Hospital mortality was 26% and was very high (64%) in patients P 2.5. Other complications included heart block requiring a pacemaker (13%) and thrombosis (5%). Pacemaker implantation was associated with the use of a mechanical valve (23% versus 6% bioprosthetic valve; P =0.01) Conclusions— Tricuspid valve replacement in young children is associated with high mortality, especially in infants

Background— Prosthesis survival, growth, and functional status after initial mechanical mitral valve replacement (MVR) in children Methods and Results— The experience of the Pediatric Cardiac Care Consortium (45 centers, 1982 to 1999), which included 102 survivors after initial MVR, was analyzed. Median follow-up: 6.0 years (interquartile range: 3.0 to 10.6 years; 96% complete). Twenty-nine survivors had undergone a second MVR at an interval of 4.8±3.8 years after initial MVR. Reasons for second MVR were prosthetic valve stenosis 24 (83%), thrombosis 4 (14%), and endocarditis 1 (3%). For those who had second MVR, prosthesis sizes were: first MVR 19±2 mm and second MVR 22±3 mm, and their body weight increased from 7.4±2.8 kg to 16.8±10.5 kg. To identify risk factors for having a second MVR, the 29 second MVR survivors were compared with the 73 who did not have a second MVR on first-MVR demographic and perioperative variables. By univariate analysis, patients with shorter prosthesis survival were younger, weighed less, had smaller prostheses, greater ratio of prosthesis size:body weight, were less likely to have a St. Jude prosthesis and more likely to have Shone’s syndrome. By multivariate analysis prosthesis survival was predicted only by first MVR age: odds ratio (OR) 7.7 (95% confidence interval [CI] 2.6–22.7) and prosthesis size: OR 6.8 (95% CI 2.6–18.2). High risk patients (age P =0.017). An estimate of current New York Heart Association (NYHA) functional status was class 1 in 76%, class 2 in 22%, and classes 3 or 4 in 2%. Conclusion— Prosthesis survival can be predicted based on first MVR age and prosthesis size. Somatic growth is comparable regardless of the need for second MVR. There is an increment in prosthesis size at second MVR, suggesting continued annular growth. Significant limitation of function after MVR is uncommon. MVR may be an appropriate strategy for children

Background Short- and long-term outcomes after prosthetic mitral valve replacement (MVR) in children aged Methods and Results MVR was performed 176 times on 139 patients. Median follow-up was 6.2 years (range 0 to 20 years, 96% complete). Age at initial MVR was 1.9±1.4 years. Complications after initial MVR included heart block requiring pacemaker (16%), endocarditis (6%), thrombosis (3%), and stroke (2%). Patient survival was as follows: 1 year, 79%; 5 years, 75%; and 10 years, 74%. The majority of deaths occurred early after initial MVR, with little late attrition despite repeat MVR and chronic anticoagulation. Among survivors, the 5-year freedom from reoperation was 81%. Age-adjusted multivariable predictors of death include the presence of complete atrioventricular canal (hazard ratio 4.76, 95% CI 1.59 to 14.30), Shone’s syndrome (hazard ratio 3.68, 95% CI 1.14 to 11.89), and increased ratio of prosthetic valve size to patient weight (relative risk 1.77 per mm/kg increment, 95% CI 1.06 to 2.97). Age- and diagnosis-adjusted prosthetic size/weight ratios predicted a 1-year survival of 91% for size/weight ratio 2, 79% for size/weight ratio 3, 61% for size/weight ratio 4, and 37% for size/weight ratio 5. Conclusions Early mortality after MVR can be predicted on the basis of diagnosis and the size/weight ratio. Late mortality is low. These data can assist in choosing between MVR and alternative palliative strategies.