Background

The red blood cell (RBC) storage lesion is a series of morphological, functional, and metabolic changes that RBCs undergo following collection, processing, and refrigerated storage for clinical use. Since the biochemical attributes of the RBC unit shifts with time, transfusion of older blood products may contribute to cardiac complications, including hyperkalemia and cardiac arrest. We measured the direct effect of storage age on cardiac electrophysiology and compared it with hyperkalemia, a prominent biomarker of storage lesion severity.

Methods and Results

Donor RBCs were processed using standard blood‐banking techniques. The supernatant was collected from RBC units, 7 to 50 days after donor collection, for evaluation using Langendorff‐heart preparations (rat) or human induced pluripotent stem cell–derived cardiomyocytes. Cardiac parameters remained stable following exposure to “fresh” supernatant from red blood cell units (day 7: 5.8±0.2 mM K⁺), but older blood products (day 40: 9.3±0.3 mM K⁺) caused bradycardia (baseline: 279±5 versus day 40: 216±18 beats per minute), delayed sinus node recovery (baseline: 243±8 versus day 40: 354±23 ms), and increased the effective refractory period of the atrioventricular node (baseline: 77±2 versus day 40: 93±7 ms) and ventricle (baseline: 50±3 versus day 40: 98±10 ms) in perfused hearts. Beating rate was also slowed in human induced pluripotent stem cell–derived cardiomyocytes after exposure to older supernatant from red blood cell units (−75±9%, day 40 versus control). Similar effects on automaticity and electrical conduction were observed with hyperkalemia (10–12 mM K⁺).

Conclusions

This is the first study to demonstrate that “older” blood products directly impact cardiac electrophysiology, using experimental models. These effects are likely caused by biochemical alterations in the supernatant from red blood cell units that occur over time, including, but not limited to hyperkalemia. Patients receiving large volume and/or rapid transfusions may be sensitive to these effects.

Background

Myocardial bridge (MB), common anatomic variant, is generally considered benign, while previous studies have shown associations between MB and various cardiovascular pathologies. This study aimed to investigate for the first time possible impact of MB on long‐term outcomes in patients with implantable cardioverter defibrillator, focusing on life‐threatening ventricular arrhythmia (LTVA).

Methods and Results

This retrospective analysis included 140 patients with implantable cardioverter defibrillator implantation for primary (n=23) or secondary (n=117) prevention of sudden cardiac death. Angiographically apparent MB was identified on coronary angiography as systolic milking appearance with significant arterial compression. The primary end point was the first episode(s) of LTVA defined as appropriate implantable cardioverter defibrillator treatments (antitachyarrhythmia pacing and/or shock) or sudden cardiac death, assessed for a median of 4.5 (2.2–7.1) years. During the follow‐up period, LTVA occurred in 37.9% of patients. Angiographically apparent MB was present in 22.1% of patients; this group showed younger age, lower rates of coronary risk factors and ischemic cardiomyopathy, higher prevalence of vasospastic angina and greater left ventricular ejection fraction compared with those without. Despite its lower risk profiles above, Kaplan–Meier analysis revealed significantly lower event‐free rates in patients with versus without angiographically apparent MB. In multivariate analysis, presence of angiographically apparent MB was independently associated with LTVA (hazard ratio, 4.24; 95% CI, 2.39–7.55; P<0.0001).

Conclusions

Angiographically apparent MB was the independent determinant of LTVA in patients with implantable cardioverter defibrillator. Although further studies will need to confirm our findings, assessment of MB appears to enhance identification of high‐risk patients who may benefit from closer follow‐up and targeted therapies.

Background

The higher cardiovascular variability and the increased prevalence of arrhythmias in patients with obstructive sleep apneas may contribute to their higher rate of fatal events during sleep. In this regard, the use of beta blockers (BB) is debated because they may induce bradyarrhythmias and alter the pattern of heart rate changes induced by apneas. Thus, the aim of our study is to quantify peri‐apneic heart‐rate swings and prevalence of nocturnal bradyarrhythmias in BB‐treated and BB‐naïve patients with obstructive sleep apnea.

Methods and Results

Our real‐life, retrospective, cohort study analyzed data from patients with obstructive sleep apnea after a basal cardiorespiratory polysomnography. Among 228 eligible participants, we enrolled 78 BB‐treated and 88 BB‐naïve patients excluding those treated with antiarrhythmic drugs or pacemakers, or with uninterpretable ECG traces during polysomnography. In each patient, type and frequency of arrhythmias were identified and peri‐apneic changes of RR intervals were evaluated for each apnea. BB‐treated patients were older and with more comorbidities than BB‐naïve patients, but had similar obstructive sleep apnea severity, similar frequency of arrhythmic episodes, and similar prevalence of bradyarrhythmias. Apnea‐induced heart‐rate swings, unadjusted for age, showed lower RR interval changes in BB‐treated (133.5±63.8 ms) than BB‐naïve patients (171.3±87.7 ms, P=0.01), lower RR interval increases during apneas (58.5±28.5 versus 74.6±40.2 ms, P=0.01), and lower RR interval decreases after apneas (75.0±42.4 versus 96.7±55.5 ms, P<0.05).

Conclusions

BB appear to be safe in patients with obstructive sleep apnea because they are not associated with worse episodes of nocturnal bradyarrhythmias and even seem protective in terms of apnea‐induced changes of heart rate.

Background

Across the globe, elective surgeries have been postponed to limit infectious exposure and preserve hospital capacity for coronavirus disease 2019 (COVID‐19). However, the ramp down in cardiac surgery volumes may result in unintended harm to patients who are at high risk of mortality if their conditions are left untreated. To help optimize triage decisions, we derived and ambispectively validated a clinical score to predict intensive care unit length of stay after cardiac surgery.

Methods and Results

Following ethics approval, we derived and performed multicenter valida tion of clinical models to predict the likelihood of short (≤2 days) and prolonged intensive care unit length of stay (≥7 days) in patients aged ≥18 years, who underwent coronary artery bypass grafting and/or aortic, mitral, and tricuspid value surgery in Ontario, Canada. Multivariable logistic regression with backward variable selection was used, along with clinical judgment, in the modeling process. For the model that predicted short intensive care unit stay, the c‐statistic was 0.78 in the derivation cohort and 0.71 in the validation cohort. For the model that predicted prolonged stay, c‐statistic was 0.85 in the derivation and 0.78 in the validation cohort. The models, together termed the CardiOttawa LOS Score, demonstrated a high degree of accuracy during prospective testing.

Conclusions

Clinical judgment alone has been shown to be inaccurate in predicting postoperative intensive care unit length of stay. The CardiOttawa LOS Score performed well in prospective validation and will complement the clinician's gestalt in making more efficient resource allocation during the COVID‐19 period and beyond.

Background

The relationship between noninvasive cardiac diagnostic testing intensity and downstream clinical outcomes is unclear. Our objective was to examine the relationship between hospital network noninvasive cardiac diagnostic testing intensity and downstream clinical outcomes in patients who were discharged from the emergency department after assessment for chest pain.

Methods and Results

We employed a retrospective cohort study design of 387 809 patients evaluated for chest pain in the emergency department between April 1, 2010 and March 31, 2016. Hospital networks were divided into tertiles based on usage of noninvasive cardiac diagnostic testing. The primary outcome was a composite of acute myocardial infarction or all‐cause mortality. Adjusted Cox proportional hazards models were used to compare the hazard of the composite outcome of myocardical infarction and/or all‐cause mortality between the tertiles. After adjustment for clinically relevant covariates, patients evaluated for chest pain in intermediate noninvasive cardiac diagnostic testing usage tertile hospital networks did not have significantly different hazards of the composite outcome when compared with those evaluated in low usage tertile hospital networks >90 days (hazard ratio [HR], 1.00; 95% CI, 0.83–1.21), 6 months (HR, 1.07; 95% CI, 0.92–1.24), and 1 year (HR, 1.03; 95% CI, 0.94–1.14). Patients evaluated in the high usage tertile also did not have significantly different hazards of the composite outcome compared with those evaluated in the low usage tertile at 90 days (HR, 0.98; 95% CI, 0.80–1.19), 6 months (HR, 1.01; 95% CI, 0.87–1.17); and 1 year (HR, 0.95; 95% CI, 0.86–1.05).

Conclusions

Our population‐based study demonstrated that high noninvasive cardiac diagnostic testing use intensity was not associated with reductions in downstream myocardial infarction or all‐cause mortality.

Background

Pregnancy increases the risk of acute myocardial infarction (AMI). The purpose of this study was to examine timing and risk factors for AMI in pregnancy and poor outcome.

Methods and Results

National Inpatient Sample (2003–2015) was screened in pregnancy, labor and delivery, and postpartum. There were 11 297 849 records extracted with 913 instances of AMI (0.008%). One hundred eleven (12.2%) women experienced AMI during labor and delivery, 338 (37.0%) during pregnancy and most during the postpartum period (464; 50.8%). The prevalence of AMI in pregnancy has increased (P=0.0005). Most major adverse cardiovascular and cerebrovascular events occurred in the postpartum period (63.5%). Inpatient mortality was 4.5%. Predictors of AMI include known coronary artery disease (odds ratio [OR], 517.4; 95% CI, 420.8–636.2), heart failure (OR, 8.2; 95% CI, 1.9–35.2), prior valve replacement (OR, 6.4; 95% CI, 2.4–17.1), and atrial fibrillation (OR, 2.7; CI, 1.5–4.7; P<0.001). Risk factors of traditional atherosclerosis including hyperlipidemia, obesity, tobacco history, substance abuse, and thrombophilia were identified (P<0.001). Gestational hypertensive disorders (eclampsia OR, 6.0; 95% CI, 3.3–10.8; preeclampsia OR, 3.2; 95% CI, 2.5–4.2) were significant risk factors in predicting AMI. Risk factors associated with major adverse cardiovascular and cerebrovascular events included prior percutaneous coronary intervention (OR, 6.6; 95% CI, 1.4–31.2) and pre‐eclampsia (OR, 2.3; 95% CI, 1.3–3.9).

Conclusions

AMI is associated with modifiable, nonmodifiable, and obstetric risk factors. These risk factors can lead to devastating adverse outcomes and highlight the need for risk factor modification and public health resource initiatives toward the goal of decreasing AMI in the pregnant population.

Background

Aortic stenosis–related mortality might vary across demographic subsets, regions, and states in the United States.

Methods and Results

We reviewed the death certificate data from the Centers for Disease Control and Prevention Wide‐Ranging OnLine Data for Epidemiologic Research database to examine aortic stenosis–related mortality trends from 2008 to 2018. Crude and age‐adjusted mortality rates (AAMRs) per 100 000 people and annual percentage change with 95% CIs were calculated. Between 2008 and 2018, AAMR reduced from 12.7 to 11.5 (average annual percentage change, −1.0 [95% CI, −1.5 to −0.5]), because of an accelerated decline between 2015 and 2018 (annual percentage change, −4.4 [95% CI, −6.0 to −2.7]). Older (aged >85 years), male, and White patients had higher death rates than younger, female, and non‐White patients, respectively. Although mortality reduction was similar across sexes, significant mortality reduction was limited to White patients only. The AAMRs were higher in rural than urban areas. States with AAMRs >90th percentile were distributed in the West and the Northeast, and <10th percentile in the South. The AAMRs for sex and race were highest in the West and lowest in the South. None of the states located in the Midwest showed a significant reduction in mortality. Mortality remained stable for hospital setting and nursing home/long‐term care facility, except that the number of deaths increased at home and hospice facility since 2014.

Conclusions

The reduction in mortality in patients with aortic stenosis was not consistent among demographic subsets and states. The substantial public health and economic implications call for determination of underlying clinical and socioeconomic factors to narrow the gap.

Background

Atrial fibrillation (AF) is the most common cardiac arrhythmia, but the pathogenesis is not completely understood. The application of metabolomics could help in discovering new metabolic pathways involved in the development of the disease.

Methods and Results

We measured 112 baseline fasting metabolites of 3770 participants in the Malmö Diet and Cancer Study; these participants were free of prevalent AF. Incident cases of AF were ascertained through previously validated registers. The associations between baseline levels of metabolites and incident AF were investigated using Cox proportional hazard models. During 23.1 years of follow‐up, 650 cases of AF were identified (incidence rate: 8.6 per 1000 person‐years). In Cox regression models adjusted for AF risk factors, 7 medium‐ and long‐chain acylcarnitines were associated with higher risk of incident AF (hazard ratio [HR] ranging from 1.09; 95% CI, 1.00–1.18 to 1.14, 95% CI, 1.05–1.24 per 1 SD increment of acylcarnitines). Furthermore, caffeine and acisoga were also associated with an increased risk (HR, 1.17; 95% CI, 1.06–1.28 and 1.08; 95% CI, 1.00–1.18, respectively), while beta carotene was associated with a lower risk (HR, 0.90; 95% CI, 0.82–0.99).

Conclusions

For the first time, we show associations between altered acylcarnitine metabolism and incident AF independent of traditional AF risk factors in a general population. These findings highlight metabolic alterations that precede AF diagnosis by many years and could provide insight into the pathogenesis of AF. Future studies are needed to replicate our finding in an external cohort as well as to test whether the relationship between acylcarnitines and AF is causal.

Background

Exhaled carbon monoxide (eCO) is directly associated with traditional cardiovascular disease risk factors and incident cardiovascular disease. However, its relation with the cardiovascular health score and incidence of heart failure (HF) has not been investigated.

Methods and Results

We measured eCO in 3521 Framingham Heart Study Offspring participants attending examination cycle 6 (mean age 59 years, 53% women). We related the cardiovascular health score (composite of blood pressure, fasting plasma glucose, total cholesterol, body mass index, smoking, diet, and physical activity) to eCO adjusting for age, sex, and smoking. Higher cardiovascular health scores were associated with lower eCO (β=−0.02, P<0.0001), even among nonsmokers. Additionally, C‐reactive protein, plasminogen activator inhibitor‐1, fibrinogen, growth differentiation factor‐15, homocysteine, and asymmetrical dimethylarginine were positively associated with eCO (P≤0.003 for all). The age‐ and sex‐adjusted and multivariable‐adjusted heritabilities of eCO were 49.5% and 31.4%, respectively. Over a median follow‐up of 18 years, 309 participants (45% women) developed HF. After multivariable adjustment, higher eCO was associated with higher risk of HF (hazards ratio per SD increment: 1.39; 95% CI, 1.19–1.62 [P<0.001]) and with higher risk of HF with reduced ejection fraction (N=144 events; hazard ratio per SD increment in eCO: 1.43; 95% CI, 1.15–1.77 [P=0.001]).

Conclusions

In our community‐based sample, higher levels of eCO were associated with lower cardiovascular health scores, an adverse cardiovascular biomarker profile, and a higher risk of HF, specifically HF with reduced ejection fraction. Our findings suggest that carbon monoxide may identify a novel pathway to HF development.

Background

Outcomes of patients from out‐of‐hospital cardiac arrest (OHCA) vary widely globally because of differences in prehospital systems of emergency care. National efforts had gone into improving OHCA outcomes in Singapore in recent years including community and prehospital initiatives. We aimed to document the impact of implementation of a national 5‐year Plan for prehospital emergency care in Singapore on OHCA outcomes from 2011 to 2016.

Methods and Results

Prospective, population‐based data of OHCA brought to Emergency Departments were obtained from the Pan‐Asian Resuscitation Outcomes Study cohort. The primary outcome was Utstein (bystander witnessed, shockable rhythm) survival‐to‐discharge or 30‐day postarrest. Mid‐year population estimates were used to calculate age‐standardized incidence. Multivariable logistic regression was performed to identify prehospital characteristics associated with survival‐to‐discharge across time. A total of 11 465 cases qualified for analysis. Age‐standardized incidence increased from 26.1 per 100 000 in 2011 to 39.2 per 100 000 in 2016. From 2011 to 2016, Utstein survival rates nearly doubled from 11.6% to 23.1% (P=0.006). Overall survival rates improved from 3.6% to 6.5% (P<0.001). Bystander cardiopulmonary resuscitation rates more than doubled from 21.9% to 56.3% and bystander automated external defibrillation rates also increased from 1.8% to 4.6%. Age ≤65 years, nonresidential location, witnessed arrest, shockable rhythm, bystander automated external defibrillation, and year 2016 were independently associated with improved survival.

Conclusions

Implementation of a national prehospital strategy doubled OHCA survival in Singapore from 2011 to 2016, along with corresponding increases in bystander cardiopulmonary resuscitation and bystander automated external defibrillation. This can be an implementation model for other systems trying to improve OHCA outcomes.

Background

Underrepresentation of older people in clinical trials remains. This study aimed to examine the inclusion of older people and associated safety and efficacy reports from clinical trials of new molecular entities for cardiovascular disease indications since commencement of the US Food and Drug Administration Drug Trial Snapshot (DTS) Program. The DTS provides concise information on participants included in clinical trials supporting US Food and Drug Administration approval of new drugs.

Methods and Results

A cross‐sectional analysis between January 1, 2015 and April 30, 2019 of DTS data including approval date, indication, number of trials and participants, age distribution, efficacy, and safety statements was conducted. Participation‐to‐prevalence ratio (PPR) was used to describe representation of older participants in trials relative to disease population. Efficacy and safety statements regarding age were compared with drug prescribing information. A total of 72 079 participants from 10 DTS reports were identified and 39 625 (55.0%) were aged ≥65 years old. Overall, 63.6% of cardiovascular disease DTS reports were representative of people aged ≥65 years old for specific cardiovascular disease conditions. Underrepresentation was observed in 4 DTS: 2 for heart failure (PPR 0.48 and 0.62), 1 for pulmonary arterial hypertension (PPR 0.72), and 1 for venous thromboembolism (PPR 0.38). Participants in clinical trials for new drugs for the treatment of atrial fibrillation (PPR 0.99 and 1.21) and hypercholesterolemia (PPR 0.84 and 0.97) were reflective of the older population for these diseases. An increased risk of adverse events in older participants was reported in 40% DTS safety statements but no differences were reported in the drug product information.

Conclusions

Despite the fact that >60% of cardiovascular disease trial participants for new molecular entities included in the DTS program were representative of the older population in real‐world clinical practice, concerns remain for conditions including heart failure or venous thromboembolism. Drug product information safety statements regarding age differences in adverse events were not reflective of trial findings. An increased directive is needed to facilitate the generation of real‐world evidence and appropriate reporting within drug product information for these potentially at‐risk patient populations.

Background

Although chronic thromboembolic pulmonary hypertension (CTEPH) and acute pulmonary embolism (APE) share some clinical manifestations, a limited proportion of patients with CTEPH have a history of APE. Moreover, in histopathologic studies, it has been revealed that pulmonary vasculature lesions similar to pulmonary arterial hypertension existed in patients with CTEPH. Thus, it remains unknown whether these 3 disorders also share genetic backgrounds.

Methods and Results

Whole exome screening was performed with DNA isolated from 51 unrelated patients with CTEPH of Japanese ancestry. The frequency of genetic variants associated with pulmonary arterial hypertension or APE in patients with CTEPH was compared with those in the integrative Japanese Genome Variation Database 3.5KJPN. Whole exome screening analysis showed 17 049 nonsynonymous variants in patients with CTEPH. Although we found 6 nonsynonymous variants that are associated with APE in patients with CTEPH, there was no nonsynonymous variant associated with pulmonary arterial hypertension. Patients with CTEPH with a history of APE had nonsynonymous variants of F5, which encodes factor V. In contrast, patients with CTEPH without a history of APE had a nonsynonymous variant of THBD, which encodes thrombomodulin. Moreover, thrombin‐activatable fibrinolysis inhibitor, which is one of the pathogenic proteins in CTEPH, was significantly more activated in those who had the variants of THBD compared with those without it.

Conclusions

These results provide the first evidence that patients with CTEPH have some variants associated with APE, regardless of the presence or absence of a history of APE. Furthermore, the variants might be different between patients with CTEPH with and without a history of APE.

Background

Peripheral artery disease (PAD) is both a common comorbidity and a contributing factor to heart failure. Whether PAD is associated with hospitalization for recurrent decompensation among patients with established heart failure is uncertain.

Methods and Results

Since 2005, the ARIC (Atherosclerosis Risk in Communities) study has conducted active surveillance of hospitalized acute decompensated heart failure (ADHF), with events verified by physician review. From 2005 to 2016, 1481 patients were hospitalized with ADHF and discharged alive (mean age, 78 years; 69% White). Of these, 207 (14%) had diagnosis of PAD. Those with PAD were more often men (55% versus 44%) and smokers (17% versus 8%), with a greater prevalence of coronary artery disease (72% versus 52%). Patients with PAD had an increased risk of at least 1 ADHF readmission, both within 30 days (11% versus 7%) and 1 year (39% versus 28%) of discharge from the index hospitalization. After adjustments, PAD was associated with twice the hazard of ADHF readmission within 30 days (HR, 2.02; 95% CI, 1.14–3.60) and a 60% higher hazard of ADHF readmission within 1 year (HR, 1.60; 95% CI, 1.25–2.05). The 1‐year hazard of ADHF readmission associated with PAD was stronger with heart failure with reduced ejection fraction (HR, 2.01; 95% CI, 1.29–3.13) than preserved ejection fraction (HR, 1.04; 95% CI, 0.69–1.56); P for interaction=0.05.

Conclusions

Patients with ADHF and concomitant PAD have a higher likelihood of ADHF readmission. Strategies to prevent ADHF readmissions in this high‐risk group are warranted.

Background

There has been significant controversy about the effects of pre‐hospitalization use of renin‐angiotensin system (RAS) inhibitors on the prognosis of patients with hypertension and coronavirus disease 2019.

Methods and Results

We retrospectively assessed 2297 hospitalized patients with coronavirus disease 2019 at Tongji Hospital in Wuhan, China, from January 10 to March 30, 2020; and identified 1182 patients with known hypertension on pre‐hospitalization therapy. We compared the baseline characteristics and in‐hospital mortality between patients with hypertension taking RAS inhibitors (n=355) versus non‐RAS inhibitors (n=827). Of the 1182 patients with hypertension (median age 68 years, 49.1% male), 12/355 (3.4%) patients died in the RAS inhibitors group versus 95/827 (11.5%) patients in the non‐RAS inhibitors group (P<0.0001). Adjusted hazard ratio for mortality was 0.28 (95% CI 0.15–0.52, P<0.0001) at 45 days in the RAS inhibitors group compared with non‐RAS inhibitors group. Similar findings were observed when patients taking angiotensin receptor blockers (n=289) or angiotensin‐converting enzyme inhibitors (n=66) were separately compared with non‐RAS inhibitors group. The RAS inhibitors group compared with non‐RAS inhibitors group had lower levels of C‐reactive protein (median 13.5 versus 24.4 pg/mL; P=0.007) and interleukin‐6 (median 6.0 versus 8.5 pg/mL; P=0.026) on admission. The protective effect of RAS inhibitors on mortality was confirmed in a meta‐analysis of published data when our data were added to previous studies (odd ratio 0.44, 95% CI 0.29–0.65, P<0.0001).

Conclusions

In a large single center retrospective analysis, we observed a protective effect of pre‐hospitalization use of RAS inhibitors on mortality in patients with hypertension and coronavirus disease 2019, which might be associated with reduced inflammatory response.

Background

Right ventricular (RV) dysfunction is a prognostic factor for cardiovascular disease. However, its mechanism and pathophysiology remain unknown. We investigated RV function using RV‐specific 3‐dimensional (3D)‐speckle‐tracking echocardiography (STE) in patients with chronic thromboembolic pulmonary hypertension. We also assessed regional wall motion abnormalities in the RV and chronological changes during balloon pulmonary angioplasty (BPA).

Methods and Results

Twenty‐nine patients with chronic thromboembolic pulmonary hypertension who underwent BPA were enrolled and underwent right heart catheterization and echocardiography before, immediately after, and 6 months after BPA. Echocardiographic assessment of RV function included both 2‐dimensional‐STE and RV‐specific 3D‐STE. Before BPA, global area change ratio measured by 3D‐STE was significantly associated with invasively measured mean pulmonary artery pressure and pulmonary vascular resistance (r=0.671 and r=0.700, respectively). Dividing the RV into the inlet, apex, and outlet, inlet area change ratio showed strong correlation with mean pulmonary artery pressure and pulmonary vascular resistance before BPA (r=0.573 and r=0.666, respectively). Only outlet area change ratio was significantly correlated with troponin T values at 6 months after BPA (r=0.470), and its improvement after BPA was delayed compared with the inlet and apex regions. Patients with poor outlet area change ratio were associated with a delay in RV reverse remodeling after treatment.

Conclusions

RV‐specific 3D‐STE analysis revealed that 3D RV parameters were novel useful indicators for assessing RV function and hemodynamics in pulmonary hypertension and that each regional RV portion presents a unique response to hemodynamic changes during treatment, implicating that evaluation of RV regional functions might lead to a new guide for treatment strategies.

Background

Hypodense filling defects within the pulmonary veins on computed tomography described as pulmonary vein sign (PVS) have been noted in acute pulmonary embolism and shown to be associated with poor prognosis. We evaluated venous flow abnormalities in chronic thromboembolic pulmonary hypertension (CTEPH) to determine its usefulness in the computed tomography assessment of CTEPH.

Methods and Results

Blinded retrospective computed tomography analysis of 50 proximal CTEPH cases and 3 control groups—50 acute pulmonary embolism, 50 nonthromboembolic cohort, and 50 pulmonary arterial hypertension. Venous flow reduction was assessed by the following: (1) presence of a filling defect of at least 2 cm in a pulmonary vein draining into the left atrium, and (2) left atrium attenuation (>160 Hounsfield units). PVS was most prevalent in CTEPH. Compared with all controls, sensitivity and specificity of PVS for CTEPH is 78.0% and 85.3% (95% CI, 64.0–88.5 and 78.6–90.6, respectively) versus 34.0% and 70.7% (95% CI, 21.2−48.8 and 62.7–77.8) in acute pulmonary embolism, 8.0% and 62% (95% CI, 2.2–19.2 and 53.7–69.8) in nonthromboembolic and 2.0% and 60% (95% CI, 0.1−10.7 and 51.7−67.9) in pulmonary arterial hypertension. In CTEPH, lobar and segmental arterial occlusive disease was most commonly associated with corresponding absent venous flow. PVS detection was highly reproducible (Kappa=0.96, 95% CI, 0.90–1.01, P<0.001).

Conclusions

PVS is easy to detect with higher sensitivity and specificity in CTEPH compared with acute pulmonary embolism and is not a feature of pulmonary arterial hypertension. Asymmetric enhancement of pulmonary veins may serve as an additional parameter in the computed tomography assessment of CTEPH and can be used to differentiate CTEPH from pulmonary arterial hypertension.

Background

Inflammation levels are lower in East Asians than in Western people. We studied the association between high‐sensitivity hs‐CRP (C‐reactive protein) and adverse outcomes in Korean patients with chronic kidney disease.

Methods and Results

We included 2018 participants from the KNOW‐CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease) between April 2011 and February 2016. The primary outcome was a composite of extended major cardiovascular events (eMACE) or all‐cause mortality. The secondary end points were separate outcomes of eMACE, all‐cause death, and adverse kidney outcome. We also evaluated predictive ability of hs‐CRP for the primary outcome. The median hs‐CRP level was 0.60 mg/L. During the mean follow‐up of 3.9 years, there were 125 (6.2%) eMACEs and 80 (4.0%) deaths. In multivariable Cox analysis after adjustment of confounders, there was a graded association of hs‐CRP with the primary outcome. The hazard ratios for hs‐CRPs of 1.0 to 2.99 and ≥3.0 mg/L were 1.33 (95% CI, 0.87–2.03) and 2.08 (95% CI, 1.30–3.33) compared with the hs‐CRP of <1.0 mg/L. In secondary outcomes, this association was consistent for eMACE and all‐cause death; however, hs‐CRP was not associated with adverse kidney outcomes. Finally, prediction models failed to show improvement of predictive performance of hs‐CRP compared with conventional factors.

Conclusions

In Korean patients with chronic kidney disease, the hs‐CRP level was low and significantly associated with higher risks of eMACEs and mortality. However, hs‐CRP did not associate with adverse kidney outcome, and the predictive performance of hs‐CRP was not strong.

Registration

URL: http://www.clinicaltrials.gov; Unique identifier: NCT01630486.

Background

In a recent multicenter study of perinatal outcome in fetuses with Ebstein anomaly or tricuspid valve dysplasia, we found that one third of live‐born patients died before hospital discharge. We sought to further describe postnatal management strategies and to define risk factors for neonatal mortality and circulatory outcome at discharge.

Methods and Results

This 23‐center, retrospective study from 2005 to 2011 included 243 fetuses with Ebstein anomaly or tricuspid valve dysplasia. Among live‐born patients, clinical and echocardiographic factors were evaluated for association with neonatal mortality and palliated versus biventricular circulation at discharge. Of 176 live‐born patients, 7 received comfort care, 11 died <24 hours after birth, and 4 had insufficient data. Among 154 remaining patients, 38 (25%) did not survive to discharge. Nearly half (46%) underwent intervention. Mortality differed by procedure; no deaths occurred in patients who underwent right ventricular exclusion. At discharge, 56% of the cohort had a biventricular circulation (13% following intervention) and 19% were palliated. Lower tricuspid regurgitation jet velocity (odds ratio [OR], 2.3 [1.1–5.0], 95% CI, per m/s; P=0.025) and lack of antegrade flow across the pulmonary valve (OR, 4.5 [1.3–14.2]; P=0.015) were associated with neonatal mortality by multivariable logistic regression. These variables, along with smaller pulmonary valve dimension, were also associated with a palliated outcome.

Conclusions

Among neonates with Ebstein anomaly or tricuspid valve dysplasia diagnosed in utero, a variety of management strategies were used across centers, with poor outcomes overall. High‐risk patients with low tricuspid regurgitation jet velocity and no antegrade pulmonary blood flow should be considered for right ventricular exclusion to optimize their chance of survival.

Background

Infants with heart failure remain at significant risk for wait list mortality, despite mechanical circulatory support (MCS). It is unclear if the outcomes are influenced by modality of support or underlying diagnosis. We sought to compare the outcomes of infants <10 kg, focusing on modality of support and underlying diagnosis.

Methods and Results

Using the Pediatric Heart Transplant Society database, we evaluated survival following first MCS device in children <10 kg who were listed for heart transplant between 2010 and 2018. There were 2049 children <10 kg, with the predominant diagnosis being congenital heart disease (CHD) (59.8% [n=1226]) and 28.1% (n=577) requiring MCS. Extracorporeal membrane oxygenation (ECMO) was the most common form of MCS at listing, with ventricular assist device (VAD) more common after listing. There was no difference in the use of ECMO at or after listing for cardiomyopathy versus CHD (8.9% versus 7.2%; P=0.2; 5.4% versus 6.4%; P=0.4). However, there was a significant difference in the use of VAD both at listing (8% versus 2.4%; P<0.001) and after (22.8% versus 5.1%; P<0.001) between the 2 groups. When comparing these groups, patients with CHD were smaller and younger and had a higher proportion with previous cardiac surgery. Survival at 3 months demonstrated better survival for VAD therapy compared with ECMO (74.3% versus 48.6%; P<0.001). In patients <5 kg, survival did not differ between ECMO and VAD (P=0.01) for the CHD or the cardiomyopathy group (P=0.38), but patients with cardiomyopathy demonstrated better survival on both forms of support.

Conclusions

Survival for patients <10 kg on ECMO is inferior compared with VAD. Patients with cardiomyopathy <5 kg had better survival with both modes of MCS compared with those with CHD. These findings support the need for small, durable devices for neonates and infants, with particular focus in patients with CHD.

Background

During the severe acute respiratory syndrome Coronavirus 2 pandemic, there has been an increase in hyperinflammatory presentation in previously healthy children with a variety of cardiac manifestations. Our objective is to describe the cardiac manifestations found in an international cohort of 55 pediatric cases with multi‐system inflammatory syndrome during the severe acute respiratory syndrome Coronavirus 2 pandemic.

Methods and Results

We reviewed data on previously healthy pediatric patients (≤18 years) with structurally normal hearts who presented at hospitals in the United States, United Kingdom, Spain, and Pakistan with multi‐system inflammatory syndrome in children and had consultation with a pediatric cardiologist. Data collected included demographics, clinical presentation, laboratory values, electrocardiographic abnormalities, echocardiographic findings, and initial therapies. A total of 55 patients presented with multi‐system inflammatory syndrome in children. Thirty‐five patients (64%) had evidence of decreased left ventricular function, 17 (31%) had valvulitis, 12 (22%) with pericardial effusion, and 11 (20%) with coronary abnormalities. Twenty‐seven (49%) required intensive care unit admission and 24 (44%) had evidence of shock. Eleven patients (20%) fulfilled complete Kawasaki disease criteria and had lower NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), D‐dimer, and ferritin levels compared with those who did not fulfill criteria. Electrophysiologic abnormalities occurred in 6 patients and included complete atrioventricular block, transient atrioventricular block, and ventricular tachycardia.

Conclusions

To our knowledge, we describe the first international cohort of pediatric patients with multi‐system inflammatory syndrome in children during the severe acute respiratory syndrome Coronavirus 2 pandemic with a range of cardiac manifestations. This article brings awareness and alertness to the global medical community to recognize these children during the pandemic and understand the need for early cardiology evaluation and follow‐up.

Background

Incidence and outcomes of out‐of‐hospital cardiac arrest (OHCA) vary between communities. We aimed to examine differences in patient characteristics, prehospital care, and outcomes in Singapore and Victoria.

Methods and Results

Using the prospective Singapore Pan‐Asian Resuscitation Outcomes Study and Victorian Ambulance Cardiac Arrest Registry, we identified 11 061 and 32 003 emergency medical services‐attended adult OHCAs between 2011 and 2016 respectively. Incidence and survival rates were directly age adjusted using the World Health Organization population. Survival was analyzed with logistic regression, with model selection via backward elimination. Of the 11 061 and 14 834 emergency medical services‐treated OHCAs (overall mean age±SD 65.5±17.2; 67.4% males) in Singapore and Victoria respectively, 11 054 (99.9%) and 5595 (37.7%) were transported, and 440 (4.0%) and 2009 (13.6%) survived. Compared with Victoria, people with OHCA in Singapore were older (66.7±16.5 versus 64.6±17.7), had less shockable rhythms (17.7% versus 30.3%), and received less bystander cardiopulmonary resuscitation (45.7% versus 58.5%) and defibrillation (1.3% versus 2.5%) (all P<0.001). Age‐adjusted OHCA incidence and survival rates increased in Singapore between 2011 and 2016 (P<0.01 for trend), but remained stable, though higher, in Victoria. Likelihood of survival increased significantly (P<0.001) with arrest in public locations (adjusted odds ratio [aOR] 1.81), witnessed arrest (aOR 2.14), bystander cardiopulmonary resuscitation (aOR 1.72), initial shockable rhythm (aOR 9.82), and bystander defibrillation (aOR 2.04) but decreased with increasing age (aOR 0.98) and emergency medical services response time (aOR 0.91).

Conclusions

Singapore reported increasing OHCA incidence and survival rates between 2011 and 2016, compared with stable, albeit higher, rates in Victoria. Survival differences might be related to different emergency medical services practices including patient selection for resuscitation and transport.

Background

The ambulance response time in out‐of‐hospital cardiac arrest (OHCA) has doubled over the past 30 years in Sweden. At the same time, the chances of surviving an OHCA have increased substantially. A correct understanding of the effect of ambulance response time on the outcome after OHCA is fundamental for further advancement in cardiac arrest care.

Methods and Results

We used data from the SRCR (Swedish Registry of Cardiopulmonary Resuscitation) to determine the effect of ambulance response time on 30‐day survival after OHCA. We included 20 420 cases of OHCA occurring in Sweden between 2008 and 2017. Survival to 30 days was our primary outcome. Stratification and multiple logistic regression were used to control for confounding variables. In a model adjusted for age, sex, calendar year, and place of collapse, survival to 30 days is presented for 4 different groups of emergency medical services (EMS)‐crew response time: 0 to 6 minutes, 7 to 9 minutes, 10 to 15 minutes, and >15 minutes. Survival to 30 days after a witnessed OHCA decreased as ambulance response time increased. For EMS response times of >10 minutes, the overall survival among those receiving cardiopulmonary resuscitation before EMS arrival was slightly higher than survival for the sub‐group of patients treated with compressions‐only cardiopulmonary resuscitation.

Conclusions

Survival to 30 days after a witnessed OHCA decreases as ambulance response times increase. This correlation was seen independently of initial rhythm and whether cardiopulmonary resuscitation was performed before EMS‐crew arrival. Shortening EMS response times is likely to be a fast and effective way of increasing survival in OHCA.

Background

Managing risk factors is crucial to prevent stroke. However, few cohort studies have evaluated socioeconomic factors together with conventional factors affecting incident stroke and its subtypes in China.

Methods and Results

A 2014 to 2016 prospective study from the China National Stroke Screening and Intervention Program comprised 437 318 adults aged ≥40 years without stroke at baseline. There were 2429 cases of first‐ever stroke during a median follow‐up period of 2.1 years, including 2206 ischemic strokes and 237 hemorrhagic strokes. The multivariable Cox regression analysis indicated that age 50 to 59 years (versus 40–49 years), primary school or no formal education (versus middle school), having >1 child (versus 1 child), living in Northeast, Central, East, or North China (versus Southwest China), physical inactivity, hypertension, diabetes mellitus, and obesity were positively associated with the risk of total and ischemic stroke, whereas age 60 to 69 years and living with spouse or children (versus living alone) were negatively associated with the risk of total and ischemic stroke. Men, vegetable‐based diet, underweight, physical inactivity, hypertension, living in a high‐income region, having Urban Resident Basic Medical Insurance, and New Rural Cooperative Medical System were positively associated with the risk of hemorrhagic stroke, whereas age 60 to 69 years was negatively associated with the risk of hemorrhagic stroke.

Conclusions

We identified socioeconomic factors that complement traditional risk factors for incident stroke and its subtypes, allowing targeting these factors to reduce stroke burden.

Background

Transcatheter aortic valve replacement (TAVR) requires large‐bore access, which is associated with bleeding and vascular complications. ProGlide and Prostar XL are vascular closure devices widely used in clinical practice, but their comparative efficacy and safety in TAVR is a subject of debate, owing to conflicting results among published studies. We aimed to compare outcomes with Proglide versus Prostar XL vascular closure devices after TAVR.

Methods and Results

This large‐scale analysis was conducted using RISPEVA, a multicenter national prospective database of patients undergoing transfemoral TAVR treated with ProGlide versus Prostar XL vascular closure devices. Both multivariate and propensity score adjustments were performed. A total of 2583 patients were selected. Among them, 1361 received ProGlide and 1222 Prostar XL. The predefined primary end point was a composite of cardiovascular mortality, bleeding, and vascular complications assessed at 30 days and 1‐year follow‐up. At 30 days, there was a significantly greater reduction of the primary end point with ProGlide versus Prostar XL (13.8% versus 20.5%, respectively; multivariate adjusted odds ratio, 0.80 [95% CI, 0.65–0.99]; P=0.043), driven by a reduction of bleeding complications (9.1% versus 11.7%, respectively; multivariate adjusted odds ratio, 0.76 [95% CI, 0.58–0.98]; P=0.046). Propensity score analysis confirmed the significant reduction of major adverse cardiovascular events and bleeding risk with ProGlide. No significant differences in the primary end point were found between the 2 vascular closure devices at 1 year of follow‐up (multivariate adjusted hazard ratio, 0.88 [95% CI, 0.72–1.10]; P=0.902). Comparable results were obtained by propensity score analysis. During the procedure, compared with Prostar XL, ProGlide yielded significant higher device success (99.2% versus 97.5%, respectively; P=0.001).

Conclusions

ProGlide has superior efficacy as compared with Prostar XL in TAVR procedures and is associated with a greater reduction of composite adverse events at short‐term, driven by lower bleeding complications.

Registration Information

URL: clini​caltr​ials.gov; Unique identifier: NCT02713932.

Background

Recent literature reports a strong thrombotic tendency in patients hospitalized for a coronavirus disease 2019 (COVID‐19) infection. This characteristic is unusual and seems specific to COVID‐19 infections, especially in their severe form. Viral infections can trigger acquired thrombophilia, which can then lead to thrombotic complications. We investigate for the presence of acquired thrombophilia, which could participate in this phenomenon, and report its prevalence. We also wonder if these thrombophilias participate in the bad prognosis of severe COVID‐19 infections.

Methods and Results

In 89 consecutive patients hospitalized for COVID‐19 infection, we found a 20% prevalence of PS (protein S) deficiency and a high (ie, 72%) prevalence of antiphospholipid antibodies: mainly lupus anticoagulant. The presence of PS deficiency or antiphospholipid antibodies was not linked with a prolonged activated partial thromboplastin time nor with D‐dimer, fibrinogen, or CRP (C‐reactive protein) concentrations. These coagulation abnormalities are also not linked with thrombotic clinical events occurring during hospitalization nor with mortality.

Conclusions

We assess a high prevalence of positive tests detecting thrombophilia in COVID‐19 infections. However, in our series, these acquired thrombophilias are not correlated with the severity of the disease nor with the occurrence of thrombotic events. Albeit the strong thrombotic tendency in COVID‐19 infections, the presence of frequent acquired thrombophilia may be part of the inflammation storm of COVID‐19 and should not systematically modify our strategy on prophylactic anticoagulant treatment, which is already revised upwards in this pathological condition.

Registration

URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT04335162.

Background

Long‐term feeding with a high‐fat diet (HFD) induces endothelial dysfunction in mice, but early HFD‐induced effects on endothelium have not been well characterized.

Methods and Results

Using an magnetic resonance imaging‐based methodology that allows characterization of endothelial function in vivo, we demonstrated that short‐term (2 weeks) feeding with a HFD to C57BL/6 mice or to E3L.CETP mice resulted in the impairment of acetylcholine‐induced response in the abdominal aorta (AA), whereas, in the thoracic aorta (TA), the acetylcholine‐induced response was largely preserved. Similarly, HFD resulted in arterial stiffness in the AA, but not in the TA. The difference in HFD‐induced response was ascribed to distinct characteristics of perivascular adipose tissue in the TA and AA, related to brown‐ and white‐like adipose tissue, respectively, as assessed by histology, immunohistochemistry, and Raman spectroscopy. In contrast, short‐term HFD‐induced endothelial dysfunction could not be linked to systemic insulin resistance, changes in plasma concentration of nitrite, or concentration of biomarkers of glycocalyx disruption (syndecan‐1 and endocan), endothelial inflammation (soluble form of vascular cell adhesion molecule 1, soluble form of intercellular adhesion molecule 1 and soluble form of E‐selectin), endothelial permeability (soluble form of fms‐like tyrosine kinase 1 and angiopoietin 2), and hemostasis (tissue plasminogen activator and plasminogen activator inhibitor 1).

Conclusions

Short‐term feeding with a HFD induces endothelial dysfunction in the AA but not in the TA, which could be ascribed to a differential response of perivascular adipose tissue to a HFD in the AA versus TA. Importantly, early endothelial dysfunction in the AA is not linked to elevation of classical systemic biomarkers of endothelial dysfunction.

Background

Intravenous high‐dose glucagon is a recommended antidote against beta‐blocker poisonings, but clinical effects are unclear. We therefore investigated hemodynamic effects and safety of high‐dose glucagon with and without concomitant beta‐blockade.

Methods and Results

In a randomized crossover study, 10 healthy men received combinations of esmolol (1.25 mg/kg bolus+0.75 mg/kg/min infusion), glucagon (50 µg/kg), and identical volumes of saline placebo on 5 separate days in random order (saline+saline; esmolol+saline; esmolol+glucagon bolus; saline+glucagon infusion; saline+glucagon bolus). On individual days, esmolol/saline was infused from −15 to 30 minutes. Glucagon/saline was administered from 0 minutes as a 2‐minute intravenous bolus or as a 30‐minute infusion (same total glucagon dose). End points were hemodynamic and adverse effects of glucagon compared with saline. Compared with saline, glucagon bolus increased mean heart rate by 13.0 beats per minute (95% CI, 8.0–18.0; P<0.001), systolic blood pressure by 15.6 mm Hg (95% CI, 8.0–23.2; P=0.002), diastolic blood pressure by 9.4 mm Hg (95% CI, 6.3–12.6; P<0.001), and cardiac output by 18.0 % (95% CI, 9.7–26.9; P=0.003) at the 5‐minute time point on days without beta‐blockade. Similar effects of glucagon bolus occurred on days with beta‐blockade and between 15 and 30 minutes during infusion. Hemodynamic effects of glucagon thus reflected pharmacologic glucagon plasma concentrations. Glucagon‐induced nausea occurred in 80% of participants despite ondansetron pretreatment.

Conclusions

High‐dose glucagon boluses had significant hemodynamic effects regardless of beta‐blockade. A glucagon infusion had comparable and apparently longer‐lasting effects compared with bolus, indicating that infusion may be preferable to bolus injections.

Registration Information

URL: https://www.clinicaltrials.gov; Unique identifier: NCT03533179.

Background

The prevalence of thoracic aortic aneurysms (TAA) in patients with known abdominal aortic aneurysms (AAA) is not well known and understudied. Our aim was to conduct a systematic review and meta‐analysis of the overall prevalence of synchronous and metachronous TAA (SM‐TAA) in patients with a known AAA and to understand the characteristics of this sub‐population.

Methods and Results

We searched MEDLINE, EMBASE, and CENTRAL (Cochrane Central Register of Controlled Trials) from inception to November 2019 for all population‐based studies reporting on the prevalence of SM‐TAAs in a cohort of patients with AAA. Article screening and data extraction were performed by 2 authors and data were pooled using a random‐effects model of proportions using Freeman‐Tukey double arcsine transformation. The main outcome was the prevalence of SM‐TAAs in patients with AAAs. Secondary outcomes were the prevalence of synchronous TAAs, metachronous TAAs, prevalence of TAAs in patients with AAA according to the anatomic location (ascending, arch, and descending) and the differences in prevalence of these aneurysms according to sex and risk factors. Six studies were included. The pooled‐prevalence of SM‐TAA in AAA patients was 19.2% (95% CI, 12.3–27.3). Results revealed that 15.2% (95% CI, 7.1–25.6) of men and 30.7% (95% CI, 25.2–36.5) of women with AAA had an SM‐TAA. Women with AAA had a 2‐fold increased risk of having an SM‐TAA than men (relative risk [RRs], 2.16; 95% CI, 1.32–3.55). Diabetes mellitus was associated with a 43% decreased risk of having SM‐TAA (RRs, 0.57; 95% CI, 0.41–0.80).

Conclusions

Since a fifth of AAA patients will have an SM‐TAA, routine screening of SM‐TAA and their clinical impact should be more thoroughly studied in patients with known AAA.

At the onset of the Coronavirus Disease 2019 (COVID‐19) pandemic, just as public institutions and businesses closed, research programs performing human participant research (HPR) also largely ceased operations. With the partial ebbing of the pandemic in some areas, universities and healthcare organizations conducting HPR are considering reopening. Whereas guidelines from governmental authorities and medical specialty societies currently exist to help restarting health services and resuming clinical trials, no clear guidance is available to aid resumption of HPR at community‐based observational cohort studies. Indefinite stoppage of observational research at cohort studies carries many drawbacks and its safe resumption is important and feasible. In this narrative review, we describe a potential path forward for safely reopening community‐based observational studies, drawing on scientific knowledge and best practices from a variety of medical and lay sources. We highlight current recommendations regarding pandemic status assessment and the metrics useful for guiding decisions regarding safe reopening/reclosing and for screening and surveillance of COVID‐19 among employees and participants. We synthesize insights from contemporary literature regarding infection prevention and environmental safety into a set of easy to operationalize plans for restructuring HPR. And lastly, we suggest ways in which observational studies can potentially aid the efforts to characterize the pandemic.

Despite consensus that excessive circulating concentrations of apoB‐lipoproteins is a key driver for the atherosclerotic process and that treatments that low‐density lipoprotein cholesterol lowering by up‐regulation of low‐density lipoprotein cholesterol receptor expression reduces that risk, divergent viewpoints on interpretation of study data have resulted in substantial differences in European and American lipid guideline recommendations. This article explores those differences and highlights the importance of understanding guideline‐based lipid management to improve patient care and reduce the risk of clinical atherosclerotic cardiovascular disease.