A DNA methylation atlas of normal human cell types.

DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2-5. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

Editor's Choice - Trends in Management and Outcomes of Type B Aortic Dissection: A Report From the International Registry of Aortic Dissection.

OBJECTIVE: To describe the trends in management and outcomes of patients with acute type B aortic dissection in the International Registry of Acute Aortic Dissection. METHODS: From 1996 - 2022, 3 908 patients were divided into similar sized quartiles (T1, T2, T3, and T4). In hospital outcomes were analysed for each quartile. Survival rates following admission were compared using Kaplan-Meier analyses with Mantel-Cox Log rank tests. RESULTS: Endovascular treatment increased from 19.1% in T1 to 37.2% in T4 (ptrend < .001). Correspondingly, medical therapy decreased from 65.7% in T1 to 54.0% in T4 (ptrend < .001), and open surgery from 14.8% in T1 to 7.0% in T4 (ptrend < .001). In hospital mortality decreased in the overall cohort from 10.7% in T1 to 6.1% in T4 (ptrend < .001), as well as in medically, endovascularly and surgically treated patients (ptrend = .017, .033, and .011, respectively). Overall post-admission survival at three years increased (T1: 74.8% vs. T4: 77.3%; p = .006). CONCLUSION: Considerable changes in the management of acute type B aortic dissection were observed over time, with a significant increase in the use of endovascular treatment and a corresponding reduction in open surgery and medical management. These changes were associated with a decreased overall in hospital and three year post-admission mortality rate among quartiles.

Universal lung epithelium DNA methylation markers for detection of lung damage in liquid biopsies.

BACKGROUND: Circulating biomarkers for lung damage are lacking. Lung epithelium-specific DNA methylation patterns can potentially report the presence of lung-derived cell-free DNA (cfDNA) in blood, as an indication of lung cell death. METHODS: We sorted human lung alveolar and bronchial epithelial cells from surgical specimens, and obtained their methylomes using whole-genome bisulfite sequencing. We developed a PCR sequencing assay determining the methylation status of 17 loci with lung-specific methylation patterns, and used it to assess lung-derived cfDNA in the plasma of healthy volunteers and patients with lung disease. RESULTS: Loci that are uniquely unmethylated in alveolar or bronchial epithelial cells are enriched for enhancers controlling lung-specific genes. Methylation markers extracted from these methylomes revealed that normal lung cell turnover probably releases cfDNA into the air spaces, rather than to blood. People with advanced lung cancer show a massive elevation of lung cfDNA concentration in blood. Among individuals undergoing bronchoscopy, lung-derived cfDNA is observed in the plasma of those later diagnosed with lung cancer, and to a lesser extent in those diagnosed with other lung diseases. Lung cfDNA is also elevated in patients with acute exacerbation of COPD compared with patients with stable disease, and is associated with future exacerbation and mortality in these patients. CONCLUSIONS: Universal cfDNA methylation markers of normal lung epithelium allow for mutation-independent, sensitive and specific detection of lung-derived cfDNA, reporting on ongoing lung injury. Such markers can find broad utility in the study of normal and pathologic human lung dynamics.

Agonist of RORA Attenuates Nonalcoholic Fatty Liver Progression in Mice via Up-regulation of MicroRNA 122.

BACKGROUND & AIMS: Development of nonalcoholic steatohepatitis (NASH) is associated with reductions in hepatic microRNA122 (MIR122); the RAR related orphan receptor A (RORA) promotes expression of MIR122. Increasing expression of RORA in livers of mice increases expression of MIR122 and reduces lipotoxicity. We investigated the effects of a RORA agonist in mouse models of NASH. METHODS: We screened a chemical library to identify agonists of RORA and tested their effects on a human hepatocellular carcinoma cell line (Huh7). C57BL/6 mice were fed a chow or high-fat diet (HFD) for 4 weeks to induce fatty liver. Mice were given hydrodynamic tail vein injections of a MIR122 antagonist (antagomiR-122) or a control antagomiR once each week for 3 weeks while still on the HFD or chow diet, or intraperitoneal injections of the RORA agonist RS-2982 or vehicle, twice each week for 3 weeks. Livers, gonad white adipose, and skeletal muscle were collected and analyzed by reverse-transcription polymerase chain reaction, histology, and immunohistochemistry. A separate group of mice were fed an atherogenic diet, with or without injections of RS-2982 for 3 weeks; livers were analyzed by immunohistochemistry, and plasma was analyzed for levels of aminotransferases. We analyzed data from liver tissues from patients with NASH included in the RNA-sequencing databases GSE33814 and GSE89632. RESULTS: Injection of mice with antagomiR-122 significantly reduced levels of MIR122 in plasma, liver, and white adipose tissue; in mice on an HFD, antagomiR-122 injections increased fat droplets and total triglyceride content in liver and reduced ß-oxidation and energy expenditure, resulting in significantly more weight gain than in mice given the control microRNA. We identified RS-2982 as an agonist of RORA and found it to increase expression of MIR122 promoter activity in Huh7 cells. In mice fed an HFD or atherogenic diet, injections of RS-2982 increased hepatic levels of MIR122 precursors and reduced hepatic synthesis of triglycerides by reducing expression of biosynthesis enzymes. In these mice, RS-2982 significantly reduced hepatic lipotoxicity, reduced liver fibrosis, increased insulin resistance, and reduced body weight compared with mice injected with vehicle. Patients who underwent cardiovascular surgery had increased levels of plasma MIR122 compared to its levels before surgery; increased expression of plasma MIR122 was associated with increased levels of plasma free fatty acids and levels of RORA. CONCLUSIONS: We identified the compound RS-2982 as an agonist of RORA that increases expression of MIR122 in cell lines and livers of mice. Mice fed an HFD or atherogenic diet given injections of RS-2982 had reduced hepatic lipotoxicity, liver fibrosis, and body weight compared with mice given the vehicle. Agonists of RORA might be developed for treatment of NASH.

Update in carcinoid heart disease - the heart of the matter.

Carcinoid heart disease (CHD) is a paraneoplastic cardiac manifestation occurring in patients with carcinoid syndrome (CS) and advanced neuroendocrine malignancy. In about 20-40% of patients with CS, chronic exposure to tumor-released circulating vasoactive peptides typically results in right-sided valvular fibrosis leading to valve dysfunction and right heart failure. CHD remains a significant cause of morbidity and mortality. The management of patients with CHD is complex, as both the systemic malignant disease and the heart involvement have to be addressed. Early diagnosis and timely surgical intervention in selected patients are of utmost importance and offer a survival benefit. In patients with advanced carcinoid heart disease, valve replacement surgery is the most effective option to alleviate cardiac symptoms and contribute to survival outcomes. A collaboration of a multidisciplinary team in centers with experience is required to provide optimal patient management. Here, we review the current literature regarding CHD presentation, pathophysiology, diagnostic tools, and available treatment strategies.

The American Society of Thoracic Surgery Score versus EuroSCORE I and EuroSCORE II in Israeli Patients Undergoing Cardiac Surgery.

BACKGROUND: Recently, Israel established the first national-level adult cardiac surgery database, which was linked to the Society of Thoracic Surgeons (STS). OBJECTIVES: To validate and compare the STS predicted risk of mortality (PROM) to logistic EuroSCORE I (LESI) and EuroSCORE II (ESII) in Israeli patients undergoing cardiac surgery. METHODS: We retrospectively studied 1279 consecutive patients who underwent cardiac surgeries with a calculable PROM. Data were prospectively entered into our database and used to calculate PROM, LESI, and ESII. Scores were normalized and correlated using linear regression and Pearson's test. To examine model calibration, we plotted the total observed versus expected mortality for each score and across five risk-score subgroups. Model discrimination was assessed by measuring the area under the receiver operating curves. RESULTS: The observed 30-day operative mortality was 1.95%. The median (IQ1; IQ3) PROM, LESI, and the ESII scores were 1.45% (0.69; 3.22), 4.54% (2.28; 9.27), and 1.88% (1.18; 3.54), respectively, with observed over expected ratios of 0.63 (95% confidence interval [95%CI] 0.42-0.93), 0.59 (95%CI 0.40-0.87), and 0.24 (95%CI 0.17-0.36), respectively, (STS vs. ESII P = 0.36, STS vs. LESI P = 0.0001). There was good correlation among all scores. All models overestimated mortality. Model discrimination was high and similar for all three scores. Model calibration of the STS, PROM, and ESII were more accurate than the LESI, particularly in higher risk subgroups. CONCLUSIONS: All scores overestimated mortality. In Israeli patients, the STS, PROM, and ESII risk-scores were more reliable metrics than LESI, particularly in higher risk patients.

Valve Replacement in Patients with Carcinoid Heart Disease: Choosing the Right Valve at the Right Time.

BACKGROUND AND AIM OF THE STUDY: The prosthetic valve of choice in patients with carcinoid valve disease (CVD) remains controversial due to the limited life expectancy of patients with advanced-stage neuroendocrine tumors (NETs) on the one hand, and concerns regarding structural valve deterioration (SVD) on the other hand. METHODS: The records of 17 patients (11 females, seven males; mean age 65 ± 11 years; undergoing 18 operations) with primarily right heart failure due to CVD were reviewed. All patients received somatostatin analogs perioperatively. Hospital and follow up data (acquired via direct patient contact and echocardiography) collected included baseline characteristics, procedural details, and clinical outcomes. RESULTS: The primary NET site was the ileum (n = 11), lungs (n = 2) and stomach, colon and appendix (n = 1 each). In one patient the primary tumor location could not be identified. Preoperative urinary levels of 5-hydroxyindole acetic acid (5-HIAA; 61 ± 36 mg/24 h) and serum levels of chromogranin A (2926 ± 4057 ng/ml) were 10- and 50-fold greater than normal, respectively. A total of 23 valves was implanted: five tricuspid valve replacements (TVR; four tissue and one mechanical), TVR and pulmonary valve replacements (PVR; three tissue and one mechanical), and TVR and mitral valve replacements (MVR; one tissue and two mechanical). The 30-day mortality was 11% (n = 2). No patient experienced a carcinoid crisis. The mean follow up was 24 ± 21 months (range: 4-85 months). Four patients (receiving seven valves) developed SVD at 12, 14, 15, and 20 months after surgery, and all of these patients died. The actuarial four-year survival and freedom from SVD were 23 ± 14% and 43 ± 15%, respectively. CONCLUSIONS: The data acquired suggested that the main advantage of tissue valve prostheses, namely to avoid lifelong, intense anticoagulation, might be offset by accelerated SVD. The use of mechanical valves should be considered in CVD patients with a large primary tumor mass and persistent high urinary levels of 5-HIAA, and who are unresponsive to therapy.

Axillary vs Femoral Arterial Cannulation in Acute Type A Dissection: International Multicenter Data.

BACKGROUND: Cannulation strategy in acute type A dissection (ATAD) varies widely without known gold standards. This study compared ATAD outcomes of axillary vs femoral artery cannulation in a large cohort from the International Registry of Acute Aortic Dissection (IRAD). METHODS: The study retrospectively reviewed 2145 patients from the IRAD Interventional Cohort (1996-2021) who underwent ATAD repair with axillary or femoral cannulation (axillary group: n = 1106 [52%]; femoral group: n = 1039 [48%]). End points included the following: early mortality; neurologic, respiratory, and renal complications; malperfusion; and tamponade. All outcomes are presented as axillary with respect to femoral. RESULTS: The proportion of patients younger than 70 years in both groups was similar (n = 1577 [74%]), as were bicuspid aortic valve, Marfan syndrome, and previous dissection. Patients with femoral cannulation had slightly more aortic insufficiency (408 [55%] vs 429 [60%]; P = .058) and coronary involvement (48 [8%] vs 70 [13%]; P = .022]. Patients with axillary cannulation underwent more total aortic arch (156 [15%] vs 106 [11%]; P = .02) and valve-sparing root replacements (220 [22%] vs 112 [12%]; P < .001). More patients with femoral cannulation underwent commissural resuspension (269 [30.9%] vs 324 [35.3%]; P = .05). Valve replacement rates were not different. The mean duration of cardiopulmonary bypass was longer in the femoral group (190 [149-237] minutes vs 196 [159-247] minutes; P = .037). In-hospital mortality was similar between the axillary (n = 165 [15%]) and femoral (n = 149 [14%]) groups (P = .7). Furthermore, there were no differences in stroke, visceral ischemia, tamponade, respiratory insufficiency, coma, or spinal cord ischemia. CONCLUSIONS: Axillary cannulation is associated with a more stable ATAD presentation, but it is a more extensive intervention compared with femoral cannulation. Both procedures have equivalent early mortality, stroke, tamponade, and malperfusion outcomes after statistical adjustment.

Sex difference and outcome trends following surgical aortic valve replacement from the National Inpatient Sample (NIS) Database.

BACKGROUND: Based on worldwide registries, approximately 50% of patients who underwent aortic valve replacement (AVR) via surgical aortic valve replacement are females. Although AVR procedures have improved greatly in recent years, differences in outcome including mortality between sexes remain. We aimed to investigate the trends in SAVR outcomes in females versus males. METHODS: Using the 2011-2017 National Inpatient Sample (NIS) database, we identified hospitalizations for patients with diagnosis of aortic stenosis during which SAVR was performed. Patients' sociodemographic and clinical characteristics, procedure complications, and mortality were analyzed. Piecewise regression analyses were performed to assess temporal trends in SAVR utilization in females versus males. Multivariable analyses were performed to identify predictors of in-hospital mortality. RESULTS: A total of 392,087 hospitalizations for SAVR across the USA were analyzed. Utilization of SAVR in both sex patients decreased significantly during the years 2011-2017. Males compared to females had significantly higher rates of hyperlipidemia, chronic renal disease, peripheral artery disease, coronary artery disease and tended to be smokers. Differences in mortality rates among sexes were observed for SAVR procedures. Women had higher in-hospital mortality with 3.7% compared to men with 2.5% (OR 1.38 [95% CI 1.33-1.43, P<0.001]). In a multivariable regression model analysis adjusted for potential confounders, women had higher mortality risk with odd ratio (OR 1.38 [95% CI 1.33-1.43], P<0.001). Women had significantly higher rates of vascular complications (5.1% compared to men with 4.6%, P=0.002). CONCLUSIONS: Utilization of SAVR showed a downward trend during the study period. Higher in-hospital mortality was recorded in females compared to males.

Resternotomy Coronary Artery Bypass 1999-2018: Insights From The Society of Thoracic Surgeons Adult Cardiac Surgery Database.

BACKGROUND: We sought to quantify the risk trend of resternotomy coronary artery bypass grafting (CABG) over the past 2 decades. METHODS: We compared the outcomes of 194 804 consecutive resternotomy CABG patients and 1 445 894 randomly selected first-time CABG patients (50% of total) reported to The Society of Thoracic Surgeons Adult Cardiac Surgery Database between 1999 and 2018. Primary outcomes were in-hospital mortality and overall morbidity. Using multiple logistic regression for each outcome for each year, we computed the annual trends of risk-adjusted odds ratios for the primary outcomes in the entire cohort and in 194 776 propensity-matched pairs. RESULTS: The annual resternotomy CABG case volume from participating centers declined by 68%, from a median of 25 (range, 14-44) to a median of 8 (range, 4-15). Compared with first-time CABG, resternotomy CABG patients were consistently older, with higher proportions of comorbidities. After propensity matching, primary outcomes of resternotomy and first-time CABG were similar (mortality: 3.5% vs 2.3%, standardized difference [SDiff], 7.5%; morbidity: 40.7% vs 40.3%, SDiff, 0.9%). Mortality of resternotomy CABG performed after prior CABG was higher than that after prior non-CABG (4.3% vs 2.4%; SDiff, 10.8). Morbidity was similar between these subgroups (41.0% vs 39.1%; SDiff, 2.9). The adjusted odds ratio for mortality after resternotomy CABG declined from 1.93 (95% CI, 1.73-2.16) to 1.22 (95% CI, 0.92-1.62), and that of morbidity declined from 1.13 (95% CI, 1.08-1.18) to 0.91 (95% CI, 0.87-0.95), P < .001 for both. CONCLUSIONS: The risk of resternotomy CABG has decreased substantially over time. Resternotomy CABG performed after a prior CABG is higher risk compared with that performed after a non-CABG operation.

Novel cfDNA Methylation Biomarkers Reveal Delayed Cardiac Cell Death after Open-heart Surgery.

The use of cardiopulmonary bypass (CPB) is thought to cause delayed cardiac damage. DNA methylation-based liquid biopsies are novel biomarkers for monitoring acute cardiac cell death. We assessed cell-free DNA molecules as markers for cardiac damage after open-heart surgery. Novel cardiomyocyte-specific DNA methylation markers were applied to measure cardiac cfDNA in the plasma of 42 infants who underwent open-heart surgery. Cardiac cfDNA was elevated following surgery, reflecting direct surgery-related tissue damage, and declined thereafter in most patients. The concentration of cardiac cfDNA post-surgery correlated with the duration of CPB and aortic cross clamping. Strikingly, cardiac cfDNA at 6 h predicted duration of mechanical ventilation and maximal vasoactive-inotropic score better than did maximal troponin levels. Cardiac cfDNA reveals heart damage associated with CPB, and can be used to monitor cardiac cell death, to predict clinical outcome of surgery and to assess performance of cardioprotective interventions.

The DNA methylome of human vascular endothelium and its use in liquid biopsies.

BACKGROUND: Vascular endothelial cells (VECs) are an essential component of each tissue, contribute to multiple pathologies, and are targeted by important drugs. Yet, there is a shortage of biomarkers to assess VEC turnover. METHODS: To develop DNA methylation-based liquid biopsies for VECs, we determined the methylome of VECs isolated from freshly dissociated human tissues. FINDINGS: A comparison with a human cell-type methylome atlas yielded thousands of loci that are uniquely unmethylated in VECs. These sites are typically gene enhancers, often residing adjacent to VEC-specific genes. We also identified hundreds of genomic loci that are differentially methylated in organotypic VECs, indicating that VECs feeding specific organs are distinct cell types with a stable epigenetic identity. We established universal and lung-specific VEC markers and evaluated their presence in circulating cell-free DNA (cfDNA). Nearly 2.5% of cfDNA in the plasma of healthy individuals originates from VECs. Sepsis, graft versus host disease, and cardiac catheterization are associated with elevated levels of VEC-derived cfDNA, indicative of vascular damage. Lung-specific VEC cfDNA is selectively elevated in patients with chronic obstructive pulmonary disease (COPD) or lung cancer, revealing tissue-specific vascular turnover. CONCLUSIONS: VEC cfDNA biomarkers inform vascular dynamics in health and disease, potentially contributing to early diagnosis and monitoring of pathologies, and assessment of drug activity. FUNDING: This work was supported by the Beutler Research Program, Helmsley Charitable Trust, JDRF, Grail and the DON Foundation (to Y.D.). Y.D holds the Walter & Greta Stiel Chair in heart studies. B.G., R.S., J.M., D.N., T.K., and Y.D. filed patents on cfDNA analysis.

Myocardial mitochondrial injury induced by pulmonary exposure to particulate matter in rats.

Exposure to air pollution has been associated with acute myocardial ischemia, impaired myocardrial function, and ST-segment depression. Particulate matter (PM)-associated metals, especially vanadium and nickel, have been implicated in observed cardiovascular impairments. We aimed to assess the effect of single intratracheal pulmonary exposure to vanadium-rich respirable oil combustion PM (HP-10) on the intrinsic myocardial ischemic tolerance and mitochondrial integrity in rats. The authors subjected isolated heart tissue slices derived from saline or PM-exposed rats to low glucose low oxygen induced ischemia followed by oxygenated condition with glucose supplementation. Mitochondrial structural integrity was determined by TEM (transmission electron microscopy) and functionality by the 3-(4, 5 dimethylthiazol-2yl)-2, 5 diphenyltetrazolium bromide (MTT) assay. Rats exposed to PM exhibited no apparent inhibition of mitochondrial dehydrogenase activity in oxygenated conditions at 24 or 48 hr post-PM exposure. However, in conditions of simulated ischemia/reoxygenation, these heart slices showed a delayed but consistent and significant decrease in dehydrogenase activity compared to controls at 48 hr after exposure to PM. Electron microscopy revealed significant myocardial mitochondrial injury upon exposure to PM characterized by mitochondrial swelling and fusion. The authors conclude that exposure to soluble vanadium-rich PM induces mitochondrial functional impairment and structural abnormality, which compromises mitochondrial respiration and results in decreased tolerance to ischemia/reoxygenation in rats.

Effect of Aortic Valve Type on Patients Who Undergo Type A Aortic Dissection Repair.

Aortic valve replacement (AVR) is common in the setting of type A aortic dissection (TAAD) repair. Here, we evaluated the association between prosthesis choice and patient outcomes in an international patient cohort. We reviewed data from the International Registry of Acute Aortic Dissection (IRAD) interventional cohort to examine the relationship between valve choice and short- and mid-term patient outcomes. Between January 1996 and March 2016, 1290 surgically treated patients with TAAD were entered into the IRAD interventional cohort. Of those, 364 patients undergoing TAAD repair underwent aortic valve replacement (AVR; mean age, 57 years). The mechanical valve cohort consisted of 189 patients, of which 151 (79.9%) had a root replacement. The nonmechanical valve cohort consisted of 5 patients who received homografts and 160 patients who received a biologic AVR, with a total of 118 (71.5%) patients who underwent root replacements. The mean follow-up time was 2.92 ± 1.75 years overall (2.46 ± 1.69 years for the mechanical valve cohort and 3.48 ± 1.8 years for the nonmechanical valve cohort). After propensity matching, Kaplan-Meier estimates of 4-year survival rates after surgery were 64.8% in the mechanical valve group compared with 74.7% in the nonmechanical valve group (p = 0.921). A stratified Cox model for 4-year mortality showed no difference in hazard between valve types after adjusting for the propensity score (p = 0.854). A biologic valve is a reasonable option in patients with TAAD who require AVR. Although this option avoids the potential risks of anticoagulation, long-term follow up is necessary to assess the effect of reoperations or transcatheter interventions for structural valve degeneration.

Sex-Based Aortic Dissection Outcomes From the International Registry of Acute Aortic Dissection.

BACKGROUND: Worse outcomes have been reported for women with type A acute aortic dissection (TAAD). We sought to determine sex-specific operative approaches and outcomes for TAAD in the current era. METHODS: The Interventional Cohort (IVC) of the International Registry of Acute Aortic Dissection (IRAD) database was queried to explore sex differences in presentation, operative approach, and outcomes. Multivariable logistic regression was performed to identify adjusted outcomes in relation to sex. RESULTS: Women constituted approximately one-third (34.3%) of the 2823 patients and were significantly older than men (65.4 vs 58.6 years, P < .001). Women were more likely to present with intramural hematoma, periaortic hematoma, or complete or partial false lumen thrombosis (all P < .05) and more commonly had hypotension or coma (P = .001). Men underwent a greater proportion of Bentall, complete arch, and elephant trunk procedures (all P < .01). In-hospital mortality during the study period was higher in women (16.7% vs 13.8%, P = .039). After adjustment, female sex trended towards higher in-hospital mortality overall (odds ratio, 1.40; P = .053) but not in the last decade of enrollment (odds ratio, 0.93; P = .807). Five-year mortality and reintervention rates were not significantly different between the sexes. CONCLUSIONS: In-hospital mortality remains higher among women with TAAD but demonstrates improvement in the last decade. Significant differences in presentation were noted in women, including older age, distinct imaging findings, and greater evidence of malperfusion. Although no distinctions in 5-year mortality or reintervention were observed, a tailored surgical approach should be considered to reduce sex disparities in early mortality rates for TAAD.

Early Mortality in Type A Acute Aortic Dissection: Insights From the International Registry of Acute Aortic Dissection.

Importance: Early data revealed a mortality rate of 1% to 2% per hour for type A acute aortic dissection (TAAAD) during the initial 48 hours. Despite advances in diagnostic testing and treatment, this mortality rate continues to be cited because of a lack of contemporary data characterizing early mortality and the effect of timely surgery. Objective: To examine early mortality rates for patients with TAAAD in the contemporary era. Design, Setting, and Participants: This cohort study examined data for patients with TAAAD in the International Registry of Acute Aortic Dissection between 1996 and 2018. Patients were grouped according to the mode of their intended treatment, surgical or medical. Exposure: Surgical treatment. Main Outcomes and Measures: Mortality was assessed in the initial 48 hours after hospital arrival using Kaplan-Meier curves. In-hospital complications were also evaluated. Results: A total of 5611 patients with TAAAD were identified based on intended treatment: 5131 (91.4%) in the surgical group (3442 [67.1%] male; mean [SD] age, 60.4 [14.1] years) and 480 (8.6%) in the medical group (480 [52.5%] male; mean [SD] age, 70.9 [14.7] years). Reasons for medical management included advanced age (n = 141), comorbidities (n = 281), and patient preference (n = 81). Over the first 48 hours, the mortality for all patients in the study was 5.8%. Among patients who were medically managed, mortality was 0.5% per hour (23.7% at 48 hours). For those whose intended treatment was surgical, 48-hour mortality was 4.4%. In the surgical group, 51 patients (1%) died before the operation. Conclusions and Relevance: In this study, the overall mortality rate for TAAAD was 5.8% at 48 hours. For patients in the medical group, TAAAD had a mortality rate of 0.5% per hour (23.7% at 48 hours). However, among those in the surgical group, 48-hour mortality decreased to 4.4%.

Moderate Versus Deep Hypothermia in Type A Acute Aortic Dissection Repair: Insights from the International Registry of Acute Aortic Dissection.

BACKGROUND: The optimal strategy for cerebral protection during repair of type A acute aortic dissection has yet to be determined. We sought to determine the impact of differing degrees of hypothermia in patients undergoing acute dissection repair. METHODS: All patients in the International Registry of Acute Aortic Dissection Interventional Cohort database who underwent type A acute aortic dissection repair between 2010 and 2018 were identified. Data for operative temperature were available for 1962 patients subsequently divided into 2 groups according to lowest temperature: moderate hypothermic circulatory arrest (MHCA) (20-28°C) versus deep hypothermic circulatory arrest (DHCA) (<20°C). We then propensity matched 362 pairs of patients and analyzed operative data and short-term outcomes. RESULTS: The median lowest temperature was 25.0°C in the matched MHCA group as compared with 18.0°C in the DHCA group. For the entire cohort of 1962 patients, in-hospital mortality was 14.2% (278 deaths) but was not significantly different between DHCA and MHCA. The perioperative stroke rate was comparable between groups, before and after propensity matching. Circulatory arrest times were significantly longer in the MHCA cohort, regardless of matching. Use of antegrade or retrograde cerebral perfusion was similar in matched groups. There were no differences in 30-day survival or in other major postoperative morbidity between the 2 matched cohorts. CONCLUSIONS: A surgical strategy of MHCA + antegrade cerebral perfusion is at least as safe as DHCA during repair of acute type A aortic dissection.

Non-invasive detection of human cardiomyocyte death using methylation patterns of circulating DNA.

Detection of cardiomyocyte death is crucial for the diagnosis and treatment of heart disease. Here we use comparative methylome analysis to identify genomic loci that are unmethylated specifically in cardiomyocytes, and develop these as biomarkers to quantify cardiomyocyte DNA in circulating cell-free DNA (cfDNA) derived from dying cells. Plasma of healthy individuals contains essentially no cardiomyocyte cfDNA, consistent with minimal cardiac turnover. Patients with acute ST-elevation myocardial infarction show a robust cardiac cfDNA signal that correlates with levels of troponin and creatine phosphokinase (CPK), including the expected elevation-decay dynamics following coronary angioplasty. Patients with sepsis have high cardiac cfDNA concentrations that strongly predict mortality, suggesting a major role of cardiomyocyte death in mortality from sepsis. A cfDNA biomarker for cardiomyocyte death may find utility in diagnosis and monitoring of cardiac pathologies and in the study of normal human cardiac physiology and development.

Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease.

Methylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent cell death events in the body. Here, we present an approach for unbiased determination of the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. The method is validated using in silico simulations as well as in vitro mixes of DNA from different tissue sources at known proportions. We show that plasma cfDNA of healthy donors originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure which can be easily adapted to study the cellular contributors to cfDNA in many settings, opening a broad window into healthy and pathologic human tissue dynamics.

Patients With Type A Acute Aortic Dissection Presenting With an Abnormal Electrocardiogram.

BACKGROUND: The electrocardiogram (ECG) is often used in the diagnosis of patients presenting with chest pain to emergency departments. Because chest pain is a common manifestation of type A acute aortic dissection (TAAAD), ECGs are obtained in much of this population. We evaluated the effect of particular ECG patterns on the diagnosis and treatment of TAAAD. METHODS: TAAAD patients (N = 2,765) enrolled in the International Registry of Acute Aortic Dissection were stratified based on normal (n = 1,094 [39.6%]) and abnormal (n = 1,671 [60.4%]) findings on presenting ECGs and further subdivided according to specific ECG findings. Time data are presented in hours as medians (quartile 1 to quartile 3). RESULTS: Patients with ECGs with abnormal findings presented to the hospital sooner after symptom onset than those with ECGs with normal findings (1.4 [0.8 to 3.3] vs 2.0 [1.0 to 3.3]; p = 0.005). Specifically, this was seen in patients with infarction with new Q waves or ST elevation (1.3 [0.6 to 2.7] vs 1.5 [0.8 to 3.3]; p = 0.049). Interestingly, the time between symptom onset and diagnosis was longer with infarction with old Q waves (6.7 [3.2 to 18.4] vs 5.0 [2.9 to 11.8]; p = 0.034) and nonspecific ST-T changes (5.8 [3.0 to 13.8] vs 4.5 [2.8 to 10.5]; p = 0.002). Surgical mortality was higher in patients with abnormal ECG findings (20.6% vs 11.9%, p < 0.001), especially in those with ischemia by ECG (25.7% vs 16.8%, p < 0.001) and infarction with new Q waves or ST elevation (30.1% vs 17.1%, p < 0.001). CONCLUSIONS: TAAAD patients presenting with abnormal ECG results are sicker, have more in-hospital complications, and are more likely to die. The frequency of nonspecific ST-T abnormalities and its association with delay in diagnosis and treatment presents an opportunity for practice improvement.