Epitranscriptomics of Ischemic Heart Disease-The IHD-EPITRAN Study Design and Objectives.

Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and result in modifications including methylation and deamination. Such modified residues as N-6-methyl-adenosine (m6A) and inosine, respectively, have been associated with cardiovascular diseases, and contribute to disease pathologies. The Ischemic Heart Disease Epitranscriptomics and Biomarkers (IHD-EPITRAN) study aims to provide a more comprehensive understanding to their nature and role in cardiovascular pathology. The study hypothesis is that pathological features of IHD are mirrored in the blood epitranscriptome. The IHD-EPITRAN study focuses on m6A and A-to-I modifications of RNA. Patients are recruited from four cohorts: (I) patients with IHD and myocardial infarction undergoing urgent revascularization; (II) patients with stable IHD undergoing coronary artery bypass grafting; (III) controls without coronary obstructions undergoing valve replacement due to aortic stenosis and (IV) controls with healthy coronaries verified by computed tomography. The abundance and distribution of m6A and A-to-I modifications in blood RNA are charted by quantitative and qualitative methods. Selected other modified nucleosides as well as IHD candidate protein and metabolic biomarkers are measured for reference. The results of the IHD-EPITRAN study can be expected to enable identification of epitranscriptomic IHD biomarker candidates and potential drug targets.

Timing of preoperative aspirin discontinuation and outcome after elective coronary artery bypass graft surgery.

OBJECTIVE: Whether aspirin should be discontinued before coronary artery bypass grafting is controversial. The potential benefits and harms associated with late use of aspirin (no discontinuation or discontinuation <3 days before surgery) were investigated in this retrospective, multicenter study. DESIGN: Retrospective, multicenter study. SETTING: Two university hospitals and one central hospital. PARTICIPANTS: A consecutive series of 859 patients who underwent elective coronary artery bypass grafting from January 2008 through December 2010. INTERVENTIONS: Aspirin (100 mg/day) was used <3 days before surgery in 240 patients and was discontinued >3 days before surgery in 619 patients. RESULTS: In the overall series, similar in-hospital mortality, amount of postoperative blood loss, rate of re-exploration for excessive bleeding, and use of blood products were observed in the study groups. However, aspirin discontinuation >3 days before surgery tended to be associated with a higher postoperative stroke rate (1.9% v 0.4%, p = 0.13). Such a trend was observed after off-pump (1.9% v 0%, p = 0.58) and on-pump (2.0% v 0.6%, p = 0.46) surgery. Among 153 pairs matched by the propensity score, patients with aspirin discontinued >3 days before surgery had a significantly higher rate of postoperative stroke (5.9% v 0.7%, p = 0.02) and tended to have a higher risk of the composite adverse outcome endpoint (19.6% v 12.4%, p = 0.09). The postoperative release of troponin I was similar in the study groups. CONCLUSIONS: Late or no discontinuation of low-dose aspirin before coronary artery bypass grafting may decrease the risk of postoperative stroke without increased postoperative bleeding and need for blood transfusion. These findings and the risk of cardiovascular events possibly occurring at the time of its discontinuation suggest that the use of aspirin until the day of elective coronary surgery may be beneficial.

Long-term outcomes after ascending aortic replacement and aortic root replacement for type A aortic dissection.

OBJECTIVES: We investigated whether the selective use of supracoronary ascending aorta replacement achieves late outcomes comparable to those of aortic root replacement for acute Stanford type A aortic dissection (TAAD). METHODS: Patients who underwent surgery for acute type A aortic dissection from 2005 to 2018 at the Helsinki University Hospital, Finland, were included in this analysis. Late mortality was evaluated with the Kaplan-Meier method and proximal aortic reoperation, i.e. operation on the aortic root or aortic valve, with the competing risk method. RESULTS: Out of 309 patients, 216 underwent supracoronary ascending aortic replacement and 93 had aortic root replacement. At 10 years, mortality was 33.8% after aortic root replacement and 35.2% after ascending aortic replacement (P = 0.806, adjusted hazard ratio 1.25, 95% confidence interval, 0.77-2.02), and the cumulative incidence of proximal aortic reoperation was 6.0% in the aortic root replacement group and 6.2% in the ascending aortic replacement group (P = 0.65; adjusted subdistributional hazard ratio 0.53, 95% confidence interval 0.15-1.89). Among 71 propensity score matched pairs, 10-year survival was 34.4% after aortic root replacement and 36.2% after ascending aortic replacement surgery (P = 0.70). Cumulative incidence of proximal aortic reoperation was 7.0% after aortic root replacement and 13.0% after ascending aortic replacement surgery (P = 0.22). Among 102 patients with complete imaging data [mean follow-up, 4.7 (3.2) years], the estimated growth rate of the aortic root diameter was 0.22 mm/year, that of its area 7.19 mm2/year and that of its perimeter 0.43 mm/year. CONCLUSIONS: When stringent selection criteria were used to determine the extent of proximal aortic reconstruction, aortic root replacement and ascending aortic replacement for type A aortic dissection achieved comparable clinical outcomes.

Ischemic Heart Disease Selectively Modifies the Right Atrial Appendage Transcriptome.

Background: Although many pathological changes have been associated with ischemic heart disease (IHD), molecular-level alterations specific to the ischemic myocardium and their potential to reflect disease severity or therapeutic outcome remain unclear. Currently, diagnosis occurs relatively late and evaluating disease severity is largely based on clinical symptoms, various imaging modalities, or the determination of risk factors. This study aims to identify IHD-associated signature RNAs from the atrial myocardium and evaluate their ability to reflect disease severity or cardiac surgery outcomes. Methods and Results: We collected right atrial appendage (RAA) biopsies from 40 patients with invasive coronary angiography (ICA)-positive IHD undergoing coronary artery bypass surgery and from 8 patients ICA-negative for IHD (non-IHD) undergoing valvular surgery. Following RNA sequencing, RAA transcriptomes were analyzed against 429 donors from the GTEx project without cardiac disease. The IHD transcriptome was characterized by repressed RNA expression in pathways for cell-cell contacts and mitochondrial dysfunction. Increased expressions of the CSRNP3, FUT10, SHD, NAV2-AS4, and hsa-mir-181 genes resulted in significance with the complexity of coronary artery obstructions or correlated with a functional cardiac benefit from bypass surgery. Conclusions: Our results provide an atrial myocardium-focused insight into IHD signature RNAs. The specific gene expression changes characterized here, pave the way for future disease mechanism-based identification of biomarkers for early detection and treatment of IHD.

Epicardial Transplantation of Autologous Cardiac Micrografts During Coronary Artery Bypass Surgery.

Background: Cardio-regenerative cell therapies offer additional biologic support to coronary artery bypass surgery (CABG) and are aimed at functionally repairing the myocardium that suffers from or is damaged by ischemia. This non-randomized open-label study assessed the safety and feasibility of epicardial transplantation of atrial appendage micrografts (AAMs) in patients undergoing CABG surgery. Methods: Twelve consecutive patients destined for CABG surgery were included in the study. Six patients received AAMs during their operation and six patients were CABG-operated without AAMs transplantation. Data from 30 elective CABG patients was collected for a center- and time-matched control group. The AAMs were processed during the operation from a biopsy collected from the right atrial appendage. They were delivered epicardially onto the infarct scar site identified in preoperative late gadolinium enhancement cardiac magnetic resonance imaging (CMRI). The primary outcome measures at the 6-month follow-up were (i) patient safety in terms of hemodynamic and cardiac function over time and (ii) feasibility of therapy administration in a clinical setting. Secondary outcome measures were left ventricular wall thickness, change in myocardial scar tissue volume, changes in left ventricular ejection fraction, plasma concentrations of N-terminal pro-B-type natriuretic peptide levels, NYHA class, number of days in hospital and changes in the quality of life. Results: Epicardial transplantation of AAMs was safe and feasible to be performed during CABG surgery. CMRI demonstrated an increase in viable cardiac tissue at the infarct site in patients receiving AAMs treatment. Conclusions and Relevance: Transplantation of AAMs shows good clinical applicability as performed during cardiac surgery, shows initial therapeutic effect on the myocardium and has the potential to serve as a delivery platform for cardiac gene therapies. Trial Registration:ClinicalTrials.gov, identifier: NCT02672163.

Miniaturized versus conventional cardiopulmonary bypass in high-risk patients undergoing coronary artery bypass surgery.

OBJECTIVE: To review our results with the use of miniaturized cardiopulmonary bypass (Mini-CPB) versus conventional cardiopulmonary bypass (C-CPB) in high-risk patients (additive EuroSCORE>or=6) who have undergone coronary artery bypass graft surgery (CABG). PATIENTS AND METHODS: This study includes a consecutive series of 236 patients with an additive EuroSCORE>or=6 who underwent CABG, employing either C-CPB or Mini-CPB. Propensity score analysis was performed. RESULTS: The study groups had similar EuroSCOREs. Stroke rate was significantly higher among C-CPB patients (5.4% vs. 0%, p=0.026). In-hospital mortality (4.8% vs. 3.4%, p=0.75) and combined adverse end-point rate were higher in C-CPB patients (20.4% vs. 13.5%, p=0.18). Postoperative bleeding and need for transfusion were similar in the study groups, but re-sternotomy for bleeding was more frequent among C-CPB patients (4.8% vs. 1.1%, p=0.26). Seventy-four propensity matched pairs had similar immediate postoperative results: C-CPB patients had higher mortality (6.8% vs. 4.1%, p=0.72), stroke (5.4% vs. 0%, p=0.12) and combined adverse end-point rates (27.0% vs. 16.2%, p=0.11), but such differences failed to reach statistical significance. CONCLUSIONS: Mini-CPB achieved somewhat better results than C-CPB in these high-risk patients undergoing isolated CABG. This study confirmed that cerebral protection could be the main benefit associated with the use of Mini-CPB.

Early experience with robotic mitral valve repair with intra-aortic occlusion.

OBJECTIVE: To report the learning curve and early results of robotic mitral valve repairs in comparison with propensity score-matched sternotomy controls after the adoption of a robotic mitral valve surgery program in a university teaching hospital. METHODS: A total of 142 patients underwent robotic mitral valve repair due to degenerative mitral regurgitation between May 2011 and December 2015. Control patients operated on via the conventional sternotomy approach were selected by the use of propensity score analysis resulting in 2 well-matched study groups. RESULTS: Valve repair rate was 98.6% and 97.9% in the robotic and sternotomy groups, respectively. Operation length, cardiopulmonary bypass, aortic crossclamp, and ventilation times were shorter in the sternotomy group. All of these times were statistically significantly reduced within the robotic group during the learning curve. Even though there was no statistically significant difference in the rate of perioperative complications between the groups, 3 patients in the robotic group required postoperative extracorporeal membrane oxygenation due to low cardiac output, and 1 patient in the robotic group died. In the robotic and sternotomy groups, 86.3% versus 84.7% of patients had grade ≤1+ mitral valve regurgitation at the latest follow-up visit, and there was no statistically significant difference in survival or reoperation rate between the 2 study groups during follow-up. CONCLUSIONS: The present series reports the entire early learning curve related to the introduction of robotic mitral valve repair in our institution. In all, repair rate and early durability were acceptable, but more patients in the robotic group had serious complications. Early major robotic complications that occurred may have been related to the simultaneous use of intra-aortic occlusion.

Epicardial delivery of autologous atrial appendage micrografts during coronary artery bypass surgery-safety and feasibility study.

BACKGROUND: The atrial appendages are a tissue reservoir for cardiac stem cells. During on-pump coronary artery bypass graft (CABG) surgery, part of the right atrial appendage can be excised upon insertion of the right atrial cannula of the heart-lung machine. In the operating room, the removed tissue can be easily cut into micrografts for transplantation. This trial aims to assess the safety and feasibility of epicardial transplantation of atrial appendage micrografts in patients undergoing CABG surgery. METHODS/DESIGN: Autologous cardiac micrografts are made from leftover right atrial appendage during CABG of 6 patients. Atrial appendage is mechanically processed to micrografts consisting of atrial appendage-derived cells (AADCs) and their extracellular matrix (ECM). The micrografts are epicardially transplanted in a fibrin gel and covered with a tissue-engineered ECM sheet. Parameters including echocardiography-reflecting cardiac insufficiency-are studied pre- and post-operatively as well as at 3 and 6 months of the follow-up. Cardiac functional magnetic resonance imaging is performed preoperatively and at 6-month follow-up. The primary outcome measures are patient safety in terms of hemodynamic and cardiac function over time and feasibility of therapy administration in a clinical setting. Secondary outcome measures are left ventricular wall thickness, change in the amount of myocardial scar tissue, changes in left ventricular ejection fraction, plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, New York Heart Association class, days in hospital, and changes in the quality of life. Twenty patients undergoing routine CAGB surgery will be recruited to serve as a control group. DISCUSSION: This study aims to address the surgical feasibility and patient safety of epicardially delivered atrial appendage micrografts during CABG surgery. Delivery of autologous micrografts and AADCs has potential applications for cell and cell-based gene therapies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02672163. Date of registration: 02.02.2016.

Comparison of 30-day and 5-year outcomes of percutaneous coronary intervention versus coronary artery bypass grafting in patients aged≤50 years (the Coronary aRtery diseAse in younG adultS Study).

Data on the outcome of young patients after coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are scarce. Data on 2,209 consecutive patients aged≤50 years who underwent CABG or PCI were retrospectively collected from 15 European institutions. PCI and CABG had similar 30-day mortality rates (0.8% vs 1.4%, p=0.27), late survival (at 5 years, 97.8% vs 94.9%, p=0.082), and freedom from stroke (at 5 years, 98.0% and 98.0%, p=0.731). PCI was associated with significantly lower freedom from major adverse cardiac and cerebrovascular events (at 5 years, 73.9% vs 85.0%, p<0.0001), repeat revascularization (at 5 years, 77.6% vs 92.5%, p<0.0001), and myocardial infarction (at 5 years, 89.9% vs 96.6%, p<0.0001) compared with CABG. These findings were confirmed in propensity score-adjusted and matched analyses. Freedom from major adverse cardiac and cerebrovascular events after PCI was particularly low in diabetics (at 5 years, 58.0% vs 75.9%, p<0.0001) and in patients with multivessel disease (at 5 years, 63.6% vs 85.1%, p<0.0001). PCI in patients with ST elevation myocardial infarction was associated with significantly better 5-year survival (97.5% vs 88.8%, p=0.001), which was driven by its lower 30-day mortality rate (1.5% vs 6.0%, p=0.017). In conclusion, patients aged≤50 years have an excellent immediate outcome after either PCI or CABG with similar long-term survival when used according to the current clinical practice. PCI was associated with significantly lower freedom from myocardial infarction and repeat revascularization.

Use of blood products and risk of stroke after coronary artery bypass surgery.

BACKGROUND: The impact of blood transfusion on the development of post-operative stroke after coronary artery bypass grafting (CABG) is not well established. We, therefore, investigated this issue. MATERIALS AND METHODS: Complete data on peri-operative blood transfusion were available for 2,226 patients who underwent CABG in three Finnish hospitals. RESULTS: Stroke occurred post-operatively in 53 patients (2.4%). Logistic regression showed that pre-operative creatinine (OR 1.003, 95% CI 1.000-1.006), extracardiac arteriopathy (OR 2.344, 95% CI 1.133-4.847), pre-operative atrial fibrillation (OR 2.409, 95% CI 1.149-5.052), and the number of packed red blood cell units transfused (OR 1.121, 95% CI 1.065-1.180) were significantly associated with post-operative stroke. When the various blood product transfusions instead of transfused units were included in the multivariable analysis, solvent/detergent treated plasma (Octaplas) transfusion (OR 2.149, 95% CI 1.141-4.047), but not red blood cell transfusion, was significantly associated with postoperative stroke. Use of blood products ranging from no transfusion (stroke rate 1.6%) to combined transfusion of red blood cells, platelets and Octaplas was associated with a significant increase in post-operative stroke incidence (6.6%, adjusted analysis: OR 1.727, 95% 1.350-2.209). Patients who received >2 units of red blood cells, >4 units of Octaplas units and >8 units of platelets had the highest stroke rate of 21%. CART analysis showed that increasing amount of transfused Octaplas, platelets and history of extracardiac arteriopathy were significantly associated with post-operative stroke. CONCLUSIONS: Transfusion of blood products after CABG has a strong, dose-dependent association with the risk of stroke. The use of Octaplas and platelet transfusions seem to have an even larger impact on the development of stroke than red blood cell transfusions.

Coronary artery bypass surgery in octogenarians: long-term outcome can be better than expected.

BACKGROUND: We have reviewed our experience with octogenarians undergoing coronary artery bypass grafting. METHODS: A consecutive series of 274 patients age 80 years or greater out of 3,474 patients who underwent isolated coronary artery bypass grafting. We have assessed the intrinsic risk aged 80 years or greater by comparing them with a propensity score-matched cohort of younger patients with similar operative risk (other than age). RESULTS: Thirty-day mortality (4.7% vs 1.3%, p<0.0001), combined adverse event rates (13.1% vs 6.6%, p<0.0001), and five-year survival (76.6% vs 90.4%, p<0.0001) were significantly poorer among patients aged 80 years or greater as compared with younger patients. These figures were, however, better than estimates of a recent systematic review by McKellar and colleagues (McKellar SH, Brown ML, Frye RL, Schaff HV, Sundt TM III. Comparison of coronary revascularization procedures in octogenarians: a systematic review and meta-analysis. Nat Clin Pract Cardiovasc Med 2008;5:738-46) (30-day mortality 7.2%, and five-year survival, 68%). When octogenarians were compared with 273 propensity score-matched patients aged less than 80 years, the 30-day mortality (4.8% vs 2.6%, p=0.17) and combined adverse event rates (13.2% vs 10.6%, p=0.36) did not significantly differ. Five-year survival, despite statistical significance, was not remarkably lower than that of propensity-matched patients aged less than 80 years (77.0% vs 81.3%, p=0.009). The decrease in survival of octogenarians was evident only during the first few months after surgery, but not later on. CONCLUSIONS: The results of this study suggest that immediate and five-year survival of octogenarians undergoing coronary artery bypass grafting may be even better than previously estimated. Survival of octogenarians may be suboptimal only during the first few months after surgery, whereas at five years may not differ remarkably from younger patients with otherwise similar operative risk.

Is it possible to improve the accuracy of EuroSCORE?

OBJECTIVE: We derived a new risk-scoring method by modifying some of the risk factors included in the EuroSCORE algorithm. METHODS: This study includes 3613 patients who underwent cardiac surgery at the Vaasa Central Hospital, Finland. The EuroSCORE variables, along with modified age classes (< 60 years, 60-69.9 years, 70-79.9 years and > or = 80 years), eGFR-based chronic kidney disease classes (classes 1-2, class 3 and classes 4-5) and the number of cardiac procedures, were entered into the regression analysis. RESULTS: An additive risk score was calculated according to the results of logistic regression by adding the risk of the following variables: patients' age classes (0, 2, 4 and 6 points), female (2 points), pulmonary disease (3 points), extracardiac arteriopathy (2 points), neurological dysfunction (4 points), redo surgery (3 points), critical preoperative status (8 points), left ventricular ejection fraction (> 50%: 0; 30-50%: 2 and < 30%: 3 points), thoracic aortic surgery (8 points), postinfarct septal rupture (9 points), chronic kidney disease classes (0, 3 and 6 points), number of procedures (1: 0; 2: 2 and 3 or more: 7 points). The modified score had a better area under the receiver operating characteristic curve (additive: 0.867; logistic: 0.873) than the EuroSCORE (additive: 0.835; logistic: 0.840) in predicting 30-day postoperative mortality. The modified score, but not EuroSCORE, correctly estimated the 30-day postoperative mortality. CONCLUSION: EuroSCORE still performs well in identifying high-risk patients, but significantly overestimates the immediate postoperative mortality. This study shows that the score's accuracy and clinical relevance can be significantly improved by modifying a few of its variables. This institutionally derived risk-scoring method represents a modification and simplification of the EuroSCORE and, likely, it would provide a more realistic estimation of the mortality risk after adult cardiac surgery.

Adjuvant arteriovenous fistula as means of rescue for infrapopliteal venous bypass with poor runoff.

OBJECTIVE: The aim of this study was to assess the outcome of infrapopliteal bypass when an adjuvant arteriovenous (AV) fistula was reconstructed as means of rescue as a result of poor runoff. The design was a retrospective multicenter case-control study. METHODS: Seventy-seven infrapopliteal vein bypasses required an adjuvant AV fistula among 1813 patients operated on for critical leg ischemia in 3 vascular centers between 1996 and 2003. The mean age was 74 years (range, 39-90 years). A total of 70% of the patients had diabetes, and 24% had undergone previous vascular surgery. In 25% of the bypasses, the distal anastomosis was in a crural artery, in 55% it was in the dorsal pedal artery, and in 20% it was in a plantar artery. An adjuvant AV fistula was reconstructed in all cases because of poor intraoperative arterial status, intraoperative angiography, or low intraoperative flow. A control group was retrieved that matched the study group according to the recipient artery and runoff score. RESULTS: The primary and secondary patency were 61% and 75%, respectively, at 1 year in the AV fistula group and 57% and 71% in the control group. The 3-year patency rates were 49% and 62% for the AV fistula group and 46% and 71% for the control group, respectively. There was a 76% leg-salvage rate at 3 years in the study group, compared with 87% in the control group. There were no major complications related to the AV fistula. Intraoperative flow was increased from a median of 20 mL/min to 115 mL/min by the AV fistula (P = .003). The graft flow was significantly higher in the AV fistula group than in the control group (P = .001). CONCLUSIONS: The adjuvant AV fistula increased graft flow significantly in a poor-outflow venous bypass. In this extreme patient group, acceptable patency and leg salvage was achieved without adverse effects. Despite this, the AV fistula did not improve the outcome.