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.

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.

Outcome of surgery for patients with renal cell carcinoma and tumour thrombus in the era of modern targeted therapy.

OBJECTIVE: This study evaluated the clinical outcome of patients with renal cell carcinoma (RCC) with tumour thrombus (TT) after surgical management. MATERIALS AND METHODS: In total, 142 consecutive RCC patients with TT who were operated on in Helsinki University Hospital between 2006 and 2014 were analysed. Eighty-eight (62%) of these patients had been operated on with radical intention and 54 (38%) with cytoreductive intention. A total of 73 patients (51%) received postoperative targeted therapy. The primary endpoint was cancer-specific survival (CSS). RESULTS: The 5 year CSS for level of involvement of TT in the renal vein, subdiaphragmatic vena cava and supradiaphragmatic vena cava was 60% (81 patients), 43% (52 patients) and 51% (nine patients), respectively (p = .42). The median CSS for lymph-node involvement was 63 months for patients with no lymph-node involvement but 10 months for patients with lymph-node involvement (p < .01). The median CSS for metastasis status was 63 months for patients with no metastases compared with 18 months for patients with metastases (p < .01). Among several factors examined, WHO performance status (p = .04), tumour necrosis (p = .05), presence of distant metastases (p = .04) and tumour histology (p = .05) were associated with CSS in the multivariate analysis. CONCLUSIONS: Operative treatment for RCC with TT is associated with good prognosis when there is no lymph-node involvement or distant metastases.

Arterial endothelial denudation by intraluminal use of papaverine-NaCl solution in coronary bypass surgery.

OBJECTIVES: Preservation of endothelial integrity during coronary artery bypass grafting is considered important for short- and long-term patency of the graft. In current literature there are controversial data about the safety of papaverine, a vasorelaxant widely used in coronary artery bypass grafting. Accordingly, we examined the immediate effects of papaverine on the endothelial morphology of arterial grafts and on viability of cultured human coronary artery endothelial cells. METHODS: Totally 22 segments of the radial artery were collected from 11 patients undergoing coronary artery bypass grafting. The segments were cut from the distal redundant parts of the arteries, which were not required for bypass grafting. A small distal segment of the artery was excised and placed into autologous heparinized whole blood (control segment). The rest of the graft, still remaining proximally attached to the circulation, was treated intraluminally with papaverine-NaCl solution (pH 4.2) for 5 min, after which another small distal segment was excised for the study (papaverine-treated segment). Segments were then perfusion-fixed and the endothelial surface was examined by scanning electron microscopy. Endothelial denudation was assessed and its severity graded. Additionally, viability of cultured human coronary artery endothelial cells after treatment with papaverine was assessed with trypan blue staining. RESULTS: Treatment with papaverine solution markedly increased the endothelial denudation (grades from 6.2+/-1.7 to 10.0+/-3.5; mean+/-SD; P=0.004). Papaverine-treatment increased trypan blue staining of cultured human coronary artery endothelial cells regardless of papaverine diluent (normal saline of pH 4.5 or 7.4 or blood). CONCLUSIONS: Treatment of arterial grafts with papaverine solutions apparently damages endothelial cells. Thus, the clinical practice of dilating arterial bypass grafts with papaverine should be reassessed, and alternative methods of vasodilatation should be considered.

Comparison of the novel Medtentia double helix mitral annuloplasty system with the Carpentier-Edwards Physio annuloplasty ring: morphological and functional long-term outcome in a mitral valve insufficiency sheep model.

BACKGROUND: The prevalence of mitral regurgitation in cardiac diseases requires annuloplasty systems that can be implanted without excessive patient burden. This study was designed to examine the morphological and functional outcome of a new double helix mitral annuloplasty ring in an ovine model in comparison to the classical Carpentier-Edwards (CE) annuloplasty ring as measured by reduction of mitral regurgitation and tissue integration. The Medtentia annuloplasty ring (MAR) is a helical device that is rotated into the annulus self-restoring the valve geometry, enabling a faster fixation without the need of elaborate repair of the valve geometry. The ventricular part of the helical ring encircles the valve chords. METHODS: Twenty adult sheep were overpaced until 2+ level mitral valve regurgitation was achieved. Seven animals per group received either the MAR or the CE ring. Implantation was performed on-pump in a beating heart through the left atrial appendix. The animals were sacrificed 3.6 ± 0.3 months after surgery following an echocardiography for assessing mitral regurgitation as primary endpoint. The annuloplasty rings with surrounding tissue were harvested for histological analyses as secondary endpoints. The remaining six sheep received the MAR system and were sampled seven, nine or 12 months after surgery. RESULTS: Implantation time (p < 0.01) and perfusion time (p < 0.001) as clinical secondary endpoints were significantly shorter in the MAR group. Echocardiography follow-ups showed sufficient valve function repair in nearly all animals with a normalization of the ventricle diameters in both groups (group difference: p = 0.147). The weights of the hearts did not differ significantly. Histology revealed adequately covered atrial annuloplasty rings with functional endothelium and lack of excessive granulation tissue or fibrosis in all specimens. The ventricular projections of the MAR systems encircling the chordae tendineae were not completely covered with neointimal tissue, although in no case were microthrombi detected and no thromboembolic events were recorded. CONCLUSIONS: The new MAR system is an easy to use annuloplasty system with a functional outcome comparable to that of the well-proven CE ring. Mitral valve regurgitation is effectively stopped both by restricting the pathological expansion of the annulus and by gathering the chords without thrombus formation.

Clinical value of intra-operative transit-time flow measurement for coronary artery bypass grafting: a prospective angiography-controlled study.

OBJECTIVE: Transit-time flow measurement (TTFM) is the most widely used method for intra-operative graft quality control in coronary artery bypass surgery. Although it may provide the opportunity for the surgeon to promptly revise the graft before the patient is discharged from the operating room, controlled clinical data on the ultimate usefulness of the TTFM are scarce. Clear cut-off values for when to revise grafts have not been set. METHODS: A total of 204 consecutive grafts (left internal mammary artery (n=46), vein graft (n=155), and radial artery (n=3)) underwent TTFM in 75 elective coronary artery bypass grafting (CABG) patients. The following parameters were recorded: mean graft flow (MGF), pulsatility index (PI), and insufficiency ratio (IR). After a mean follow-up of 199 ± 42 days, coronary angiography was performed for assessment of graft patency. RESULTS: A total of 166 grafts were found to be patent (85%), and 29 (15%) were completely occluded. The median and interquartile range (IQR) of MGF for the occluded grafts at the time of surgery was 38 ml min(-1) (IQR, 2549 ml min(-1)) and for the patent grafts 45 ml min(-1) (IQR, 31-71 ml min(-1); p=ns]. The corresponding PI values were 3.3 (IQR, 2.8-5.0) and 2.2 (IQR, 1.7-3.2; p=0.003), and the IR values were 1.6 (IQR, 0.6-6.1) and 0.2 (IQR, 0-2.2; p=0.03). By receiver operating characteristic (ROC) analysis, the highest sensitivity (72%) and specificity (70%) were associated with a PI value>3.0. However, 49 out of 70 such grafts (70%) were found to be patent. Furthermore, 10 out of 16 (63%) grafts, that had a combination of low flow (MGF<15 ml min(-1)) and high PI (>3.0), were patent at control angiography. CONCLUSIONS: TTFM predicts graft failure within the 6 months after CABG. However, specific cut-off recommendations for when to revise a graft cannot be set on the basis of TTFM. The cut-off values suggested in the literature lead to unnecessary graft revisions in the majority of cases, and, on the other hand, many technical defects probably remain unnoticed. Better methods to assess the quality of coronary artery bypass grafts are needed.

Medtentia double helix mitral annuloplasty system evaluated in a porcine experimental model.

OBJECTIVE: : To further develop and improve minimally invasive surgical procedures, dedicated appropriate surgical devices are mandatory. In this study, the safety and feasibility of implanting the novel Medtentia double helix mitral annuloplasty ring, which uses the key-ring principle to potentially allow faster and sutureless implantation, was assessed using both minimally invasive and conventional surgical techniques. Because of ethical concerns, a human compatible porcine experimental model of mitral valve surgery was used. METHODS: : Twelve 50-kg pigs were allocated to implantation of the Medtentia double helix annuloplasty ring using conventional midline sternotomy including cardioplegic arrest or a minimally invasive approach using peripheral cannulation and left ventricular fibrillation. Ten weeks after surgery, echocardiography was performed to assess mitral valve function. Animals were then killed, and gross mitral valve anatomy was examined ex vivo. RESULTS: : All animals survived 10 weeks without developing mitral regurgitation, structural leaflet damage, ring dehiscence, or endocarditis. In the minimally invasive compared with the midline sternotomy group (mean ± SD), significantly reduced recovery time (80 ± 16 vs. 327 ± 23 minutes, P < 0.01) and a tendency toward increased operating time (199 ± 33 vs. 168 ± 15 minutes, P > 0.05) and cardiopulmonary bypass time (98 ± 12 vs. 91 ± 11 minutes, P > 0.05) were observed. CONCLUSIONS: : By using a both minimally invasive and conventional midline sternotomy implantation techniques, the Medtentia double helix annuloplasty ring showed no mitral valve dysfunction or tissue damage 10 weeks postoperatively.

Wall motion and perfusion analysis of transmyocardial laser revascularization.

OBJECTIVE: Transmyocardial laser revascularization (TMLR) creates channels in the myocardium. The aim of the treatment is to relieve angina in patients with end-stage coronary artery disease. We studied the effect of TMLR on myocardial function and perfusion with the combination of cine magnetic resonance imaging (MRI) and thallium scintigraphy. DESIGN: Eight patients with severe triple-vessel coronary artery disease were studied with MRI and thallium scintigraphy before and 6 months after laser treatment. RESULTS: TMLR did not improve global left ventricular (LV) function or myocardial perfusion. However, systolic wall thickening deprived in segments with fixed perfusion defects in 6 months and laser treatment prevented this deprivation (p = 0.03). In addition single photon emission computed tomography (SPECT) imaging indicated that TMLR prevented conversion of reversible into fixed defects. CONCLUSION: In severe, progressing coronary artery disease TMLR does not improve global LV function or myocardial perfusion, but it preserves systolic wall thickening in fixed defects (scar). It also prevents changes from ischemic myocardial regions to scar.