[Thirty-five-year angiographic follow-up of the first coronary bypass surgery by internal mammary artery in Hungary]. / A Magyarországon végzett elso arteria mammaria interna graftolás harmincöt éves coronarographiás utánkövetése.

Coronary artery bypass grafting (CABG) plays an important role in the treatment of symptomatic coronary artery disease. During the fifty years since the first operation, a great amount of clinical observations confirm that the internal mammary artery (IMA) can be used for the bypass grafting by the most favorable outcome. IMA's histological structure and physiological properties make it resistant to atherosclerosis. In our article, we remember the first CABG operation in Hungary using IMA graft and we also confirm the favorable properties of IMA by the results of the 35-year follow-up, with the longest reported coronary angiography in the literature after IMA grafting. On the basis of this case, we can speculate that the prostacyclin secretion of the mammary graft can prevent the run-off tract of the left anterior descending (LAD) artery from the atherosclerotic progression. Large-scale study is warranted to compare the long-term prognosis of the run-off tract after grafting versus stenting of the LAD. Orv Hetil. 2020; 161(9): 354-358.

Olaparib induces browning of in vitro cultures of human primary white adipocytes.

Mitochondrial biogenesis is a key feature of energy expenditure and organismal energy balance. Genetic deletion of PARP1 or PARP2 was shown to induce mitochondrial biogenesis and energy expenditure. In line with that, PARP inhibitors were shown to induce energy expenditure in skeletal muscle. We aimed to investigate whether pharmacological inhibition of PARPs induces brown or beige adipocyte differentiation. SVF fraction of human pericardial adipose tissue was isolated and human adipose-derived mesenchymal stem cells (hADMSCs) were differentiated to white and beige adipocytes. A subset of hADMSCs were differentiated to white adipocytes in the presence of Olaparib, a potent PARP inhibitor currently in clinical use, to induce browning. Olaparib induced morphological changes (smaller lipid droplets) in white adipocytes that is a feature of brown/beige adipocytes. Furthermore, Olaparib induced mitochondrial biogenesis in white adipocytes and enhanced UCP1 expression. We showed that Olaparib treatment inhibited nuclear and cytosolic PAR formation, induced NAD+/NADH ratio and consequently boosted SIRT1 and AMPK activity and the downstream transcriptional program leading to increases in OXPHOS. Olaparib treatment did not induce the expression of beige adipocyte markers in white adipocytes, suggesting the formation of brown or brown-like adipocytes. PARP1, PARP2 and tankyrases are key players in the formation of white adipose tissue. Hereby, we show that PARP inhibition induces the transdifferentiation of white adipocytes to brown-like adipocytes suggesting that PARP activity could be a determinant of the differentiation of these adipocyte lineages.

AMP-Activated Kinase (AMPK) Activation by AICAR in Human White Adipocytes Derived from Pericardial White Adipose Tissue Stem Cells Induces a Partial Beige-Like Phenotype.

Beige adipocytes are special cells situated in the white adipose tissue. Beige adipocytes, lacking thermogenic cues, morphologically look quite similar to regular white adipocytes, but with a markedly different response to adrenalin. White adipocytes respond to adrenergic stimuli by enhancing lipolysis, while in beige adipocytes adrenalin induces mitochondrial biogenesis too. A key step in the differentiation and function of beige adipocytes is the deacetylation of peroxisome proliferator-activated receptor (PPARγ) by SIRT1 and the consequent mitochondrial biogenesis. AMP-activated protein kinase (AMPK) is an upstream activator of SIRT1, therefore we set out to investigate the role of AMPK in beige adipocyte differentiation using human adipose-derived mesenchymal stem cells (hADMSCs) from pericardial adipose tissue. hADMSCs were differentiated to white and beige adipocytes and the differentiation medium of the white adipocytes was supplemented with 100 µM [(2R,3S,4R,5R)-5-(4-Carbamoyl-5-aminoimidazol-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate (AICAR), a known activator of AMPK. The activation of AMPK with AICAR led to the appearance of beige-like morphological properties in differentiated white adipocytes. Namely, smaller lipid droplets appeared in AICAR-treated white adipocytes in a similar fashion as in beige cells. Moreover, in AICAR-treated white adipocytes the mitochondrial network was more fused than in white adipocytes; a fused mitochondrial system was characteristic to beige adipocytes. Despite the morphological similarities between AICAR-treated white adipocytes and beige cells, functionally AICAR-treated white adipocytes were similar to white adipocytes. We were unable to detect increases in basal or cAMP-induced oxygen consumption rate (a marker of mitochondrial biogenesis) when comparing control and AICAR-treated white adipocytes. Similarly, markers of beige adipocytes such as TBX1, UCP1, CIDEA, PRDM16 and TMEM26 remained the same when comparing control and AICAR-treated white adipocytes. Our data point out that in human pericardial hADMSCs the role of AMPK activation in controlling beige differentiation is restricted to morphological features, but not to actual metabolic changes.

Plasma homocysteine levels are related to medium-term venous graft degeneration in coronary artery bypass graft patients.

OBJECTIVE: Saphenous venous grafts (SVGs) are established choices for coronary artery bypass grafting (CABG); however, their lumen patency is limited. Our goal was to investigate the risk factors of SVG degeneration. METHODS: Seventy-five patients (mean age, 57.5±10.4 years) with 133 SVG conduits who had cardiac catheterization ≥1 year after CABG were selected; follow-up period was 67.6±36.8 months. Patients were divided into 3 groups according to angiographic status at follow up [intact: <20% (n=23); narrowed: 20-99% (n=24); and occluded (n=28)]. Baseline clinical conditions were evaluated in relation to follow-up angiography. As onset date of chronic total occlusions is usually uncertain, they arise typically from thrombotic lesions; thus, their value in evaluation is limited. RESULTS: There were no significant differences between the 3 groups in clinical parameters. Linear correlation analysis found significant (p<0.01) positive connection of SVG disease (luminal diameter reduction 20-99%) with C-reactive protein (CRP) and homocysteine (Hcy), as well as between CRP and Hcy. Multiple regression analysis showed plasma Hcy level to be significantly related to graft diameter reduction normalized to time elapsed until angiography in narrowed grafts: 1 µmol/L increase of Hcy was associated with 0.053%/month decrease in lumen diameter (p<0.01; R2=0.428); extrapolating: +10 µmol/L higher Hcy level during 5 years is associated with 32.1% lumen reduction. CONCLUSION: Medium- to long-term SVG degeneration is related to elevated plasma total Hcy in patients with sub-occlusive graft stenosis, while in cases with intact SVGs, the beneficial local flow conditions may protect the grafts from degeneration.

Low tidal volume ventilation during cardiopulmonary bypass reduces postoperative chemokine serum concentrations.

BACKGROUND: Open-heart surgery with cardiopulmonary bypass (CPB) is associated with a generalized immune response and postoperative lung dysfunction. Chemokines are involved in the pathogenesis of postoperative lung dysfunction. We investigated whether continued mechanical ventilation during CPB has an impact on chemokine serum concentrations. METHODS: A total of 30 patients undergoing coronary artery bypass graft operation were randomized to either continuous ventilated group (n=15) or nonventilated group (n=15). Blood samples were drawn at the beginning and at the end of surgery and on the 5 consecutive days. Serum CCL2, CCL4, and CCL20 concentrations were measured and given as mean ± standard deviation. RESULTS: Chemokine concentrations were elevated at the end of surgery in both groups. CCL2 and CCL4 levels returned to baseline on postoperative day (POD)-1 in the ventilation group and stayed elevated in the nonventilation group. CCL4 serum levels were significantly lower in ventilated-group patients on POD-1 (10.9 [39.0] vs. 153.2 [168.1]; p=0.005), POD-2 (16.8 [36.8] vs. 147.9 [165.4]; p=0.019), POD-3 (14.2 [24.0] vs. 97.9 [87.1]; p=0.005), and POD-5 (6.5 [25.0] vs. 33.6 [38.4]; p=0.045). CONCLUSION: Continued mechanical ventilation during CPB results in reduced CCL4 concentrations on POD-1 to -5.

New perspectives in the renin-angiotensin-aldosterone system (RAAS) II: albumin suppresses angiotensin converting enzyme (ACE) activity in human.

About 8% of the adult population is taking angiotensin-converting enzyme (ACE) inhibitors to treat cardiovascular disease including hypertension, myocardial infarction and heart failure. These drugs decrease mortality by up to one-fifth in these patients. We and others have reported previously that endogenous inhibitory substances suppress serum ACE activity, in vivo, similarly to the ACE inhibitor drugs. Here we have made an effort to identify this endogenous ACE inhibitor substance. ACE was crosslinked with interacting proteins in human sera. The crosslinked products were immunoprecipitated and subjected to Western blot. One of the crosslinked products was recognized by both anti-ACE and anti-HSA (human serum albumin) antibodies. Direct ACE-HSA interaction was confirmed by binding assays using purified ACE and HSA. HSA inhibited human purified (circulating) and human recombinant ACE with potencies (IC50) of 5.7 ± 0.7 and 9.5 ± 1.1 mg/mL, respectively. Effects of HSA on the tissue bound native ACE were tested on human saphenous vein samples. Angiotensin I evoked vasoconstriction was inhibited by HSA in this vascular tissue (maximal force with HSA: 6.14 ± 1.34 mN, without HSA: 13.54 ± 2.63 mN), while HSA was without effects on angiotensin II mediated constrictions (maximal force with HSA: 18.73 ± 2.17 mN, without HSA: 19.22 ± 3.50 mN). The main finding of this study is that HSA was identified as a potent physiological inhibitor of the ACE. The enzymatic activity of ACE appears to be almost completely suppressed by HSA when it is present in its physiological concentration. These data suggest that angiotensin I conversion is limited by low physiological ACE activities, in vivo.

Continued mechanical ventilation during coronary artery bypass graft operation attenuates the systemic immune response.

OBJECTIVES: Cardiopulmonary bypass (CPB) is known to induce a short pro- and long-lasting anti-inflammatory immune response. The anti-inflammatory protein soluble ST2 (sST2) may be involved in the pathogenesis of postoperative immune dysfunction. We investigated whether continued mechanical ventilation during CPB has an impact on postoperative serum sST2 and cytokine release. METHODS: Thirty patients undergoing conventional coronary artery bypass graft (CABG) operation were randomized into a ventilated on CPB (VG; n = 15) and non-ventilated on CPB group (NVG; n = 15). Blood samples were drawn at the beginning and at the end of surgery, and at the 5 consecutive days. sST2, IL-4, IL-10, IgM, IgG, IL-6 and endotoxin were measured by ELISA. Data are given as mean standard deviation (SD). A Mann-Whitney U-test was used for statistical analysis. RESULTS: Serum levels of sST2 and IL-10 were significantly higher in the NVG when compared with the VG at the first postoperative day (POD-1) [sST2 pg/ml: 1366.4 (433) (VG) vs 2296.3 (1795.5) (NVG) P = 0.029; IL-10 pg/ml: 10.7 (4.0) (VG) vs 15.4 (6.8) (NVG) P = 0.038]. In addition, the secretion of proinflammatory IL-6 was slightly reduced in the VG at POD-1 [IL-6 pg/ml: 83.1 (52.5) (VG) vs 110.2 (42.3) (NVG) P = 0.033]. IL-4, endotoxin, IgM and IgG showed no differences between groups. CONCLUSION: These data suggest that continued mechanical ventilation during CABG attenuates inflammatory and anti-inflammatory immune responses after CPB. Continued mechanical ventilation may have beneficial effects in the attenuation of the CPB-induced immune activation.

[Simple surgical method for intraoperative evaluation of adequacy of tricuspid annuloplasty]. / Egyszeru sebészi módszer a tricuspidalis annuloplasztika eredményének mutét alatti értékelésére.

In tricuspid annuloplasty intraoperative "real time" evaluation using transoesophageal echocardiography requires normal flow to get reliable result. It means that the patient has to be already weaned from the cardiopulmonary bypass by the time of evaluation. In the authors' experience a well functioning tricuspid annuloplasty prevents back-flow through the valve. It can be observed on on-pump beating heart. If the tricuspid valve is competent, it is unnecessary to suck the blood flowing back through the coronary sinus while closing the right atrium. This observation seems to correlate well with post cardiopulmonary bypass transoesophageal echocardiography measurements and the control transthoracic echocardiography right before discharging the patients. These statements are based on a group of 72 patients. Sixty-nine patients (95.8%) were discharged (early mortality 4.2%). Only in one case we could observe a discrepancy between the intraoperative surgical observation and the postoperative echocardiographic finding. Development of functional tricuspid regurgitation in left-sided heart disease is a warning sign for myocardial impairment, which is an indication for surgery. Tricuspid annuloplasty can be performed even with moderate to medium grade regurgitation because it improves the early and late outcome. The described method is an adequate method for intraoperative evaluation of the repaired tricuspid valve competency.

[A complementary clinical method to minimize air embolism during open-heart surgery]. / Kiegészíto klinikai módszer a nyitott szívmutéteknél fellépo légembolisatio csökkentésére.

Air from the left heart is ejected even up to several hours after cardiopulmonary bypass (CPB) despite the use of CO2. The following method is complementary in addition to surgical de-airing in order to further reduce the chance of air embolism, especially from the pulmonary veins. After re-expanding the lungs with standard bag inflation, the ventilation is restarted in consultation with the surgeon. The ventilator is set to the respiratory minute volume used before the CPB but at a respiratory frequency of 10/minutes whereas the regularly beating heart is filled from the heart lung machine. Transoesophageal echocardiography (TEE) reliably controls the effect.

Different characteristics of postoperative heart failure after surgery for aortic stenosis and coronary disease.

OBJECTIVE: Postoperative heart failure (PHF) remains a major determinant of outcome after cardiac surgery. However, possible differences in characteristics of PHF after valve surgery and coronary surgery (CABG) have received little attention. Therefore, this issue was studied in patients undergoing aortic valve replacement (AVR) and CABG, respectively. DESIGN: Three hundred and ninety-eight patients undergoing isolated AVR for aortic stenosis were compared with 398 patients, matched for age and sex, undergoing on-pump isolated CABG. Forty-five AVR and 47 CABG patients required treatment for PHF and these were studied in detail. RESULTS: The AVR group had longer aortic cross-clamp time and higher rate of isolated right ventricular heart failure postoperatively. Myocardial ischemia during induction and perioperative myocardial infarction were more common in the CABG group. One-year mortality was 8.9% in the AVR group vs 25.5% in the CABG group (p = 0.05). CONCLUSIONS: The incidence of PHF was similar in both groups but different characteristics were found. Isolated right ventricular failure and PHF precipitated by septicemia were more common in AVR patients. PHF was more clearly associated with myocardial ischemia and infarction in CABG patients, which could explain their less favorable survival.