Discovery of a new class of potent pyrrolo[3,4-c]quinoline-1,3-diones based inhibitors of human dihydroorotate dehydrogenase: Synthesis, pharmacological and toxicological evaluation.

Twenty N-substituted pyrrolo[3,4-c]quinoline-1,3-diones 3a-t were synthesized by a cyclization reaction of Pfitzinger's quinoline ester precursor with the selected aromatic, heteroaromatic and aliphatic amines. The structures of all derivatives were confirmed by IR, 1H NMR, 13C NMR and HRMS spectra, while their purity was determined using HPLC techniques. Almost all compounds were identified as a new class ofpotent inhibitors against hDHODH among which 3a and 3t were the most active ones with the same IC50 values of 0.11 µM, about seven times better than reference drug leflunomide. These two derivatives also exhibited very low cytotoxic effects toward healthy HaCaT cells and the optimal lipophilic properties with logP value of 1.12 and 2.07 respectively, obtained experimentally at physiological pH. We further evaluated the comparative differences in toxicological impact of the three most active compounds 3a, 3n and 3t and reference drug leflunomide. The rats were divided into five groups and were treated intraperitoneally, control group (group I) with a single dose of leflunomide (20 mg/kg) group II and the other three groups, III, IV and V were treated with 3a, 3n and 3t (20 mg/kg bw) separately. The investigation was performed in liver, kidney and blood by examining serum biochemical parameters and parameters of oxidative stress.

Noncanonical atherosclerosis as the driving force in tricuspid aortic valve associated aneurysms - A trace collection.

Pathogenic mechanisms in degenerative thoracic aortic aneurysms (TAA) are still unclear. There is an ongoing debate about whether TAAs are caused by uniform or distinct processes, which would obviously have a major impact on future treatment strategies. Clearly, the ultimate outcome of TAA subgroups associated with a tricuspid aortic valve (TAV) or a bicuspid aortic valve (BAV) is the same, namely a TAA. Based on results from our own and others' studies, we decided to compare the different TAAs (TAV and BAV) and controls using a broad array of analyses, i.e., metabolomic analyses, gene expression profiling, protein expression analyses, histological characterization, and matrix-assisted laser desorption ionization imaging. Central findings of the present study are the presence of noncanonical atherosclerosis, pathological accumulation of macrophages, and disturbances of lipid metabolism in the aortic media. Moreover, we have also found that lipid metabolism is impaired systemically. Importantly, all of the above-described phenotypes are characteristic for TAV-TAA only, and not for BAV-TAA. In summary, our results suggest different modes of pathogenesis in TAV- and BAV-associated aneurysms. Intimal atherosclerotic changes play a more central role in TAV-TAA formation than previously thought, particularly as the observed alterations do not follow classical patterns. Atherosclerotic alterations are not limited to the intima but also affect and alter the TAV-TAA media. Further studies are needed to i) clarify patho-relevant intima-media interconnections, ii) define the origin of the systemic alteration of lipid metabolism, and iii) to define valid biomarkers for early diagnosis, disease progression, and successful treatments in TAV-TAAs.

Synthesis and biological evaluation of new quinoline-4-carboxylic acid-chalcone hybrids as dihydroorotate dehydrogenase inhibitors.

Fourteen novel quinoline-4-carboxylic acid-chalcone hybrids were obtained via Claisen-Schmidt condensation and evaluated as potential human dihydroorotate dehydrogenase (hDHODH) inhibitors. The ketone precursor 2 was synthesized by the Pfitzinger reaction and used for further derivatization at position 3 of the quinoline ring for the first time. Six compounds showed better hDHODH inhibitory activity than the reference drug leflunomide, with IC50 values ranging from 0.12 to 0.58 µM. The bioactive conformations of the compounds within hDHODH were resolved by means of molecular docking, revealing their tendency to occupy the narrow tunnel of hDHODH within the N-terminus and to prevent ubiquinone as the second cofactor from easily approaching the flavin mononucleotide as a cofactor for the redox reaction within the redox site. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that 4d and 4h demonstrated the highest cytotoxic activity against the A375 cell line, with IC50 values of 5.0 and 6.8 µM, respectively. The lipophilicity of the synthesized hybrids was obtained experimentally and expressed as logD7.4 values at physiologicalpH while the solubility assay was conducted to define physicochemical characteristics influencing the ADMET properties.

Backbone distortions in lactam-bridged helical peptides.

Side-chain-to-side-chain cyclization is frequently used to stabilize the α-helical conformation of short peptides. In a previous study, we incorporated a lactam bridge between the side chains of Lys-i and Asp-i+4 in the nonapeptide 1Y, cyclo-(2,6)-(Ac-VKRLQDLQY-NH2 ), an artificial ligand of the inhibitor of DNA binding and cell differentiation (ID) protein with antiproliferative activity on cancer cells. Herein, we show that only the cyclized five-residue segment adopts a helical turn whereas the C-terminal residues remain flexible. Moreover, we present nine 1Y analogs arising from different combinations of hydrophobic residues (leucine, isoleucine, norleucine, valine, and tyrosine) at positions 1, 4, 7, and 9. All cyclopeptides except one build a lactam-bridged helical turn; however, residue-4 reveals less helix character than the neighboring Arg-3 and Gln-5, especially with residue-4 being isoleucine, valine, and tyrosine. Surprisingly, only two cyclopeptides exhibit helix propagation until the C-terminus, whereas the others share a remarkable outward tilting of the backbone carbonyl of the lactam-bridged Asp-6 (>40° deviation from the orientation parallel to the helix axis), which prevents the formation of the H-bond between Arg-3 CO and residue-7 NH: As a result, the propagation of the helix beyond the lactam-bridged sequence becomes unfavorable. We conclude that, depending on the amino-acid sequence, the lactam bridge between Lys-i and Asp-i+4 can stabilize a helical turn but deviations from the ideal helix geometry are possible: Indeed, besides the outward tilting of the backbone carbonyls, the residues per turn increased from 3.6 (typical of a regular α-helix) to 4.2, suggesting a partial helix unwinding.

Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors as potential human dihydroorotate dehydrogenase inhibitors.

Twenty novel 2-substituted quinoline-4-carboxylic acids bearing amide moiety were designed and synthesized by Doebner reaction. Human dihydroorotate dehydrogenase (hDHODH) was recognized as a biological target and all compounds were screened as potential hDHODH inhibitors in an enzyme inhibition assay. The prepared heterocycles were also evaluated for their cytotoxic effects on the healthy HaCaT cell line while lipophilic properties were considered on the basis of experimentally determined logD values at physiological pH. The most promising compound 5j, with chlorine at para-position of terminal phenyl ring, showed good hDHODH inhibitory activity, low cytotoxicity, and optimal lipophilicity. The bioactive conformation of 5j on the hDHODH, determined by means of molecular docking, revealed the compound's pharmacology and provide guidelines for further lead optimization.

Potent human dihydroorotate dehydrogenase inhibitory activity of new quinoline-4-carboxylic acids derived from phenolic aldehydes: Synthesis, cytotoxicity, lipophilicity and molecular docking studies.

A series of novel 2-substituted quinoline-4-carboxylic acids was synthesized by Doebner reaction starting from freely available protocatechuic aldehyde and vanillin precursors. Human dihydroorotate dehydrogenase (hDHODH) was recognised as a clear molecular target for these heterocycles. All compounds were also tested for their antiproliferative potential against three cancer cells (MCF-7, A549, A375) and one normal cell line (HaCaT) to evaluate the selective cytotoxicity. Quinoline derivatives 3f and 3g were identified as potent hDHODH inhibitors while 3k and 3l demonstrated high cytotoxic activity against MCF-7 and A375 cells and good selectivity. In addition, the logD7.4 values obtained by the experimental method were found to be in the range from -1.15 to 1.69. The chemical structures of all compounds were confirmed by IR, NMR and elemental analysis. The compounds pharmacology on the molecular level was revealed by means of molecular docking, highlighting the structural differences that distinguish highly active from medium and low active hDHODH inhibitors.

Early inhibition of endothelial retinoid uptake upon myocardial infarction restores cardiac function and prevents cell, tissue, and animal death.

Physiologically, following myocardial infarction (MI), retinoid levels elevate locally in the infarcted area. Whereas therapeutic systemic application of retinoids was shown to reduce the progression of ventricular dilatation and the onset of heart failure, the role of acute physiologically increased retinoids in the infarction zone is unknown to date. To reveal the role of local retinoids in the MI zone is the central aim of this study. Using human cell culture and co-culture models for hypoxia as well as various assays systems, lentivirus-based transgene expression, in silico molecular docking studies, and an MI model in rats, we analysed the impact of the retinoid all-trans retinoic acid (ATRA) on cell signalling, cell viability, tissue survival, heart function, and MI-induced death in rats. Based on our results, ATRA-mediated signalling does aggravate the MI phenotype (e.g. 2.5-fold increased mortality compared to control), whereas 5'-methoxyleoligin (5ML), a new agent which interferes with ATRA-signalling rescues the ATRA-dependent phenotype. On the molecular level, ATRA signalling causes induction of TXNIP, a potent inhibitor of the physiological antioxidant thioredoxin (TRX1) and sensitizes cells to necrotic cell death upon hypoxia. 5ML-mediated prevention of ATRA effects were shown to be based on the inhibition of cellular ATRA uptake by interference with the cholesterol (and retinol) binding motif of the transmembrane protein STRA6. 5ML-mediated inhibition of ATRA uptake led to a strong reduction of ATRA-dependent gene expression, reduced ROS formation, and protection from necrotic cell death. As 5ML exerted a cardioprotective effect, also independent of its inhibition of cellular ATRA uptake, the agent likely has another cardioprotective property, which may rely on the induction of TRX1 activity. In summary, this is the first study to show i) that local retinoids in the early MI zone may worsen disease outcome, ii) that inhibition of endothelial retinoid uptake using 5ML may constitute a novel treatment strategy, and iii) that targeting endothelial and myocardial retinoid uptake (e.g. via STRA6 inhibition) may constitute a novel treatment target in acute MI.

Moderate Hypothermic Circulatory Arrest (≥ 28°C) with Selective Antegrade Cerebral Perfusion for Total Arch Replacement with Frozen Elephant Trunk Technique.

OBJECTIVES: The optimal hypothermic level during circulatory arrest in aortic arch surgery remains controversial, particularly in frozen elephant trunk (FET) procedures. We describe herein our experience for total arch replacement with FET technique under moderate systemic hypothermic circulatory arrest (≥ 28°C) during selective antegrade cerebral perfusion. METHODS: Between January 2009 and January 2016, 38 consecutive patients underwent elective total arch replacement for various aortic arch pathologies with FET technique using the E-vita Open hybrid prosthesis (Jotec GmbH, Hechingen, Germany). Selective unilateral or bilateral cerebral perfusion under moderate systemic hypothermic circulatory arrest (28.7°C ± 0.5°C) was used in all patients. Minimally invasive total arch replacement with FET via partial upper sternotomy was performed in 15 patients (39%) and in the remaining 23 patients (61%) via full sternotomy. Mean late follow-up was 3 ± 2 years and was 98% complete. Clinical data were prospectively entered into our institutional database. RESULTS: Cardiopulmonary bypass time accounted for 198 ± 58 minutes and the myocardial ischemic time 109 ± 29 minutes. Selective antegrade cerebral perfusion time was 55 ± 6 minutes. Lower body circulatory arrest time was 39 ± 11 minutes. Unilateral cerebral perfusion was performed in 31 patients (82%), and bilateral in 7 patients (18%). Intensive care unit stay was 4 ± 3 days. Thirty-day mortality was 5% (n = 2). Late survival at 3 years was 87 ± 3%. Two patients (5%) required reexploration for bleeding. Patients were discharged after a hospital length of stay of 7 ± 2 days. Postoperative permanent neurologic complication occurred in two patients (5%). Three patients (8%) experienced a transient neurologic disorder. New transient renal replacement therapy was necessary in three patients (8%). No spinal cord injury was noted. CONCLUSIONS: Our data suggest that moderate systemic hypothermic circulatory arrest (≥ 28°C) in combination with antegrade cerebral perfusion can safely be applied for total aortic arch replacement with FET and offers sufficient neurologic and visceral organ protection.

External Prosthetic Reinforcement of the Pulmonary Autograft.

BACKGROUND: Neo-aortic root dilatation accounts for the majority of reoperations needed after the Ross procedure with implantation of the pulmonary autograft as complete root replacement. This study evaluates early results of external prosthetic reinforcement of the autograft. METHODS: From July 2015 to October 2017, 16 adolescent and adult patients received a Ross procedure at our department by this technique. A congenital-dysplastic valve was present in 13 patients, including 9 patients with a bicuspid aortic valve. Clinical and echocardiographic follow-up is complete with a mean duration of 19.7 ± 5.8 months. RESULTS: The mean age at operation was 27.1 ± 16.1 years. Mean aortic cross-clamping time was 102 ± 39 minutes. No bleeding complication occurred. The median stay on the intensive care unit was 2 days. In-hospital mortality was 0%. All patients were discharged with no or trivial aortic regurgitation. In one patient both the autograft and homograft were replaced because of endocarditis 3 months after the primary operation, leading to 93.8% freedom from reoperation at 2 years. There were no late deaths during the study period. The latest echocardiography confirmed absence of aortic regurgitation grade >I in all patients. Neo-aortic root diameters remained stable during follow-up. CONCLUSION: The presented modification of the Ross procedure does not prolong ischemia time, and can be performed with a low operative morbidity and mortality and an excellent early valve function.

Intravenous Levosimendan and Vasopressin in New-Onset Acute Pulmonary Hypertension After Weaning from Cardiopulmonary Bypass.

OBJECTIVE: A novel treatment with intravenous levosimendan and vasopressin for new-onset acute pulmonary hypertension after weaning from cardiopulmonary bypass is described. DESIGN: Retrospective analysis of a case series. SETTING: Single-center study. PARTICIPANTS: Nineteen patients undergoing cardiac surgery exhibited new-onset acute pulmonary hypertension with acute right ventricular dysfunction after cardiopulmonary bypass. INTERVENTION: Pulmonary hypertension with acute right heart dysfunction was treated with levosimendan as inodilator therapy and vasopressin combined with norepinephrine for systemic vasopressor therapy. MEASUREMENTS AND MAIN RESULTS: Mean pulmonary artery pressure decreased from 32 ± 9 to 26 ± 6 mmHg (p = 0.039) in the first 24 hours along with an increase in cardiac output (3.2 ± 1 to 4.2 ± 1.1 L/min; p = 0.012) and resolution of lactic acidosis. The ratio between mean pulmonary artery pressure and mean arterial pressure decreased from 1:2 to 1:3, and Wood units decreased from 3 ± 1 to 1.5 ± 2 (p = 0.042). At 30 days after intervention, 3 patients died. CONCLUSION: The combination of levosimendan for inotropic support of the right ventricle in conjunction with its vasodilatory effect on the pulmonary circulation, along with the combination of vasopressin and norepinephrine for systemic vasopressor therapy, may be an effective alternative for the treatment of acute new-onset pulmonary hypertension and acute right heart dysfunction after cardiopulmonary bypass. Although there are many confounding variables in this case series, these findings justify additional sufficiently powered trials.

Incidence and outcomes of emergent cardiac surgery during transfemoral transcatheter aortic valve implantation (TAVI): insights from the European Registry on Emergent Cardiac Surgery during TAVI (EuRECS-TAVI).

Aims: Life-threatening complications occur during transcatheter aortic valve implantation (TAVI) which can require emergent cardiac surgery (ECS). Risks and outcomes of patients needing ECS during or immediately after TAVI are still unclear. Methods and results: Incidence, risk factors, management, and outcomes of patients requiring ECS during transfemoral (TF)-TAVI were analysed from a contemporary real-world multicentre registry. Between 2013 and 2016, 27 760 patients underwent TF-TAVI in 79 centres. Of these, 212 (0.76%) patients required ECS (age 82.4 ± 6.3 years, 67.5% females, logistic EuroSCORE: 17.1%, STS-score 5.8%). The risk of ECS declined from 2013 (1.07%) to 2014 (0.70%) but remained stable since. Annual TF-TAVI numbers have more than doubled from 2013 to 2016. Leading causes for ECS were left ventricular perforation by the guidewire (28.3%) and annular rupture (21.2%). Immediate procedural mortality (<72 h) of TF-TAVI patients requiring ECS was 34.6%. Overall in-hospital mortality was 46.0%, and highest in case of annular rupture (62%). Independent predictors of in-hospital mortality following ECS were age > 85 years [odds ratio (OR) 1.87, 95% confidence interval (95% CI) (1.02-3.45), P = 0.044], annular rupture [OR 1.96, 95% CI (0.94-4.10), P = 0.060], and immediate ECS [OR 3.12, 95% CI (1.07-9.11), P = 0.037]. One year of survival of the 114 patients surviving the in-hospital period was only 40.4%. Conclusion: Between 2014 and 2016, the need for ECS remained stable around 0.7%. Left ventricular guidewire perforation and annular rupture were the most frequent causes, accounting for almost half of ECS cases. Half of the patients could be salvaged by ECS-nevertheless, 1 year of all-cause mortality was high even in those ECS patients surviving the in-hospital period.

Midterm Results of a Minimally Invasive Approach in David Procedure.

BACKGROUND: The David procedure is a well-known technique in selected patients with aortic root pathology. A minimally invasive approach in heart surgery increases open interest. METHODS: From 1991 to 2015, the David technique was performed in 296 patients in our unit. In 90 cases, operations were performed through partial upper sternotomy. The patient mean age was 57 ± 14 years in the minimally invasive group (n = 90) and 58 ± 14 years in the complete sternotomy group (n = 206; p = 0.2). The neosinus modification was performed in 80 patients (89%) in the minimally invasive group and in 79 patients (38%) in the complete sternotomy group (p < 0.01). Mean follow-up was 3 ± 2 years in the minimally invasive group and 8 ± 4 years in the complete sternotomy group. RESULTS: Thirty-day mortality was zero in the minimally invasive group and was 3% (n = 6) in the complete sternotomy group (p = 0.1). The need for packed red blood cells was significantly lower in the minimally invasive group (1.6 ± 3 U) than in the complete sternotomy group (3.7 ± 6 U; p < 0.01). Thirty late deaths (2% per patient-year) were observed in the complete sternotomy group versus zero in the minimally invasive group (p < 0.01). One patient (0.5% per patient-year) in the minimally invasive group and 12 patients (0.8% per patient-year) in the complete sternotomy group required reoperation in the follow-up period (p = 0.05). CONCLUSIONS: Minimally invasive David technique for patients with ascending aortic aneurysm and aortic valve insufficiency offers a good solution with low perioperative blood transfusion rate. Our midterm results show low valve-related complications and reoperation rate. However, long-term follow-up of the minimally invasive group is necessary.

Is More than One Hour of Selective Antegrade Cerebral Perfusion in Moderate-to-Mild Systemic Hypothermic Circulatory Arrest for Surgery of Acute Type A Aortic Dissection Safe?

OBJECTIVES: Surgery for acute type A aortic dissection (AAD) remains a surgical challenge with considerable risk of morbidity and mortality. Antegrade cerebral perfusion (ACP) has been popularized, offering a more physiologic method of brain perfusion during complex aortic arch repair, often necessary in setting of AAD. The safe limits of this approach under moderate-to-mild systemic hypothermic circulatory arrest (≥ 28°C) are yet to be defined. Thus, the current study investigates our clinical results after surgical treatment for AAD in patients with a selective ACP and systemic circulatory arrest time of ≥ 60 minutes in moderate-to-mild hypothermia (≥ 28°C). METHODS: Between January 2000 and April 2016, 63 consecutive patients underwent surgical treatment for AAD employing selective ACP during moderate-to-mild systemic hypothermia (≥ 28°C) with prolonged ACP and circulatory arrest times. Patients' mean age was 59 ± 15 years, and 39 patients (62%) were men. Hemiarch replacement and total arch replacement were performed in 13 (21%) and 50 (79%) patients, respectively. Frozen elephant trunk, arch light, and elephant trunk technique were performed in nine (14%), six (10%), and three patients (5%), respectively. Clinical data were prospectively entered into our institutional database. Mean late follow-up was 6 ± 4 years and was 98% complete. RESULTS: Cardiopulmonary bypass time accounted for 245 ± 81 minutes and the myocardial ischemic time accounted for 140 ± 43 minutes. Mean duration of ACP was 74 ± 12 minutes. The mean lowest core temperature accounted for 28.9 ± 0.8°C. Unilateral ACP was performed in 44 patients (70%); bilateral ACP was used in the remaining 19 patients (30%). Intensive care unit stay reached 6 ± 5 days. New onset of acute renal failure requiring hemofiltration was observed in 8% of patients (n = 5). New postoperative permanent neurologic deficits were found in five patients (8%) and transient neurologic deficits in six patients (10%). There was one case of paraplegia. Thirty-day mortality and in-hospital mortality were 8 (n = 5) and 11% (n = 7), respectively. Overall survival at 5 years was 76 ± 9%. CONCLUSION: Our preliminary data suggest that selective ACP during moderate-to-mild systemic hypothermic circulatory arrest (≥ 28°C) can safely be applied for more than 1 hour even in the setting of AAD.

One-Year Patency of Valvulotomized Vein Grafts Is Similar to That of Arterial Grafts.

BACKGROUND: Inferior vein graft patency after coronary artery bypass grafting (CABG) is attributed to various factors. Venous valves may limit flow, cause thrombus formation, and diminish diastolic backflow. The aim of our study was to compare clinical outcome and midterm patency rate of valvulotomized vein grafts and arterial grafts in patients undergoing CABG. METHODS: Between 2007 and 2010, valvulotomized saphenous vein segments were used to graft the right coronary artery (RCA) in 147 patients undergoing CABG with mean 2.8 ± 1 arterial and 1.5 ± 0.6 venous anastomoses. Outcome, reintervention, and reoperation were assessed after 4 ± 1.6 years. Intraoperative bypass flow rate was measured before and after valvulotomy of venous bypass grafts in 12 patients. Patency of the grafts was assessed by means of multislice computed tomography (MSCT) in 45 patients. RESULTS: A total of 102 patients underwent isolated CABG and 45 had combined procedures. In-hospital mortality was 2%. At 4 years' clinical follow-up, 95% of the patients were asymptomatic. Five patients underwent recoronary angiography because of angina pectoris. The MSCT and reangiography patency rate of all valvulotomized saphenous vein grafts was 97.1 versus 95.8% of arterial grafts 18 ± 6 months postoperatively. Intraoperative measurements showed a significant increase (+20.2 mL/min; p = 0.01) of flow in the venous bypass grafts to the RCA after valvulotomy. There were no reoperations at the latest follow-up. CONCLUSION: Patients with valvulotomized venous grafts had good clinical outcome. The one-year patency rate of those grafts is comparable to that of arterial grafts. However, long-term results and angiography studies will be needed to strengthen these findings.

Digital Carotid Compression: A Simple Method to Reduce Solid Cerebral Emboli During Cardiac Surgery.

OBJECTIVES: Serious neurologic injury can be attributed to embolization of solid particles into cerebral vessels during cardiac surgery. Previous studies using transcranial Doppler (TCD) identified arterial cannulation and aortic declamping to be associated with cerebral embolization. The purpose of this study was to investigate the impact of transient compression of the carotid arteries during these maneuvers on the embolic load during cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective, randomized, clinical trial/pilot study. SETTING: Single-center study at a university hospital. PARTICIPANTS: Patients with multiple types of procedures were included and they were prospectively, randomly assigned to group I (n = 20, carotid compression during arterial cannulation and aortic declamping) and group II (n = 20, no carotid compression). INTERVENTIONS: Bilateral continuous monitoring of the middle cerebral arteries was performed with a multirange, multifreqency transcranial Doppler (DopplerBoxX, DWL, Singen, Germany), allowing for discrimination between solid and gaseous emboli. For aortic cannulation the carotid arteries were compressed for 5 seconds and for declamping for 3 seconds, and microemboli signals were detected within the following 45 seconds. MEASUREMENTS AND MAIN RESULTS: A reduction of intraoperative solid emboli was detected in group I compared with group II (26±16 v 38±18; p = 0.04). Looking specifically at the maneuver of arterial cannulation, the observed difference was 0.5±0.8 in group I versus 5.7±5.8 in group II (p<0.0001). During aortic declamping, 6.6±6.2 emboli were encountered in group I and 10.8±5.2 in group II (p = 0.02). The incidence of neurologic events was not significantly different between groups (2 patients in group II had pathologic changes on magnetic resonance imaging). CONCLUSIONS: The data of this preliminary trial demonstrated that transient compression of the carotid arteries during arterial cannulation and aortic declamping led to a decreased number of solid cerebral emboli. Further prospective, randomized clinical studies should be undertaken to investigate the influence of transient carotid artery compression during specific surgical procedures.

Linear Closure of the Left Ventricular Apex Following Transcatheter-Based Aortic Valve Implantation.

Transcatheter-based aortic valve implantation (TAVI) provides a reliable and attractive alternative to the established gold standard of classic aortic valve replacement in patients with severe comorbidities carrying an unacceptably high perioperative risk. Despite the minimally invasive nature of the transfemoral approach, the transapical route remains an attractive alternative allowing antegrade valve deployment. Purse-string sutures with interrupted Teflon pledgets represent the classic approach for secure closure of the transapical access site. We describe herein a simple yet effective and time-saving linear technique for apical closure following transapical TAVI.

Hematologic Effects of Heart Valve Prostheses and Vascular Grafts after Aortic Root Replacement.

BACKGROUND: Heart valve prosthesis as well as vascular grafts cause changes in blood parameters. This may correlate with valve-related complications, less frequently observed after repair surgery. We thus studied changes in rheology after Bentall, Ross, or Tirone David (TD) procedure. METHODS: Seventeen patients underwent a TD, 17 patients underwent a Ross, and 16 patients underwent a Bentall procedure. Venous blood samples were collected 4 ± 3 (TD), 4 ± 3 (Ross), and 6 ± 3 years mean (Bentall) postoperatively. Concentrations of fibrinogen, leucocytes, platelets, haptoglobin, hemoglobin, lactate dehydrogenase (LDH), bilirubin, hematocrit, and ß-thromboglobulin were determined. Platelet function and activity were analyzed. Results were compared with those of healthy control subjects. RESULTS: Level of fibrinogen was higher in the Bentall than in the other two groups (338 ± 63 vs. 298 ± 43 Ross and 308 ± 48 mg/dL TD, p > 0.05). LDH was also elevated in the Bentall group (311 ± 45 vs. 205 ± 30 Ross, p < 0.01 and 203 ± 34 U/l TD, p < 0.01). Platelet count and haptoglobin levels were significantly reduced in the Bentall (190 ± 43/nL, 2.4 ± 1 mg/dL) and TD groups (183 ± 52/nL, 89 ± 57 mg/dL) in comparison to the control group (250 ± 86/nL, 140 ± 53 mg/dL) with p < 0.05, whereas there were no significant differences in the Ross group (214 ± 47/nL and 129 ± 54 mg/dL) in comparison to the control group. Leucocyte count and platelet function showed no significant differences between the groups. CONCLUSION: Polyester ascending aortic prostheses and more pronounced when combined with a prosthetic aortic valve cause hematologic changes compared with minimal deviations in Ross patients. We observed mild hemolysis, a decreased platelet count, and an increase in fibrinogen level in patients after conduit root replacement compared with procedures retaining an autologous aortic valve at midterm follow-up.

Two cases of valve surgery through right anterior minithoracotomy in presence of severe postmastectomy irradiation sternal damage.

High dose postmastectomy radiation therapy for breast cancer can lead to severe postirradiation sternal damage. Under these circumstances, median sternotomy may be associated with a prohibitive risk of postoperative deep sternal wound infection and alternative approaches have to be evaluated. We report herein the use of a right anterior minithoracotomy through the third intercostal space for isolated aortic valve replacement in one and combined aortic and mitral valve replacement in combination with mitral ring decalcification and coronary artery bypass grafting to the proximal right coronary artery in another patient.

Long-term follow-up of minimally invasive cardiac surgery using an endoaortic occlusion system.

OBJECTIVES: We reviewed the initial patient series (n=116) of our institution performing minimally invasive coronary artery bypass grafting (CABG) (n=79), mitral valve surgery (n=1), or atrial septal closure (ASD) procedures (n=26) using an endoaortic occlusion system. With this technique relevant intra-aortic pressures are exerted on the aortic wall during the clamping time. This might lead to late aortic degeneration and aneurysm formation. Our study sought to evaluate postoperative aortic complications and the quality of life (modified SF-12). METHODS: One hundred sixteen patients (56% male; 54 years ± 14.5; range 19 years to 77 years) underwent a cardiac procedure using an endoaortic clamp. The endoaortic balloon clamp catheter was used to occlude the ascending aorta at pressures >300 mmHg. Patients were rescheduled for echocardiographic examination after a mean follow-up period of 8.8 years. RESULTS: The analysis performed among 78 patients showed no incidence of any structural damage to the ascending aorta at the intraoperative position of the endoaortic balloon. The physical and mental summary scores are equal to those of comparable patient groups. CONCLUSIONS: The endoaortic occlusion system causes no damage to the aortic wall. If the system causes any problems, they occur immediately during surgery. Patients treated with this minimally invasive technique exhibited the same quality of life as those undergoing conventional surgery.

Perioperative and Long-Term Outcomes in Patients Undergoing Synchronous Carotid Endarterectomy and Coronary Artery Bypass Grafting: A Single-Center Experience.

INTRODUCTION: Patients requiring coronary artery bypass grafting (CABG) and carotid endarterectomy (CEA) can be managed with staged (CEA before CABG), reverse staged (CABG before CEA) or synchronous treatment. This single-center retrospective study evaluated the outcomes in patients undergoing planned synchronous CEA and CABG. METHODS: Between 2000 and 2020 a total of 185 patients with symptomatic triple-vessel or left main coronary artery disease associated with 70-99% asymptomatic or 50-99% symptomatic uni- or bilateral internal carotid artery (ICA) stenosis underwent synchronous CEA and CABG at our institution. Study endpoints were defined as mortality, stroke and myocardial infarction at 30 days. Additionally, the composite endpoint of these events was investigated. RESULTS: At 30 days, mortality, stroke and myocardial infarction rates were 5.9%, 8.1% (permanent [unresolved deficit at discharge] 5.4%) and 3.8%, respectively, and the composite endpoint was reached in 13.0% of patients. Patients suffering from a stroke more frequently had a contralateral 70-99% ICA stenosis (60.0% vs. 17.3%; p < 0.001), peripheral artery disease (73.3% vs. 38.9%; p = 0.013) and prolonged cardiopulmonary bypass time (mean 119 ± 62 min vs. 84 ± 29 min; p = 0.012). Multivariate logistic regression analysis revealed the duration of cardiopulmonary bypass (odds ratio [OR] 1.024; 95% confidence interval [CI] 1.002-1.046; p = 0.034), a history of type 2 diabetes mellitus (OR 5.097; 95% CI 1.161-22.367; p = 0.031) and peripheral artery disease (OR 5.814; 95% CI 1.231-27.457; p = 0.026) as independent risk factors for reaching the composite endpoint. CONCLUSION: Patients undergoing synchronous CEA and CABG face an elevated risk of perioperative cardiovascular events, particularly an increased stroke risk in patients with symptomatic and bilateral ICA stenosis. Graphical Abstract available for this article.