Revascularization of Occluded Right Coronary Artery and Outcome After Coronary Artery Bypass Grafting.

OBJECTIVES: The aim of the present study was to evaluate the results of isolated coronary artery bypass grafting (CABG) with or without revascularization of the occluded right coronary artery (RCA). METHODS: Patients undergoing isolated CABG were included in a prospective European multicenter registry. Outcomes were adjusted for imbalance in preoperative variables with propensity score matching analysis. Late outcomes were evaluated with Kaplan-Meier's method and competing risk analysis. RESULTS: Out of 2,948 included in this registry, 724 patients had a total occlusion of the RCA and were the subjects of this analysis. Occluded RCA was not revascularized in 251 (34.7%) patients with significant variability between centers. Among 245 propensity score-matched pairs, patients with and without revascularization of occluded RCA had similar early outcomes. The nonrevascularized RCA group had increased rates of 5-year all-cause mortality (17.7 vs. 11.7%, p = 0.039) compared with patients who had their RCA revascularized. The rates of myocardial infarction and repeat revascularization were only numerically increased but contributed to a significantly higher rate of MACCE (24.7 vs. 15.7%, p = 0.020) at 5 year among patients with nonrevascularized RCA. CONCLUSION: In this multicenter study, one-third of totally occluded RCAs was not revascularized during isolated CABG for multivessel coronary artery disease. Failure to revascularize an occluded RCA in these patients increased the risk of all-cause mortality and MACCEs at 5 years.

Impact of Surgeon Experience and Centre Volume on Outcome After Off-Pump Coronary Artery Bypass Surgery: Results From the European Multicenter Study on Coronary Artery Bypass Grafting (E-CABG) Registry.

AIM: The aim of this study was to assess the impact of surgeon experience and centre volume on early operative outcomes in patients undergoing off-pump coronary artery bypass (OPCAB) surgery. METHOD: Of 7,352 patients in the European Multicenter Study on Coronary Artery Bypass Grafting (E-CABG) registry, 1,549 underwent OPCAB and were included in the present analysis. Using adjusted regression analysis, we compared major early adverse events after procedures performed by experienced OPCAB surgeons (i.e., ≥20 cases per year; n=1,201) to those performed by non-OPCAB surgeons (n=348). Furthermore, the same end points were compared between procedures performed by OPCAB surgeons in high OPCAB volume centres (off-pump technique used in >50% of cases; n=894) and low OPCAB volume centres (n=307). RESULTS: In the experienced OPCAB surgeon group, we observed shorter procedure times (ß -43.858, 95% confidence interval [CI] -53.322 to -34.393; p<0.001), a lower rate of conversion to cardiopulmonary bypass (odds ratio [OR] 0.284, 95% CI 0.147-0.551; p<0.001), a lower rate of prolonged inotrope or vasoconstrictor use (OR 0.492, 95% CI 0.371-0.653; p<0.001), a lower rate of early postprocedural percutaneous coronary interventions (OR 0.335, 95% CI 0.169-0.663; p=0.002), and lower 30-day mortality (OR 0.423, 95% CI 0.194-0.924; p=0.031). In high OPCAB volume centres, we found a lower rate of prolonged inotrope use (OR 0.584, 95% CI 0.419-0.814; p=0.002), a lower rate of postprocedural acute kidney injury (OR 0.382, 95% CI 0.198-0.738; p=0.004), shorter duration of intensive care unit (ß -1.752, 95% CI -2.240 to -1.264; p<0.001) and hospital (ß -1.967; 95% CI -2.717 to -1.216; p<0.001) stays, and lower 30-day mortality (OR 0.316, 95% CI 0.114-0.881; p=0.028). CONCLUSIONS: Surgeon experience and centre volume may play an important role on the early outcomes after OPCAB surgery.

Coronary Artery Bypass Grafting in Patients With High Risk of Bleeding.

BACKGROUND: Postoperative bleeding after cardiac surgery is associated with increased morbidity and mortality. We tested the hypothesis that patients with a preoperatively estimated high risk of severe perioperative bleeding may have impaired early outcome after on-pump versus off-pump coronary artery bypass grafting (CABG). METHOD: Data from 7,352 consecutive patients who underwent isolated CABG from January 2015 to May 2017 were included in the multicentre European Coronary Artery Bypass Grafting registry. The postoperative bleeding risk was estimated using the WILL-BLEED risk score. Of all included patients, 3,548 had an increased risk of severe perioperative bleeding (defined as a WILL-BLEED score ≥4) and were the subjects of this analysis. We compared the early outcomes between patients who underwent on-pump or off-pump CABG using a multivariate mixed model for risk-adjusted analysis. RESULTS: Off-pump surgery was performed in 721 patients (20.3%). On-pump patients received more packed red blood cell units (on-pump: 1.41 [95% confidence interval {CI} 0.99-1.86]; off-pump: 0.86 [95% CI 0.64-1.08]; p<0.001), had a longer stay in the intensive care unit (on-pump: 4.4 [95% CI 3.6-8.1] days; off-pump: 3.2 [95% CI 2.0-4.4] days; p=0.049), and a higher rate of postoperative atrial fibrillation (on-pump: 46.5% [95% CI 34.9-58.1]; off-pump: 31.3% [95% CI 21.7-40.9]; p=0.025). Furthermore, on-pump patients showed a trend towards a higher rate of postoperative stroke (on-pump: 2.4% [95% CI 0.9-4.1]; off-pump: 1.1 [95% CI 0.2-2.7]; p=0.094). CONCLUSION: Our data suggest that in patients with an increased risk of bleeding, the use of cardiopulmonary bypass is associated with higher morbidity. These patients may benefit from off-pump surgery if complete revascularisation can be ensured.

Prospective validation of the International Warfarin Pharmacogenetics Consortium algorithm in high-risk elderly people (VIALE study).

We assessed the predictive accuracy of the Warfarin Pharmacogenetics Consortium (IWPC) algorithm in a prospective cohort of 376 high-risk elderly patients (≥65 years) who required new treatment with warfarin for either medical (non valvular atrial fibrillation) or surgical conditions (heart valve replacement), had ≥1 comorbid conditions, and regularly used ≥2 other drugs. Follow-up visits were performed according to clinical practice and lasted for a maximum of 1 year. Two hundred and eighty-three (75%) patients achieved a stable maintenance dose. Warfarin maintenance doses were low on average (median 20.3 mg/week, interquartile range, 14.1-27.7 mg/week) and were substantially overestimated by the IWPC algorithm. Overall the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable dose was equal to 37.5%, (95% CI 32.0-43.3%). IWPC algorithm explained only 31% of the actual warfarin dose variability. Modifications of the IWPC algorithm are needed in high-risk elderly people.

A Possible Early Biomarker for Bicuspid Aortopathy: Circulating Transforming Growth Factor ß-1 to Soluble Endoglin Ratio.

RATIONALE: The pathogenesis of bicuspid aortic valve (BAV)-associated aortopathy is poorly understood, and no prognostic biomarker is currently available. OBJECTIVE: We aimed to identify putative circulating biomarkers pathogenetically and prognostically linked to bicuspid aortopathy. METHODS AND RESULTS: By reverse transcription polymerase chain reaction, we evaluated gene expression variations (versus normal aorta) of transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor, matrix metalloproteinase-2 (MMP-2), MMP-14, endoglin (ENG), and superoxide dismutase 3 in ascending aorta samples from 50 tricuspid and 70 patients with BAV undergoing surgery for aortic stenosis (aorta diameter ≤45 mm: BAVnon-dil or >45 mm: BAVdil). Expression changes of the TGF-ß1 active dimer and ENG were analyzed also by Western blot in ascending aorta samples from other 10 tricuspid aortic valve, 10 BAVnon-dil, and 10 BAVdil patients. The serum concentration of study targets was assessed through ELISA and the ratio of serum TGF-ß1/ENG (T/E) was evaluated. All BAVnon-dil patients underwent follow-up echocardiography to assess aortic growth rate. In BAVnon-dil patients, TGF-ß1 and MMP-2 gene expression increased significantly, whereas MMP-14 and ENG expression decreased versus controls. Expression changes were confirmed at protein level for TGF-ß1 and ENG. TGF-ß1 serum concentration significantly decreased in tricuspid aortic valve and BAVnon-dil patients versus healthy subjects. ENG serum concentration decreased in all patients, more markedly in BAVdil. A significant increase of the T/E ratio versus healthy subjects was unique of patients with BAV. In BAVnon-dil patients, a T/E ≥9 was independently associated in multivariable analysis with higher MMP-2 and lower superoxide dismutase 3 gene expression, independent of age and aortic diameter. A significant correlation was observed between baseline T/E ratio and aortic diameter growth rate in BAVnon-dil patients (r=0.66, P<0.001). CONCLUSIONS: The novel evidence of a possible value of the T/E ratio as a biomarker of BAV aortopathy was presented: further validation studies are warranted.

Impact of preoperative thrombocytopenia on the outcome after coronary artery bypass grafting.

The impact of thrombocytopenia on postoperative bleeding and other major adverse events after cardiac surgery is unclear. This issue was investigated in a series of patients who underwent isolated coronary artery bypass grafting (CABG) from the prospective, multicenter E-CABG registry. Preoperative thrombocytopenia was defined as preoperative platelet count <150 × 109/L and it was considered moderate-severe when preoperative platelet count was <100 × 109/L. Multilevel mixed-effects regression analysis was performed to adjust the effect of thrombocytopenia on outcomes for baseline and operative covariates as well as for interinstitutional differences in patient-blood management. Among 7189 patients included in this analysis, 599 (8.3%) had preoperative thrombocytopenia. Patient with preoperative thrombocytopenia had an increased chest drainage output at 12 h (mean, 519 vs. 456 mL, adjusted coeff. 39, 95%CI 18-60) and rates of severe-massive bleeding (Universal Definition of Perioperative Bleeding (UDPB) severity grades 3-4: 12.7% vs. 8.1%, adjusted OR 1.47, 95%CI 1.11-1.93; E-CABG bleeding severity grades 2-3: 10.4% vs. 6.1%, adjusted OR 1.78, 95%CI 1.30-2.43). Thrombocytopenia was associated with an increased risk of hospital/30-day death (3.2% vs. 1.9%, adjusted OR 2.02, 95%CI 1.20-3.42), 1-year death (5.7% vs. 3.4%, adjusted HR 1.68, 95%CI 1.16-2.44), deep sternal wound infection (3.5% vs. 2.4%, adjusted OR 1.65, 95%CI 1.02-2.66), acute kidney injury (28.1% vs. 22.2%, OR 1.45, 1.18-1.78), and prolonged stay in the intensive care unit (mean, 3.6 vs 2.8 days, adjusted coeff. 0.74, 95%CI 0.40-1.09). Similar results were observed in a subset of patients with moderate-severe thrombocytopenia (51 patients, 0.7%). In particular, these patients had a markedly higher rate of acute kidney injury (40%, adjusted OR, 1.94, 95%CI 1.05-3.57), resternotomy for bleeding (7.8%, adjusted OR 3.49, 95%CI 1.20-10.21), and severe-massive bleeding (UDPB severity grades 3-4: 23.5%, adjusted OR 3.08, 95%CI 1.52-6.22; E-CABG bleeding severity grades 2-3: 23.5%, adjusted OR 4.43, 95%CI 2.15-9.15) compared to patients with normal preoperative platelet count. Mild preoperative thrombocytopenia is associated with increased risk of severe-massive bleeding, mortality, and other major adverse events after CABG. Such risks are markedly increased in patients with moderate-severe preoperative thrombocytopenia.

Nonvitamin K Antagonist Oral Anticoagulants Use in Patients with Atrial Fibrillation and Bioprosthetic Heart Valves/Prior Surgical Valve Repair: A Multicenter Clinical Practice Experience.

This is an observational study to investigate the efficacy and safety of nonvitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with bioprosthetic valves or prior surgical valve repair in clinical practice. A total of 122 patients (mean age: 74.1 ± 13.2; 54 females) with bioprosthetic heart valve or surgical valve repair and AF treated with NOACs were included in the analysis. The mean CHA2DS2-VASc (Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, prior Stroke or transient ischemic attack, Vascular disease) and HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INR [international normalized ratio], Elderly, Drugs or alcohol) score values were 3.6 ± 1.2 and 2.6 ± 1.4, respectively. Of the total study population, 28.6% was taking apixaban 5 mg twice daily (BID), 24.5% apixaban 2.5 mg BID, 18% dabigatran 150 mg BID, 13% dabigatran 110 mg BID, 9.8% rivaroxaban 20 mg daily (QD), and 5.7% rivaroxaban 15 mg QD. Also, 92% of the study population previously had warfarin replaced with NOACs due to lack compliance and labile INR control (time in therapeutic range < 60%). NOAC therapy for AF was started on average 934 ± 567 days after bioprosthetic heart valve implantation or surgical repair for an average duration of 835 ± 203 days. The study population included 24 (19.6%) patients with bioprosthetic mitral valve, 52 (43%) patients with bioprosthetic aortic valve, 41 (33.6%) patients with previous surgical mitral repair, 5 (4%) patients with previous surgical aortic repair, and concomitant use of NOACs. All patients were evaluated for thromboembolic events (ischemic stroke, transient ischemic attack, systemic embolism) as well as major bleeding events during the follow-up period. In our study population, we recorded a low mean annual incidence of thromboembolism (0.8%) and major bleeding (1.3%). According to our data, anticoagulation therapy with NOACs seems to be an effective and a safe treatment strategy for nonvalvular AF patients with bioprosthetic valves or prior surgical valve repair.

Prognostic Impact of Asymptomatic Carotid Artery Stenosis in Patients Undergoing Coronary Artery Bypass Grafting.

OBJECTIVES: The aim of this study was to evaluate the prognostic impact of untreated asymptomatic carotid artery stenosis (CS) in patients undergoing isolated coronary artery bypass grafting (CABG). METHODS: This was a post hoc analysis of data from a prospective multicentre observational study. Patients without history of stroke or transient ischaemic attack from the multicentre E-CABG registry who were screened for CS before isolated CABG were included. RESULTS: Among 2813 patients screened by duplex ultrasound and who did not undergo carotid intervention for asymptomatic CS, 11.1% had a stenosis of 50-59%, 6.0% of 60-69%, 3.1% of 70-79%, 1.4% of 80-89%, 0.5% of 90-99%, and 1.1% had carotid occlusion. In the screened population post-operative stroke occurred in 25 patients (0.9%), with an incidence of 1.5% among patients with CS ≥ 50% (n = 649). Pre-operative screening had not found a relevant CS in 15 of 25 patients suffering stroke after CABG. Brain imaging identified cerebral ischaemic injury in 20 patients, which was bilateral in five patients (25%), ipsilateral to a CS ≥ 50% in six (30%), and ipsilateral to a CS ≥ 70% in three (15%). In univariable analysis, the severity of CS was associated with a significantly increased risk of stroke (CS < 50%, 0.7%; 50-59%, 1.0%; 60-69%, 0.6%; 70-79%, 1.2%; 80-89%, 5.1%; 90-99%, 7.7%; occluded, 6.7%, p < .001). In multivariable analysis, a CS of 90-99% (OR 12.03, 95% CI 1.34-108.23) and the presence of an occluded internal carotid artery (OR 8.783, 95% CI 1.820-42.40) were independent predictors of stroke along with urgency of the procedure, severe massive bleeding according to the E-CABG classification, and the presence of a porcelain ascending aorta. CONCLUSIONS: Among screened patients with untreated asymptomatic patients, CS ≥ 90% was an independent predictor of post-operative stroke. As this condition has a low prevalence and when left untreated is associated with a relatively low rate of stroke, pre-operative screening of asymptomatic CS before CABG may not be justified. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov. Unique identifier: NCT02319083.

Ascending aortas from heart donors and CABG patients are not equivalent as control in aortopathy studies.

OBJECTIVES: A careful selection of reference samples in studies on the pathogenesis of thoracic ascending aorta (TAA) dilation is crucial for reliability, consistency and reproducibility of experimental results. Several studies include control TAA samples from heart donors. Others include samples harvested during coronary artery bypass graft (CABG) procedures or a mix of samples from heart donors and CABG patients. We verified the equivalence/homogeneity of TAA samples from heart donors and CABG patients in terms of basal gene expression and thus their reliability as reference groups in aortopathy studies. DESIGN: We analysed by RT-PCR and Western blot the differential expression of smoothelin, α-smooth muscle actin (α-SMA) and transforming growth factor-ß1 (TGF-ß1), selected as major players in smooth muscle cell and myofibroblast phenotype and remodelling. The mean age and comorbidities of subjects were consistent with data routinely seen in clinical practice. RESULTS: Data revealed the loss of smoothelin in samples from CABG patients, together with a significant increase of α-SMA, while TGF-ß1 dimer showed a marked increase in CABG patients versus heart donors, accompanied by a decrease of the corresponding mRNA. Differences in gene expression were maintained after adjustment for age. However, TGF-ß1 mRNA and CABG patients' age showed a positive correlation (ρ = 0.89, p < .05), while α-SMA mRNA and age showed a negative correlation (ρ = -0.85, p < .05). CONCLUSIONS: We revealed the non-equivalence of samples from heart donors and CABG patients, presumably for the presence of microscopic atherosclerotic lesions in CABG patients, suggesting the necessity of a careful selection of control groups in aortopathy studies.

Polyamine concentration is increased in thoracic ascending aorta of patients with bicuspid aortic valve.

Polyamines are cationic molecules synthesized via a highly regulated pathway, obtained from the diet or produced by the gut microbiota. They are involved in general molecular and cellular phenomena that play a role also in vascular disease. Bicuspid aortic valve (BAV) is a congenital malformation associated to a greater risk of thoracic ascending aorta (TAA) aneurysm, whose pathogenesis is not yet well understood. We focused on differential analysis of key members of polyamine pathway and on polyamine concentration in non-dilated TAA samples from patients with either stenotic tricuspid aortic valve (TAV) or BAV (diameter ≤ 45 mm), vs. normal aortas from organ donors, with the aim of revealing a potential involvement of polyamines in early aortopathy. Changes of gene expression in TAA samples were evaluated by RT-PCR. Changes of ornithine decarboxylase 1 (ODC1), a key enzyme in polyamine formation, and cationic amino acid transporter 1 (SLC7A1/CAT-1) expression were analyzed also by Western blot. ODC1 subcellular localization was assessed by immunohistochemistry. Polyamine concentration in TAA samples was evaluated by HPLC. BAV TAA samples showed an increased concentration of putrescine and spermidine vs. TAV and donor samples, together with a decreased mRNA level of polyamine anabolic enzymes and of the putative polyamine transporter SLC7A1/CAT-1. The catabolic enzyme spermidine/spermine N1-acetyltransferase 1 showed a significant mRNA increase in TAV samples only, together with a decreased concentration of spermine. The decreased expression of SLC7A1/CAT-1 and ODC1 mRNAs in BAV corresponded to increased or unchanged expression of the respective proteins. ODC was located mainly in smooth muscle cell (SMC) nucleus in TAV and donor samples, while it was present also in SMC cytoplasm in BAV samples, suggesting its activation. In conclusion, BAV, but not TAV non-dilated samples show increased polyamine concentration, accompanied by the activation of a regulatory negative feedback mechanism.

Incidence and prognostic impact of bleeding and transfusion after coronary surgery in low-risk patients.

BACKGROUND: Excessive bleeding and blood transfusion are associated with adverse outcome after cardiac surgery, but their mechanistic effects are difficult to disentangle in patients with increased operative risk. This study aimed to evaluate the incidence and prognostic impact of bleeding and transfusion of blood products in low-risk patients undergoing coronary artery bypass grafting (CABG). STUDY DESIGN AND METHODS: Sixteen tertiary European centers of cardiac surgery contributed to the prospective European registry of CABG (E-CABG). The severity of bleeding was defined by the E-CABG bleeding severity classification and universal definition of perioperative bleeding (UDPB) classification. RESULTS: Of 1213 patients with EuroSCORE II of less than 2% (mean, 1.1 ± 0.4%), 18.5% suffered from mild bleeding (E-CABG bleeding Grade 1) and 3.4% experienced severe bleeding (E-CABG bleeding Grade 2-3). Similarly, 19.7% had UDPB Class 2 and 5.9% had UDPB Classes 3 and 4. Mild and severe bleeding defined by the E-CABG and UDPB classifications were associated with an increased risk of several adverse events as adjusted by multiple covariates. The risk of death, stroke, and acute kidney injury was particularly increased in patients with severe bleeding. CONCLUSION: Severe bleeding is rather uncommon in low-risk patients undergoing CABG, but it is associated with an increased risk of major adverse events. Prevention of excessive perioperative bleeding and patient blood management may improve the outcome of cardiac surgery also in low-risk patients.

Patients with bicuspid and tricuspid aortic valve exhibit distinct regional microrna signatures in mildly dilated ascending aorta.

MicroRNAs are able to modulate gene expression in a range of diseases. We focused on microRNAs as potential contributors to the pathogenesis of ascending aorta (AA) dilatation in patients with stenotic tricuspid (TAV) or bicuspid aortic valve (BAV). Aortic specimens were collected from the 'concavity' and the 'convexity' of mildly dilated AAs and of normal AAs from heart transplant donors. Aortic RNA was analyzed through PCR arrays, profiling the expression of 84 microRNAs involved in cardiovascular disease. An in silico analysis identified the potential microRNA-mRNA interactions and the enriched KEGG pathways potentially affected by microRNA changes in dilated AAs. Distinct signatures of differentially expressed microRNAs are evident in TAV and BAV patients vs. donors, as well as differences between aortic concavity and convexity in patients only. MicroRNA changes suggest a switch of SMC phenotype, with particular reference to TAV concavity. MicroRNA changes potentially affecting mechanotransduction pathways exhibit a higher prevalence in BAV convexity and in TAV concavity, with particular reference to TGF-ß1, Hippo, and PI3K/Akt/FoxO pathways. Actin cytoskeleton emerges as potentially affected by microRNA changes in BAV convexity only. MicroRNAs could play distinct roles in BAV and TAV aortopathy, with possible implications in diagnosis and therapy.

Validation of a New Classification Method of Postoperative Complications in Patients Undergoing Coronary Artery Surgery.

OBJECTIVE: The authors aimed to validate the European Multicenter Study on Coronary Artery Bypass Grafting (E-CABG) classification of postoperative complications in patients undergoing coronary artery bypass grafting (CABG). DESIGN: Retrospective, observational study. SETTING: University hospital. PARTICIPANTS: A total of 2,764 patients with severe coronary artery disease. Complete baseline, operative, and postoperative data were available for patients who underwent isolated CABG. INTERVENTIONS: Isolated CABG. MEASUREMENTS AND MAIN RESULTS: The E-CABG complication classification was used to stratify the severity and prognostic impact of adverse postoperative events. Primary outcome endpoints were 30-day, 90-day, and long-term all-cause mortality. The secondary outcome endpoints was the length of intensive care unit stay. Both the E-CABG complication grades and additive score were predictive of 30-day (area under the receiver operating characteristics curve 0.866, 95% confidence interval [CI] 0.829-0.903; and 0.876; 95% CI 0.844-0.908, respectively) and 90-day (area under the receiver operating characteristics curve 0.850, 95% CI 0.812-0.887; and 0.863, 95% CI 0.829-0.897, respectively) all-cause mortality. The complication grades were independent predictors of increased mortality at actuarial (log-rank: p<0.0001) and adjusted analysis (p<0.0001; grade 1: hazard ratio [HR] 1.757, 95% CI 1.111-2.778; grade 2: HR 2.704, 95% CI 1.664-4.394; grade 3: HR 5.081, 95% CI 3.148-8.201). When patients who died within 30 days were excluded from the analysis, this grading method still was associated with late mortality (p<0.0001). The grading method (p<0.0001) and the additive score (rho, 0.514; p<0.0001) were predictive of the length of intensive care unit stay. CONCLUSIONS: The E-CABG postoperative complication classification seems to be a promising tool for stratifying the severity and prognostic impact of postoperative complications in patients undergoing cardiac surgery.

Pattern of resolution of pulmonary hypertension, long-term allograft right ventricular function, and exercise capacity in high-risk heart transplant recipients listed under oral sildenafil.

Unresponsive pulmonary hypertension (PH) implies poor posttransplant outcomes. Data on late adaptation of the right ventricle (RV) are still few. This study evaluated three-yr RV function and remodeling, exercise capacity, and hemodynamic data in a selected group of patients initially disqualified because of PH. Between May 2005 and December 2009, 31 consecutive patients were qualified for oral sildenafil because of unresponsive PH at baseline right heart catheterization (RHC). After a 12-wk trial, RHC disclosed PH reversibility (mean PVR: 5.41 ± 3 Wood units, mean TPG 14.5 ± 5.6 mmHg, and mean systolic PAP 68.9 ± 15.1 mmHg), allowing listing even though as high-risk procedures. All patients underwent heart transplantation. RV failure developed in three patients (9.6%), and hospital mortality was 3.2%. Protocol RHC disclosed pulmonary hemodynamic profile normalization within the third postoperative month, allowing weaning from sildenafil in the 30 hospital survivors. One- and three-yr RHCs confirmed stable PH reversal (n = 26, all three-yr survivors). Parameters of late RV function and remodeling proved satisfactory. Parameters of functional capacity (Vo2 peak 19.7 ± 3.6 mL/kg/min and slope VE/Vco2 34.8 ± 2.7) proved homogeneous to those measured in transplant recipients with normal preoperative pulmonary artery pressure. Oral sildenafil is effective in allowing candidacy, safe transplantation, and long-term survival in PH recipients initially disqualified.

Open aortic arch repair without circulatory arrest by frozen elephant trunk in Ishimaru zone 0.

BACKGROUND: Open arch surgery is technically demanding for the surgeon and surgically and biologically invasive for the patient, requiring a variably long period of hypothermic circulatory arrest. CASE PRESENTATION: Here we present a case of an elderly patient with chronic renal failure and multiple splanchnic artery disease successfully treated for a rupturing pseudoaneurysm of the aortic arch with a technique that we developed for particularly frail patients. The procedure includes: triple supra-aortic vessel perfusion; distal thoracic aorta antegrade perfusion; balloon endo-clamping of the descending aorta; and anastomosis of an off-the-shelf hybrid arch prosthesis in Ishimaru zone 0. These maneuvers allowed to maintain an extracorporeal circulation in the phase of distal anastomosis, instead of a period of circulatory arrest, employing just mild hypothermia: technical details are depicted and discussed also in comparison with other methods proposed in the literature. CONCLUSIONS: Being able to take advantage of both open surgery advancements and endovascular methods is the key to cardiovascular surgery success today in front of complex pathologies of the aorta: increasing safety and reducing invasiveness of therapeutic options may progressively extend surgical candidacy to the frailest patients.

Cardiac primitive cells become committed to a cardiac fate in adult human heart with chronic ischemic disease but fail to acquire mature phenotype: genetic and phenotypic study.

Adult human heart hosts a population of cardiac primitive CD117-positive cells (CPCs), which are responsible for physiological tissue homeostasis and regeneration. While the bona fide stem cells express telomerase, their progenies are no longer able to preserve telomeric DNA; hence the balance between their proliferation and differentiation has to be tightly controlled in order to prevent cellular senescence and apoptosis of CPCs before their maturation can be accomplished. We have examined at cellular and molecular level the proliferation, apoptosis and commitment of CPCs isolated from normal (CPC-N) and age-matched pathological adult human hearts (CPC-P) with ischemic heart disease. In the CPC-P, genes related to early stages of developmental processes, nervous system development and neurogenesis, skeletal development, bone and cartilage development were downregulated, while those involved in mesenchymal cell differentiation and heart development were upregulated, together with the transcriptional activation of TGFß/BMP signaling pathway. In the pathological heart, asymmetric division was the prevalent type of cardiac stem cell division. The population of CPC-P consisted mainly of progenitors of cardiac cell lineages and less precursors; these cells proliferated more, but were also more susceptible to apoptosis with respect to CPC-N. These results indicate that CPCs fail to reach terminal differentiation and functional competence in pathological conditions. Adverse effects of underlying pathology, which disrupts cardiac tissue structure and composition, and cellular senescence, resulting from cardiac stem cell activation in telomere dysfunctional environment, can be responsible for such outcome.

Early cell changes and TGFß pathway alterations in the aortopathy associated with bicuspid aortic valve stenosis.

Previous studies on BAV (bicuspid aortic valve)-related aortopathy, whose aetiology is still debated, have focused mainly on severe dilatations. In the present study, we aimed to detect earlier signs of aortopathy. Specimens were collected from the 'concavity' (lesser curvature) and the 'convexity' (greater curvature) of mildly dilated AAs (ascending aortas; diameter ≤4 cm) with stenotic TAV (tricuspid aortic valve) or BAV and from donor normal aortas. Specimens were submitted to morphometry, immunohistochemistry and differential gene-expression analysis, focusing on SMC (smooth muscle cell) phenotype, remodelling, MF (myofibroblast) differentiation and TGFß (transforming growth factor ß) pathway. Smoothelin and myocardin mRNAs decreased in all the samples from patients, with the exception of those from BAV convexity, where a change in orientation of smoothelin-positive SMCs and an increase of α-SMA (α-smooth muscle actin) mRNA occurred. Dilated aortas from BAV and TAV patients showed both shared and distinct alterations concerning the TGFß pathway, including an increased TGFß and TGFßR2 (TGFß receptor 2) expression in both groups and a decreased TGFßR1 expression in BAV samples only. Despite a decrease of the mRNA coding for the ED-A (extra domain-A) isoform of FN (fibronectin) in the BAV convexity, the onset of the expression of the corresponding protein in the media was observed in dilated aortas, whereas the normal media from donors was negative for this isoform. This discrepancy could be related to modifications in the intima, normally expressing ED-A FN and showing an altered structure in mild aortic dilatations in comparison with donor aorta. Our results suggest that changes in SMC phenotype and, likely, MF differentiation, occur early in the aortopathy associated with valve stenosis. The defective expression of TGFßR1 in BAV might be a constitutive feature, while other changes we reported could be influenced by haemodynamics.

Late Myocardial Infarction and Repeat Revascularization after Coronary Artery Bypass Grafting in Patients with Prior Percutaneous Coronary Intervention.

OBJECTIVES: The aim of the present study was to evaluate the risk of late mortality and major adverse cardiovascular and cerebral events after coronary artery bypass grafting (CABG) in patients with prior percutaneous coronary intervention (PCI). METHODS: A total of 2948 patients undergoing isolated CABGs were included in a prospective multicenter registry. Outcomes were adjusted for multiple covariates in logistic regression, Cox proportional hazards analysis and competing risk analysis. RESULTS: In all, 2619 patients fulfilled the inclusion criteria of this analysis. Of them, 2199 (79.1%) had no history of PCI and 420 (20.9%) had a prior PCI. An adjusted analysis showed that a single prior PCI and multiple prior PCIs did not increase the risk of 30-day and 5-year mortality. Patients with multiple prior PCIs had a significantly higher risk of 5-year myocardial infarction (SHR 2.566, 95%CI 1.379-4.312) and repeat revascularization (SHR 1.774, 95%CI 1.140-2.763). Similarly, 30-day and 5-year mortality were not significantly increased in patients with prior PCI treatment of single or multiple vessels. Patients with multiple vessels treated with PCI had a significantly higher risk of 5-year myocardial infarction (SHR 2.640, 95%CI 1.497-4.658), repeat revascularization (SHR 1.648, 95%CI 1.029-2.638) and stroke (SHR 2.215, 95%CI 1.056-4.646) at 5-year. The risk for repeat revascularization was also increased with a prior single vessel PCI, but not for other outcomes. CONCLUSIONS: Among patients undergoing CABGs, multiple prior PCIs seem to increase the risk of late myocardial infarction and the need for repeat revascularization, but not the risk of mortality.

Implications of abnormal ascending aorta geometry for risk prediction of acute type A aortic dissection.

OBJECTIVES: Recently, increased length of the ascending aorta has been suggested as a possible risk factor for acute type A aortic dissection (ATAAD). Our goal was to identify measurable aortic geometrical characteristics associated with elongation that could differentiate ATAAD from uncomplicated aortic dilation (>45 mm). METHODS: In angiographic computed tomography scans performed in 180 patients having cardiac surgery, aortic diameters, root length, length of the ascending aorta at both the centreline and the greater curvature (convexity) and the root-ascending (root-asc) angle (that between the root axis and the axis of the ascending tract) and the ascending-arch (asc-arch) angle (that between the axis of the ascending aorta and the arch axis) were measured and compared among 3 patient groups: normal aorta (diameter < 45 mm), dilation/aneurysm (>45 mm) and ATAAD. Correlations between diameters and angles, diameters and lengths and lengths and angles were analysed; multivariable analysis including geometrical factors was performed to identify independent predictors of ATAAD. RESULTS: Both patients with aneurysms and patients with ATAAD showed significantly elongated ascending aortas (P < 0.001 vs normal). However, in the aneurysms, the root-asc angle (136° ± 20° vs 147° ± 17°; P < 0.001) and in ATAAD the asc-arch angle were uniquely narrower than that in the normal aorta (116° ± 11° vs 132° ± 19°; P < 0.001). All patients with an ATAAD had an asc-arch angle ≤130°. Both in patients with ATAAD and in those without ATAAD, narrowing of the asc-arch angle was associated with elongation of the root segment (P < 0.001). In multivariable analysis, the asc-arch angle and the total length of the ascending aorta (root + tubular) were significant predictors of ATAAD. CONCLUSIONS: The asc-arch angle is a promising measurement that could help predict aortic dissection along with aortic diameter and length: further verification is warranted.

Epithelial-mesenchymal transition of epicardial mesothelium is a source of cardiac CD117-positive stem cells in adult human heart.

Epithelial-mesenchymal transition is implicated in the remodelling of tissues during development and in the adult life. In the heart, it gives origin to progenitors of fibroblasts, coronary endothelium, smooth muscle cells, and cardiomyocytes. Moreover, epicardially-derived cells determine myocardial wall thickness and Purkinje fibre network. Recently, the presence of numerous cardiac stem cells in the subepicardium of the adult human heart has been described and the hypothesis that epicardially-derived cells can contribute to the population of cardiac stem cells in the adult heart has been advanced. In an effort to test this hypothesis and establish a possible link between epicardium, epicardially-derived cells and cardiac stem cells in the adult human heart we have examined epicardial mesothelial cells in the normal and pathological adult human heart with ischemic cardiomyopathy in vivo and we have induced and documented their epithelial-mesenchymal transition in vitro. Noticeably, epicardial cells were missing from the surface of pathological hearts and the cells with the expression of epithelial and mesenchymal markers populated thick subepicardial space. When the fragments of epicardium from the normal hearts were cultured on the specific substrate formed by extracellular matrix derived from cardiac fibroblasts, we obtained the outgrowth of the epithelial sheet with the mRNA and protein expression characteristic of epicardium. TGFß induced cellular and molecular changes typical of epithelial-mesenchymal transition. Moreover, the epicardially-derived cells expressed CD117 antigen. Thus, this study provides evidence that cardiac stem cells can originate from epithelial-mesenchymal transition of the epicardial cells in the adult human heart.