Implantation of a double allogeneic human engineered tissue graft on damaged heart: insights from the PERISCOPE phase I clinical trial.

BACKGROUND: In preclinical studies, the use of double allogeneic grafts has shown promising results in promoting tissue revascularization, reducing infarct size, preventing adverse remodelling and fibrosis, and ultimately enhancing cardiac function. Building upon these findings, the safety of PeriCord, an engineered tissue graft consisting of a decellularised pericardial matrix and umbilical cord Wharton's jelly mesenchymal stromal cells, was evaluated in the PERISCOPE Phase I clinical trial (NCT03798353), marking its first application in human subjects. METHODS: This was a double-blind, single-centre trial that enrolled patients with non-acute myocardial infarction eligible for surgical revascularization. Seven patients were implanted with PeriCord while five served as controls. FINDINGS: Patients who received PeriCord showed no adverse effects during post-operative phase and one-year follow-up. No significant changes in secondary outcomes, such as quality of life or cardiac function, were found in patients who received PeriCord. However, PeriCord did modulate the kinetics of circulating monocytes involved in post-infarction myocardial repair towards non-classical inflammation-resolving macrophages, as well as levels of monocyte chemoattractants and the prognostic marker Meteorin-like in plasma following treatment. INTERPRETATION: In summary, the PeriCord graft has exhibited a safe profile and notable immunomodulatory properties. Nevertheless, further research is required to fully unlock its potential as a platform for managing inflammatory-related pathologies. FUNDING: This work was supported in part by grants from MICINN (SAF2017-84324-C2-1-R); Instituto de Salud Carlos III (ICI19/00039 and Red RICORS-TERAV RD21/0017/0022, and CIBER Cardiovascular CB16/11/00403) as a part of the Plan Nacional de I + D + I, and co-funded by ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER) and AGAUR (2021-SGR-01437).

Mechanical complications in STEMI: prevalence and mortality trends in the primary PCI era. The Ruti-STEMI registry.

INTRODUCTION AND OBJECTIVES: Mechanical complications confer a dreadful prognosis in ST-elevation myocardial infarction (STEMI). Their prevalence and prognosis are not well-defined in the current era of primary percutaneous coronary intervention (pPCI) reperfusion networks. We aimed to analyze prevalence and mortality trends of post-STEMI mechanical complications over 2 decades, before and after the establishment of pPCI networks. METHODS: Prospective, consecutive registry of STEMI patients within a region of 850 000 inhabitants over 2 decades: a pre-pPCI period (1990-2000) and a pPCI period (2007-2017). We analyzed the prevalence of mechanical complications, including ventricular septal rupture, papillary muscle rupture, and free wall rupture (FWR). Twenty eight-day and 1-year mortality trends were compared between the 2 studied decades. RESULTS: A total of 6033 STEMI patients were included (pre-pPCI period, n=2250; pPCI period, n=3783). Reperfusion was supported by thrombolysis in the pre-pPCI period (99.1%) and by pPCI in in the pPCI period (95.7%). Mechanical complications developed in 135 patients (2.2%): ventricular septal rupture in 38 patients, papillary muscle rupture in 24, and FWR in 73 patients. FWR showed a relative reduction of 60% in the pPCI period (0.8% vs 2.0%, P<.001), without significant interperiod changes in the other mechanical complications. After multivariate adjustment, FWR remained higher in the pre-pPCI period (OR, 1.93; 95%CI, 1.10-3.41; P=.023). At 28 days and 1 year, mortality showed no significant changes in all the mechanical complications studied. CONCLUSIONS: The establishment of regional pPCI networks has modified the landscape of mechanical complications in STEMI. FWR is less frequent in the pPCI era, likely due to reduced transmural infarcts.

Long-term outcomes with the On-X bileaflet mitral valve: clinical events up to 17 years in 661 patients.

OBJECTIVES: This study reports long-term clinical outcomes-up to 17 years-among patients undergoing mitral valve replacement with the On-X bileaflet mechanical valve. Prior data regarding long-term outcomes with the On-X mitral valve have been limited. METHODS: This retrospective observational study included all patients who underwent mitral valve replacement with the On-X (Standard or Conform-X) valve at 2 major Spanish cardiac surgery centres between 2001 and 2018. The primary study end point was freedom from death. The secondary study end points included surgical mortality and freedom from any valve-related events. Data were obtained from an institutional database, medical records review, direct telephone interviews or the Spanish population registry. Statistical and Kaplan-Meier analyses were performed. RESULTS: A total of 661 patients (mean age 63.1 ± 10.9 years, 63% female) were followed for a mean of 5.6 years (range, 0-17.4 years). Survival at 5, 10 and 15 years was 85%, 71% and 63%, respectively. Surgical mortality was 7.3% (48/661). The linearized rate of global mortality was 1.3% patient-year. Freedom from reoperation was 97%, 95% and 92% at 5, 10 and 15 years, respectively; freedom from anticoagulation-related events was 94%, 89% and 89%, respectively. Multivariable analysis showed that mortality increased with total length of stay, age, smoking history, severe pulmonary hypertension and a permanent pacemaker. Patients who received the On-X 25 -mm valve had decreased long-term survival relative to patients who received other On-X valve sizes, possibly due to underlying risk factors. CONCLUSIONS: Patients in this study showed good long-term survival and freedom from valve-related events.

Intermediate Care Unit After Cardiac Surgery: Impact on Length of Stay and Outcomes.

INTRODUCTION AND OBJECTIVES: Current postoperative management of adult cardiac surgery often comprises transfer from the intensive care unit (ICU) to a conventional ward. Intermediate care units (IMCU) permit hospital resource optimization. We analyzed the impact of an IMCU on length of stay (both ICU and in-hospital) and outcomes (in-hospital mortality and 30-day readmissions) after adult cardiac surgery (IMCU-CS). METHODS: From November 2012 to April 2015, 1324 consecutive patients were admitted to a university hospital for cardiac surgery. In May 2014, an IMCU-CS was established for postoperative care. For the purposes of this study, patients were classified into 2 groups, depending on the admission period: pre-IMCU-CS (November 2012-April 2014, n=674) and post-IMCU-CS (May 2014-April 2015, n=650). RESULTS: There were no statistically significant differences in age, sex, risk factors, comorbidities, EuroSCORE 2, left ventricular ejection fraction, or the types of surgery (valvular in 53%, coronary in 26%, valvular plus coronary in 11.5%, and aorta in 1.8%). The ICU length of stay decreased from 4.9±11 to 2.9±6 days (mean±standard deviation; P<.001); 2 [1-4] to 1 [0-3] (median [Q1-Q3]); in-hospital length of stay decreased from 13.5±15 to 12.7±11 days (mean±standard deviation; P=.01); 9 [7-13] to 9 [7-11] (median [Q1-Q3]), in pre-IMCU-CS to post-IMCU-CS, respectively. There were no statistically significant differences in in-hospital mortality (4.9% vs 3.5%; P=.28) or 30-day readmission rate (4.3% vs 4.2%; P=.89). CONCLUSIONS: After the establishment of an IMCU-CS for postoperative cardiac surgery, there was a reduction in ICU and in-hospital mean lengths of stay with no increase in in-hospital mortality or 30-day readmissions.

Rationale and design of a multicentre, prospective, randomised, controlled clinical trial to evaluate the efficacy of the adipose graft transposition procedure in patients with a myocardial scar: the AGTP II trial.

INTRODUCTION: Cardiac adipose tissue is a source of progenitor cells with regenerative capacity. Studies in rodents demonstrated that the intramyocardial delivery of cells derived from this tissue improves cardiac function after myocardial infarction (MI). We developed a new reparative approach for damaged myocardium that integrates the regenerative properties of cardiac adipose tissue with tissue engineering. In the adipose graft transposition procedure (AGTP), we dissect a vascularised flap of autologous pericardial adipose tissue and position it over the myocardial scarred area. Following encouraging results in acute and chronic MI porcine models, we performed the clinical trial (NCT01473433, AdiFLAP trial) to evaluate safety in patients with chronic MI undergoing coronary artery bypass graft. The good safety profile and trends in efficacy warranted a larger trial. STUDY DESIGN: The AGTP II trial (NCT02798276) is an investigator initiated, prospective, randomised, controlled, multicentre study to assess the efficacy of the AGTP in 108 patients with non-revascularisable MI. Patients will be assigned to standard clinical practice or the AGTP. The primary endpoint is change in necrotic mass ratio by gadolinium enhancement at 91 and 365 days. Secondary endpoints include improvement in regional contractibility by MRI at 91 and 365 days; changes in functional MRI parameters (left ventricular ejection fraction, left and right ventricular geometric remodelling) at 91 and 365 days; levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) at 7, 91 and 365 days; appearance of arrhythmias from 24 hour Holter monitoring at 24 hours, and at 91 and 365 days; all cause death or re-hospitalisation at 365 days; and cardiovascular death or re-hospitalisation at 365 days. ETHICS AND DISSEMINATION: The institutional review board approved the trial which will comply with the Declaration of Helsinki. All patients will provide informed consent. It may offer a novel, effective and technically simple technique for patients with no other therapeutic options. The results will be submitted to indexed medical journals and national and international meetings. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT02798276, pre-results.

Incidence and predictors of new-onset atrioventricular block requiring pacemaker implantation after sutureless aortic valve replacement.

OBJECTIVES: In high-risk patients with severe aortic stenosis, aortic valve replacement (AVR) with a sutureless Perceval prosthesis (SU-AVR) can be performed instead of conventional AVR or transcatheter aortic valve implantation. Little data are available regarding postoperative conduction disorders after SU-AVR. We aimed to determine the incidence and predictors of new-onset complete atrioventricular block (NO-AVB) requiring permanent cardiac stimulation following SU-AVR. METHODS: We studied consecutive patients who underwent SU-AVR between 2013 and 2015. Early patients underwent partial aortic decalcification and subannular valve implantation (standard technique), while later patients underwent complete/symmetrical decalcification and intra-annular valve deployment (modified technique). Predictive baseline and procedural variables and electrocardiographic parameters were identified using a logistic regression model. RESULTS: We included 140 patients (mean age, 78 ± 6.5 years; mean Log EuroSCORE II, 8.9 ± 10%; 28.6% concomitant myocardial revascularization). The most common postoperative conduction disturbances were LBBB (25%), NO-AVB (12.1%) and first-degree atrioventricular block (AVB) (7.9%). The incidence of NO-AVB was 61% lower with the modified versus the standard technique (P= 0.04). NO-AVB predominantly appeared within 24 h post-surgery, occurring >24 h post-surgery in only 2 patients (both with baseline conduction defects). Independent predictors of NO-AVB included baseline left QRS axis deviation (LaQD; P= 0.03), first-degree AVB (P< 0.01) and standard surgical technique (P= 0.02). CONCLUSIONS: NO-AVB is a frequent complication following SU-AVR, and its incidence strongly depends on the surgical technique. Baseline first-degree AVB and LaQD independently predict NO-AVB and should be considered when deciding the duration of postoperative electrocardiographic monitoring.

Adipo/cytokines in atherosclerotic secretomes: increased visfatin levels in unstable carotid plaque.

BACKGROUND: Novel pro-inflammatory and anti-inflammatory derivatives from adipose tissue, known as adipokines, act as metabolic factors. The aim of this study was to analyse the secreted expression of different adipo/cytokines in secretomes of unstable carotid atherosclerotic plaque versus non-atherosclerotic mammary artery. METHODS: We evaluated the secretion levels of adiponectin, visfatin, lipocalin-2, resistin, IL-6 and TNFR2 by ELISA in human secretomes from cultured unstable carotid atherosclerotic plaque (n = 18) and non-atherosclerotic mammary artery (n = 13). We also measured visfatin serum levels in patients suffering from atherosclerosis and in a serum cohort of healthy subjects (n = 16). RESULTS: We found that visfatin levels were significantly increased in unstable carotid atherosclerotic plaque secretome than in non-atherosclerotic mammary artery secretome. No differences were found with regard the other adipo/cytokines studied. Regarding visfatin circulating levels, there were no differences between unstable carotid atherosclerotic plaque and non-atherosclerotic mammary artery group. However, these visfatin levels were increased in comparison to serum cohort of healthy subjects. CONCLUSIONS: Of all the adipo/cytokines analysed, only visfatin showed increased levels in secretomes of unstable carotid atherosclerotic plaque. Additional human studies are needed to clarify the possible role of visfatin as prognostic factor of unstable carotid atherosclerotic plaque.

First-in-man Safety and Efficacy of the Adipose Graft Transposition Procedure (AGTP) in Patients With a Myocardial Scar.

BACKGROUND: The present study evaluates the safety and efficacy of the Adipose Graft Transposition Procedure (AGTP) as a biological regenerative innovation for patients with a chronic myocardial scar. METHODS: This prospective, randomized single-center controlled study included 10 patients with established chronic transmural myocardial scars. Candidates for myocardial revascularization were randomly allocated into two treatment groups. In the control arm (n=5), the revascularizable area was treated with CABG and the non-revascularizable area was left untouched. Patients in the AGTP-treated arm (n=5) were treated with CABG and the non-revascularizable area was covered by a biological adipose graft. The primary endpoint was the appearance of adverse effects derived from the procedure including hospital admissions and death, and 24-hour Holter monitoring arrhythmias at baseline, 1week, and 3 and 12months. Secondary endpoints of efficacy were assessed by cardiac MRI. FINDINGS: No differences in safety were observed between groups in terms of clinical or arrhythmic events. On follow-up MRI testing, participants in the AGTP-treated arm showed a borderline smaller left ventricular end systolic volume (LVESV; p=0.09) and necrosis ratio (p=0.06) at 3months but not at 12months. The AGTP-treated patient with the largest necrotic area and most dilated chambers experienced a noted improvement in necrotic mass size (-10.8%), and ventricular volumes (LVEDV: -55.2mL and LVESV: -37.8mL at one year follow-up) after inferior AGTP. INTERPRETATION: Our results indicate that AGTP is safe and may be efficacious in selected patients. Further studies are needed to assess its clinical value. (ClinicalTrials.org NCT01473433, AdiFlap Trial).

Proteomic Profile of Unstable Atheroma Plaque: Increased Neutrophil Defensin 1, Clusterin, and Apolipoprotein E Levels in Carotid Secretome.

Because of the clinical significance of carotid atherosclerosis, the search for novel biomarkers has become a priority. The aim of the present study was to compare the protein secretion profile of the carotid atherosclerotic plaque (CAP, n = 12) and nonatherosclerotic mammary artery (MA, n = 10) secretomes. We used a nontargeted proteomic approach that incorporated tandem immunoaffinity depletion, iTRAQ labeling, and nanoflow liquid chromatography coupled to high-resolution mass spectrometry. In total, 162 proteins were quantified, of which 25 showed statistically significant differences in secretome levels between carotid atherosclerotic plaque and nondiseased mammary artery. We found increased levels of neutrophil defensin 1, apolipoprotein E, clusterin, and zinc-alpha-2-glycoprotein in CAP secretomes. Results were validated by ELISA assays. Also, differentially secreted proteins are involved in pathways such as focal adhesion and leukocyte transendothelial migration. In conclusion, this study provides a subset of identified proteins that are differently expressed in secretomes of clinical significance.

First experience with a new negative pressure incision management system on surgical incisions after cardiac surgery in high risk patients.

BACKGROUND: Sternal wound infection remains a serious potential complication after cardiac surgery. A recent development for preventing wound complications after surgery is the adjunctive treatment of closed incisions with negative pressure wound therapy. Suggested mechanisms of preventive action are improving the local blood flow, removing fluids and components in these fluids, helping keep the incision edges together, protecting the wound from external contamination and promoting incision healing. This work reports on our initial evaluation and clinical experience with the Prevena™Incision Management System, a recently introduced new negative pressure wound therapy system specifically developed for treating closed surgical incisions and helping prevent potential complications. We evaluated the new treatment on sternal surgical incisions in patients with multiple co-morbidities and consequently a high risk for wound complications. METHODS: The Prevena™incision management system was used in 10 patients with a mean Fowler risk score of 15.1 [Range 8-30]. The negative pressure dressing was applied immediately after surgery and left in place for 5 days with a continuous application of -125 mmHg negative pressure. Wounds and surrounding skin were inspected immediately after removal of the Prevena™ incision management system and at day 30 after surgery. RESULTS: Wounds and surrounding skin showed complete wound healing with the absence of skin lesions due to the negative pressure after removal of the Prevena™ dressing. No device-related complications were observed. No wound complications occurred in this high risk group of patients until at least 30 days after surgery. CONCLUSIONS: The Prevena™system appears to be safe, easy to use and may help achieve uncomplicated wound healing in patients at risk of developing wound complications after cardiothoracic surgery.

Is early antithrombotic therapy necessary after tissue mitral valve replacement?

BACKGROUND AND AIM OF THE STUDY: Patients with prosthetic heart valves have a higher risk of developing valve thrombosis and arterial thromboembolism. Antithrombotic therapy during the early postoperative period after biologic mitral valve replacement (MVR) is controversial. Hence, a retrospective study was conducted to investigate the efficacy of different antithrombotic therapies in patients after MVR with bioprostheses. METHODS: Between January 2000 and January 2006, a total of 99 patients presenting with preoperative sinus rhythm underwent isolated bioprosthetic MVR. Of these patients, 59 (58%) received a bovine pericardial xenograft, and 40 (42%) a porcine bioprosthesis. The postoperative antithrombotic therapy was prescribed according to the surgeon's preference. RESULTS: Fifty-one (51%) patients received acetylsalicylic acid (ASA group, 100 mg/day), 12 (13%) did not receive any specific antithrombotic therapy (NT group), and 36 (36%) received a vitamin K antagonist (VKA group, INR 2-3). The primary endpoints were the rate of cerebral ischemic events, bleeding events, and survival. The mean follow up was 23 months (range: 3-68 months). There were five early deaths (5%), and eight late deaths (8%). There were five episodes of cerebral ischemic events; these included three patients (8.3%) in the VKA group, one patient (2.0%) in ASA group, and one patient (8.3%) in the NT group (p = 0.351). Of these episodes, two occurred between 24 h and three months after surgery. Only one (2.8%) episode of major bleeding occurred (in the VKA group), due to poor anticoagulation management. CONCLUSION: Each of the antithrombotic therapies evaluated appeared to be safe. There was no evidence to suggest that any specific antithrombotic therapy would be superior in preventing valve thrombosis in patients undergoing bioprosthetic MVR.

Critical stenosis of pulmonary homograft induced by Surgicel in Ross procedure.

Surgicel is bio-absorbable cellulose used to control bleeding. A 52-year-old woman with severe aortic valve regurgitation and aortic dilatation underwent the Ross procedure and ascending aortic replacement. After 48 h, she suffered severe hypotension and hypoxemia. Arteriography revealed stenosis of the pulmonary homograft, which required urgent re-intervention. Extrinsic compression of the posterior wall of the homograft due to Surgicel was found.

Aortic valve replacement with minimal extracorporeal circulation versus standard cardiopulmonary bypass.

The purpose of this study was to evaluate the safety and the clinical outcomes of aortic valve replacement (AVR) performed with minimally invasive extracorporeal circulation (miniECC) technique vs. standard cardiopulmonary bypass (CPB). From February 2006 to December 2007 a total of 181 isolated AVR were performed, of these 53 patients were operated using minimal extracorporeal circulation system and 128 patients were operated using the standard CPB. Demographic characteristics and operative data were similar in both groups except for EuroSCORE (P<0.0001). Operative mortality (<30 days) was 3.8% for miniECC group and 4.7% for CPB group (P=ns). Patients in both groups showed similar postoperative chest tube drainage (432+/-325 ml vs. 460+/-331 ml, P=ns). The percentage of transfused patients was similar in both groups (37.7% vs. 43.8%, P=0.45). The number of transfused blood bank products was higher in patients with a body surface area >1.7 m(2) and who underwent traditional CPB in respect to miniECC system. Postoperatively renal injury, atrial fibrillation episodes, neurologic event rate, ICU and hospital stay length were similar in both groups. The miniECC is suitable for AVR providing good clinical results but the present results should not identify the miniECC system to be superior to the conventional CPB.