Reproducing extracellular matrix adverse remodelling of non-ST myocardial infarction in a large animal model.

The rising incidence of non-ST-segment elevation myocardial infarction (NSTEMI) and associated long-term high mortality constitutes an urgent clinical issue. Unfortunately, the study of possible interventions to treat this pathology lacks a reproducible pre-clinical model. Indeed, currently adopted small and large animal models of MI mimic only full-thickness, ST-segment-elevation (STEMI) infarcts, and hence cater only for an investigation into therapeutics and interventions directed at this subset of MI. Thus, we develop an ovine model of NSTEMI by ligating the myocardial muscle at precise intervals parallel to the left anterior descending coronary artery. Upon histological and functional investigation to validate the proposed model and comparison with STEMI full ligation model, RNA-seq and proteomics show the distinctive features of post-NSTEMI tissue remodelling. Transcriptome and proteome-derived pathway analyses at acute (7 days) and late (28 days) post-NSTEMI pinpoint specific alterations in cardiac post-ischaemic extracellular matrix. Together with the rise of well-known markers of inflammation and fibrosis, NSTEMI ischaemic regions show distinctive patterns of complex galactosylated and sialylated N-glycans in cellular membranes and extracellular matrix. Identifying such changes in molecular moieties accessible to infusible and intra-myocardial injectable drugs sheds light on developing targeted pharmacological solutions to contrast adverse fibrotic remodelling.

Elastin-like recombinamers-based hydrogel modulates post-ischemic remodeling in a non-transmural myocardial infarction in sheep.

Ischemic heart disease is a leading cause of mortality due to irreversible damage to cardiac muscle. Inspired by the post-ischemic microenvironment, we devised an extracellular matrix (ECM)-mimicking hydrogel using catalyst-free click chemistry covalent bonding between two elastin-like recombinamers (ELRs). The resulting customized hydrogel included functional domains for cell adhesion and protease cleavage sites, sensitive to cleavage by matrix metalloproteases overexpressed after myocardial infarction (MI). The scaffold permitted stromal cell invasion and endothelial cell sprouting in vitro. The incidence of non-transmural infarcts has increased clinically over the past decade, and there is currently no treatment preventing further functional deterioration in the infarcted areas. Here, we have developed a clinically relevant ovine model of non-transmural infarcts induced by multiple suture ligations. Intramyocardial injections of the degradable ELRs-hydrogel led to complete functional recovery of ejection fraction 21 days after the intervention. We observed less fibrosis and more angiogenesis in the ELRs-hydrogel-treated ischemic core region compared to the untreated animals, as validated by the expression, proteomic, glycomic, and histological analyses. These findings were accompanied by enhanced preservation of GATA4+ cardiomyocytes in the border zone of the infarct. We propose that our customized ECM favors cardiomyocyte preservation in the border zone by modulating the ischemic core and a marked functional recovery. The functional benefits obtained by the timely injection of the ELRs-hydrogel in a clinically relevant MI model support the potential utility of this treatment for further clinical translation.

The use of neutrophil lymphocyte ratio to predict complications post cardiac surgery.

BACKGROUND: Cardiac surgery remains the gold standard treatment for select cohorts of patients with coronary artery and valvular heart diseases. It induces an acute systemic inflammatory response due to cardiopulmonary bypass (CPB), myocardial arrest, and surgical trauma. There is growing evidence that increased inflammation leads to greater complications and poorer outcomes for patients post cardiac surgery. Neutrophil/lymphocyte ratio (NLR) is a promising marker of inflammation. This study assessed if NLR could predict postoperative atrial fibrillation and acute kidney injury after cardiac surgery. METHODS: A retrospective review of patients undergoing first-time on-pump cardiac surgery was performed. Postoperative atrial fibrillation and acute kidney injury within 7 days of surgery was recorded. Preoperative, day 1, and day 2 NLR were recorded. Potential confounders such as age, sex, comorbidities, and operative factors were included in univariate analysis. Backwards stepwise multivariate regression analysis was performed to identify independent predictors of these complications. RESULTS: Nine hundred and six patients were included for analysis. Higher preoperative NLR was significantly associated with postoperative atrial fibrillation. Day 1 and day 2 NLR were associated with postoperative atrial fibrillation in analyses including all patients. Older age, male gender, preexisting atrial arrhythmias, and higher EuroSCORE II also had a significant association. Diabetes mellitus was protective for postoperative arrhythmias. Preoperative NLR was not significantly associated with acute kidney injury. Day 2 NLR, older age, higher EuroSCORE II, and longer CPB time were independently associated with acute kidney injury post cardiac surgery. CONCLUSIONS: Higher preoperative and postoperative NLRs are associated with higher rates of complications post cardiac surgery.

Transcatheter Aortic Valve Implantation in a Nonagenarian with Aortic Aneurysm: Futility or Utility?

Transcatheter aortic valve implantation (TAVI) has emerged as the standard of care for older patients with symptomatic severe aortic stenosis (AS) at high or excessive operative risk. There remain patients that are of such considerable risk that even TAVI can be futile. Such patients present ethical conundrums for institutional heart teams. Herein we present a case of a 90-year-old female patient with symptomatic severe AS and significant comorbidities including diffuse peripheral vascular disease and a large ascending aortic aneurysm. Would TAVI be utile or futile in this patient?

Rationale and design of the Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR trial): A randomized multicenter controlled event-driven trial.

Aortic valve replacement (AVR) therapy is an obvious choice for symptomatic severe aortic stenosis (AS) patients as it improves symptoms, left ventricular function, and survival. The treatment decisions and indication for AVR in asymptomatic patients with severe AS and normal left ventricular ejection fraction are less well established and the subject of ongoing debate. Many efforts have been made to define the best treatment option in asymptomatic AS patients with normal left ventricular ejection fraction. Retrospective and observational data imply that elective AVR for asymptomatic severe AS may lead to improvement in outcomes in comparison to surgery performed after onset of symptoms. The AVATAR trial will aim to assess outcomes among asymptomatic AS patients randomized to either elective early AVR or medical management with vigilant follow-up. In the latter group, AVR would be delayed until either the onset of symptoms or changes in predefined echocardiographic parameters. To the best of the authors' knowledge, it will be the first large prospective, randomized, controlled, multicenter clinical trial that will evaluate the safety and efficacy of elective AVR in this specific group of patients.

A biomimetic hyperbranched poly(amino ester)-based nanocomposite as a tunable bone adhesive for sternal closure.

A novel mussel-inspired adhesive can bond well to the surface of wet bone and be programmed to set in a suitable manner for sternal closure applications. With good wet adhesion properties, low exothermic properties, biodegradability and low toxicity, we believe that this technology, which can be further built upon and modified, will endow intriguing potential for sternal closure.

Cardiac papillary fibroelastoma presenting as acute stroke.

We present a case of a young woman who was initially diagnosed with acute stroke with no obvious risk factors. Preliminary investigation with transthoracic echocardiography and subsequent advanced imaging with transoesophageal echocardiography suggested the diagnosis of a benign cardiac tumour on the anterior leaflet of mitral valve. The patient underwent urgent surgical resection. Histology confirmed the diagnosis of cardiac papillary fibroelastoma. She made complete clinical recovery with no recurrence of symptoms.

Surgical coronary revascularization in severe left ventricular dysfunction.

Surgical revascularization in patients with coronary artery disease and severe left ventricular dysfunction is a common practice and poses a surgical challenge. From September 2002 to May 2004, 50 patients (47 men and 3 women; mean age, 59 +/- 9 years) with a mean preoperative ejection fraction of 19.7% +/- 3.2% underwent surgical revascularization. The mean EuroSCORE was 7.2 +/- 3.4. Indications for surgery were congestive heart failure in 8 patients (16%), angina in 20 (40%), ventricular arrhythmias in 4 (8%), and critical left main stem disease in 12 (24%). Twenty-two patients (44%) had emergency surgery for critical anatomy and unstable symptoms. The number of grafts per patient was 3.7 +/- 0.8. Seventeen patients (34%) required intra-aortic balloon pump support, 16 (32%) needed pacing, and 48 (96%) had inotropic support postoperatively. Morbidity included re-operation for bleeding (2%), acute renal failure (10%), hemodialysis (4%), and fatal multiorgan failure (4%). Postoperative (4.9 +/- 3.7 months) 2-dimentional echocardiography was available in 18 patients of whom 11 (61%) showed improved left ventricular function (range, 5% to 45%). Thirty-day hospital mortality was 8%. These data indicate that surgical revascularization can be performed safely with acceptable hospital mortality in high-risk patients with severe left ventricular dysfunction.

Acetylcholine attenuates cardiomyocyte oxidant stress during simulated ischemia and reoxygenation.

We wanted to determine whether oxygen radicals open the mitochondrial ATP-dependent potassium channels (K(ATP)) during an ischemic period to reduce cell death and oxidant stress. Chick embryonic cardiomyocytes were used. Cell viability was quantified with propidium iodide (5 microM), and free radicals was measured using 2',7'-dichlorofluorescein diacetate. Preconditioning was produced by 10 min of simulated ischemia followed by 10 min of reoxygenation. Acetylcholine (1 mM), infused for 10 min instead of preconditioning, reduced cell death similarly (24 +/- 5%, n = 7 and 18 +/- 2%, n = 7, respectively, vs. controls, 49 +/- 6%, n = 8). In control series, 60 min of simulated ischemia and 3 h of reoxygenation generated free radicals more than 300% above the baseline (ischemia: 3.63 +/- 0.58, reoxygenation: 3.66 +/- 0.47, n = 8). Preconditioning and acetylcholine markedly attenuated the oxidant stress during simulated ischemia (1.18 +/- 0.41, n = 6 and 1.34 +/- 0.60, n = 7 vs. controls 3.63 +/- 0.58, n = 8) and re-oxygenation (1.23 +/- 0.36, n = 6 and 1.50 +/- 0.59, n = 7 vs. controls 3.66 +/- 0.47, n = 8). The protection of acetylcholine was abolished with pretreatment with the antioxidant thiol reductant 2-mercaptopropionyl glycine and posttreatment with 5-hydroxydecanoate, a selective mitochondrial K(ATP) channel antagonist (37 +/- 7%, n = 7). These results demonstrate that oxygen radicals open mitochondrial K(ATP) channels, which mediates the acetylcholine-induced preconditioning effect, and that stimulation of this signaling pathway attenuates oxidant stress.