Daniele Linardi

Myocardial fibrosis (MF) is the excessive deposition of extracellular matrix (ECM) from myofibroblasts and is crucial in patients with heart failure (HF). Much work is still needed to fully understand its features and clinical role. This review aims to summarize the state-of-the-art of MF knowledge, focusing on assessment, quantification, predictive value, and future therapies. We performed a literature search about MF studies published between 2014 and 2024, including clinical studies on MF assessment or quantification, the role of MF as a prognostic factor in patients with HF, basic science studies on fibrosis assessment, and the role of the main mechanisms involved in MF. We identified 5161 potentially relevant articles. After excluding non-appropriate ones, we had 186 potentially suitable studies. After full reading and a review of references, 40 articles were included in our review: 8 were about MF assessment, 5 about quantification, and 27 about fibrosis as a prognostic factor. MF is a crucial process in patients with cardiac diseases and leads to HF and arrhythmias. Assessment and quantification have taken great steps forward, but more research is needed to strengthen MF’s role as a prognostic factor in the future. Basic science will play a key role in anti-fibrosis treatment.

As spontaneous ascending aortic thrombi (AATs) are uncommon in modern clinical practice, despite the application of new technology and the widespread use of contrast-enhanced computer tomography during primary assessments in patients without underlying predisposing conditions, a thrombus floating in the ascending aorta is rarely discovered in a timely manner; moreover, the ascending tract represents an unusual site for thrombus formation. The clinical presentation of AATs is also often in the form of peripheral arterial embolization, which can cause a wide variety of symptoms, from stroke to limb ischemia, and thus delay correct diagnosis. Medical management is a risky strategy, while surgical treatment is usually challenging due to the risk of thrombus dislodgement and difficulties related to prior embolization complication management. In this study, faced with a peculiar case of embolic stroke in an otherwise healthy 71-year-old woman, we analyzed the status of knowledge on spontaneous ascending aortic thrombus treatments and outcomes. A multidisciplinary approach represents the best choice for defining a patient’s timing of surgery and ensuring the management of complications. Sequential multistage treatment minimizes further complications and prevents worsening patient outcomes, leading to the best management for every possible clinical presentation. A less invasive surgical approach could lead to complete resolution of the pathology, avoiding further potentially lethal complications, facilitating postoperative management, avoiding delayed treatments, and resulting in better outcomes.

The treatment of complex aortic pathologies requires specialized techniques and tailored approaches due to each patient’s unique anatomical and clinical challenges. The European Association for Cardiothoracic Surgery (EACTS) and the Society of Thoracic Surgeons (STS) new guidelines identify the aorta as the body’s 24th organ and reiterate that multidisciplinary aortic teams are recommended for shared decision-making to determine optimal treatment strategies. Patients treated for conditions such as aneurysms, dissections, intramural hematomas, or penetrating aortic ulcers may develop complex forms over time, necessitating careful follow-up and timely corrective actions. Endovascular solutions can be favorable for older patients with complex anatomies and multiple comorbidities. However, when endovascular treatment is not feasible, hybrid treatments or open surgery must be considered if the patient’s condition allows it. The risk–benefit ratio of each procedure must be carefully evaluated; choosing the best intervention or deciding not to intervene becomes a critical and challenging decision. At our Cardiac Surgery Center in Verona, a multidisciplinary team with over 20 years of experience in treating complex aortic arch pathologies extensively discussed different cases of complex aortic pathologies treated with endovascular, hybrid, or surgical approaches, emphasizing the importance of considering both anatomical and patient-specific characteristics. The decisions and treatments were often challenging, and unanimity was not always achieved, reflecting the complexity of finding the best solutions.

Penetrating Atherosclerotic Ulcer (PAU) is one of the acute aortic syndromes representing a medical and surgical emergency that could lead to rapid evolution and significant complications. Depending on the aortic section involved in the PAU, the treatment with endovascular prosthesis could be challenging and often requires personalized prosthesis to face anatomical peculiarities. The aortic arch could be one of the most complex locations due to the origin of supra-aortic branches and the need for previous or subsequent carotid-subclavian bypass grafting. The use of scalloped and fenestrated prostheses makes it possible to manage aortic pathology without further vascular surgery.

Endothelial nitric oxide (NO) production is crucial in maintaining vascular homeostasis. However, in the context of ischemia–reperfusion (I/R) injury, uncoupled endothelial nitric oxide synthase (eNOS) can exacerbate reactive oxygen species (ROS) generation. Supplementation with S-nitroso human serum albumin (S-NO-HSA) offers a potential solution by mitigating eNOS uncoupling, thereby enhancing NO bioavailability. In a study conducted at the University of Verona, male rats underwent thoracotomy followed by 30 min left anterior descendant coronary (LAD) occlusion and subsequent reperfusion. Hemodynamic parameters were meticulously assessed using a conductance catheter inserted via the carotid artery. The rats were stratified into two main groups based on reperfusion duration and the timing of drug infusion, with the effects of S-NO-HSA evaluated after 2 or 24 h. Remarkably, intravenous administration of S-NO-HSA, initiated before or during ischemia, exhibited notable benefits. It significantly improved left ventricular function, safeguarded energetic substrates such as phosphocreatine and ATP, and sustained glutathione levels akin to basal conditions, indicative of diminished oxidative stress. The data from this study strongly suggest a protective role for S-NO-HSA in mitigating I/R injury induced by LAD artery occlusion, a phenomenon observed at both 2 and 24 h post-reperfusion. These findings underscore the promising therapeutic potential of NO supplementation in alleviating myocardial damage subsequent to ischemic insult.

Background: Selective antegrade cerebral perfusion (SACP) is adopted as an alternative to deep hypothermic circulatory arrest (DHCA) during aortic arch surgery. However, there is still no preclinical evidence to support the use of SACP associated with moderate hypothermia (28–30°C) instead of DHCA (18–20°C). The present study aims to develop a reliable and reproducible preclinical model of cardiopulmonary bypass (CPB) with SACP applicable for assessing the best temperature management. Materials and methods: A central cannulation through the right jugular vein and the left carotid artery was performed, and CPB was instituted. Animals were randomized into two groups: normothermic circulatory arrest without or with cerebral perfusion (NCA vs SACP). EEG monitoring was maintained during CPB. After 10 min of circulatory arrest, rats underwent 60 min of reperfusion. After that, animals were sacrificed, and brains were collected for histology and molecular biology analysis. Results: Power spectral analysis of the EEG signal showed decreased activity in both cortical regions and lateral thalamus in all rats during the circulatory arrest. Only SACP determined complete recovery of brain activity and higher power spectral signal compared to NCA ( p < 0.05). Histological damage scores and western blot analysis of inflammatory and apoptotic proteins like caspase-3 and Poly-ADP ribose polymerase (PARP) were significantly lower in SACP compared to NCA. Vascular endothelial growth factor (VEGF) and RNA binding protein 3 (RBM3) involved in cell-protection mechanisms were higher in SACP, showing better neuroprotection ( p < 0.05). Conclusions: SACP by cannulation of the left carotid artery guarantees good perfusion of the whole brain in this rat model of CPB with circulatory arrest. The present model of SACP is reliable, repeatable, and not expensive, and it could be used in the future to achieve preclinical evidence for the best temperature management and to define the best cerebral protection strategy during circulatory arrest.

Background: Hypothermic circulatory arrest (HCA) in aortic arch surgery has a significant risk of neurological injury despite the newest protective techniques and strategies. Nitric oxide (NO) could exert a protective role, reduce infarct area and increase cerebral perfusion. This study aims to investigate the possible neuroprotective effects of NO administered in the oxygenator of selective antegrade cerebral perfusion (SCP) during HCA.Methods: Thirty male SD adult rats (450–550 g) underwent cardiopulmonary bypass (CPB), cooling to 22°C body core temperature followed by 30 min of HCA. Rats were randomized to receive SCP or SCP added with NO (20 ppm) administered through the oxygenator (SCP-NO). All animals underwent CPB-assisted rewarming to a target temperature of 35°C in 60 min. At the end of the experiment, rats were sacrificed, and brain collected. Immunofluorescence analysis was performed in blind conditions.Results: Neuroinflammation assessed by allograft inflammatory factor 1 or ionized calcium-binding adapter molecule 1 expression, a microglia activation marker was lower in SCP-NO compared to SCP (4.11 ± 0.59 vs. 6.02 ± 0.18%; p < 0.05). Oxidative stress measured by 8oxodG, was reduced in SCP-NO (0.37 ± 0.01 vs. 1.03 ± 0.16%; p < 0.05). Brain hypoxic area extent, analyzed by thiols oxidation was attenuated in SCP-NO (1.85 ± 0.10 vs. 2.74 ± 0.19%; p < 0.05). Furthermore, the apoptotic marker caspases 3 was significantly reduced in SCP-NO (10.64 ± 0.37 vs. 12.61 ± 0.88%; p < 0.05).Conclusions: Nitric oxide administration in the oxygenator during SCP and HCA improves neuroprotection by decreasing neuroinflammation, optimizing oxygen delivery by reducing oxidative stress and hypoxic areas, finally decreasing apoptosis.

OBJECTIVES: Among the factors that could determine neurological outcome after hypothermic circulatory arrest (HCA) rewarming is rarely considered. The optimal rewarming rate is still unknown. The goal of this study was to investigate the effects of 2 different protocols for rewarming after HCA on neurological outcome in an experimental animal model.METHODS: Forty-four Sprague Dawley rats were cooled to 19 ± 1°C body core temperature by cardiopulmonary bypass (CPB). HCA was maintained for 60 min. Animals were randomized to receive slow (90 min) or fast (45 min) assisted rewarming with CPB to a target temperature of 35°C. After a total of 90 min of reperfusion in both groups, brain samples were collected and analysed immunohistochemically and with immunofluorescence. In 10 rats, magnetic resonance imaging was performed after 2 and after 24 h to investigate cerebral perfusion and cerebral oedema.RESULTS: Interleukin 6, chemokine (C-C motif) ligand 5, intercellular adhesion molecule 1 and tumour necrosis factor α in the hippocampus are significantly less expressed in the slow rewarming group, and microglia cells are significantly less activated in the slow rewarming group. Magnetic resonance imaging analysis demonstrated better cerebral perfusion and less water content in brains that underwent slow rewarming at 2 and 24 h.CONCLUSIONS: Slow rewarming after HCA might be superior to fast rewarming in neurological outcome. The present experimental study demonstrated reduction in the inflammatory response, reduction of inflammatory cell activation in the brain, enhancement of cerebral blood flow and reduction of cerebral oedema when slow rewarming was applied.

Consumption of flavonoid-rich nutraceuticals has been associated with a reduction in coronary events. The present study analyzed the effects of cocoa flavonols on myocardial injury following acute coronary ischemia-reperfusion (I/R). A commercially available cocoa extract was identified by chromatographic mass spectrometry. Nineteen different phenolic compounds were identified and 250 mg of flavan-3-ols (procyanidin) were isolated in 1 g of extract. Oral administration of cocoa extract in incremental doses from 5 mg/kg up to 25 mg/kg daily for 15 days in Sprague Dawley rats (n = 30) produced a corresponding increase of blood serum polyphenols and become constant after 15 mg/kg. Consequently, the selected dose (15 mg/kg) of cocoa extract was administered orally daily for 15 days in a treated group (n = 10) and an untreated group served as control (n = 10). Both groups underwent surgical occlusion of the left anterior descending coronary artery and reperfusion. Cocoa extract treatment significantly reversed membrane peroxidation, nitro-oxidative stress, and decreased inflammatory markers (IL-6 and NF-kB) caused by myocardial I/R injury and enhanced activation of both p-Akt and p-Erk1/2. Daily administration of cocoa extract in rats is protective against myocardial I/R injury and attenuate nitro-oxidative stress, inflammation, and mitigates myocardial apoptosis.