MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs.

Prompt coronary catheterization and revascularization have markedly improved the outcomes of myocardial infarction, but have also resulted in a growing number of surviving patients with permanent structural damage of the heart, which frequently leads to heart failure. There is an unmet clinical need for treatments for this condition1, particularly given the inability of cardiomyocytes to replicate and thereby regenerate the lost contractile tissue2. Here we show that expression of human microRNA-199a in infarcted pig hearts can stimulate cardiac repair. One month after myocardial infarction and delivery of this microRNA through an adeno-associated viral vector, treated animals showed marked improvements in both global and regional contractility, increased muscle mass and reduced scar size. These functional and morphological findings correlated with cardiomyocyte de-differentiation and proliferation. However, subsequent persistent and uncontrolled expression of the microRNA resulted in sudden arrhythmic death of most of the treated pigs. Such events were concurrent with myocardial infiltration of proliferating cells displaying a poorly differentiated myoblastic phenotype. These results show that achieving cardiac repair through the stimulation of endogenous cardiomyocyte proliferation is attainable in large mammals, however dosage of this therapy needs to be tightly controlled.

Ingestible light source for intragastric antibacterial phototherapy: a device safety study on a minipig model.

Helicobacter pylori gastric infections are among the most diffused worldwide, suffering from a rising rate of antibiotic resistance. In this context, some of the authors have previously designed an ingestible device in the form of a luminous capsule to perform antibacterial photodynamic inactivation in the stomach. In this study, the light-emitting capsules were tested to verify the safety of use prior to perform clinical efficacy studies. First, laboratory tests measured the capsule temperature while in function and verified its chemical resistance in conditions mimicking the gastric and gut environments. Second, safety tests in a healthy minipig model were designed and completed, to verify both the capsule integrity and the absence of side effects, associated with its illumination and transit throughout the gastrointestinal tract. To this aim, a capsule administration protocol was defined considering a total of 6 animals with n = 2 treated with 8 capsules, n = 2 treated with 16 capsules and n = 2 controls with no capsule administration. Endoscopies were performed in sedated conditions before-after every capsule administration. Biopsies were taken from the corpus and antrum regions, while the gastric cavity temperature was monitored during illumination. The bench tests confirmed a very good chemical resistance and a moderate (about 3 °C) heating of the capsules. The animal trials showed no significant effects on the gastric wall tissues, both visually and histologically, accompanied with overall good animal tolerance to the treatment. The integrity of the administered capsules was verified as well. These encouraging results pose the basis for the definition of successive trials at the clinical level.

Leptin resistance before and after obesity: evidence that tissue glucose uptake underlies adipocyte enlargement and liver steatosis/steatohepatitis in Zucker rats from early-life stages.

BACKGROUND: Leptin resistance occurs in obese patients, but its independent contribution to adiposity and the accompanying metabolic diseases, i.e., diabetes, liver steatosis, and steatohepatitis, remains to be established. This study was conducted in an extreme model of leptin resistance to investigate mechanisms initiating diabetes, fat expansion, liver steatosis, and inflammatory disease, focusing on the involvement of glucose intolerance and organ-specific glucose uptake in brown and subcutaneous adipose tissues (BAT, SAT) and in the liver. METHODS: We studied preobese and adult Zucker rats (fa/fa, fa/+ ) during fasting or glucose loading to assess glucose tolerance. Relevant pancreatic and intestinal hormonal levels were measured by Milliplex. Imaging of 18F-fluorodeoxyglucose by positron emission tomography was used to quantify glucose uptake in SAT, BAT, and liver, and evaluate its relationship with adipocyte size and biopsy-proven nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). RESULTS: Preobese fa/fa pups showed impaired glucose tolerance, adipocyte enlargement, hepatic microsteatosis, and lobular inflammation, with elevated hepatic post-glucose load glucose uptake and production. Adult fa/fa rats had more severe glucose intolerance, fasting hyperglycemia, hormonal abnormalities, elevated glucose uptake in SAT and BAT, and more markedly in the liver, together with macrosteatosis, and highly prevalent hepatic inflammation. Organ glucose uptake was proportional to the degree of fat accumulation and tissue inflammation and was able to dissect healthy from NAFLD and NAFLD/NASH livers. Most severe NASH livers showed a decline in glucose uptake and liver enzymes. CONCLUSIONS: In fa/fa Zucker rats, leptin resistance leads to glucose intolerance, mainly due to hepatic glucose overproduction, preceding obesity, and explaining pancreatic and intestinal hormonal changes and fat accumulation in adipocytes and hepatocytes. Our data support the involvement of liver glucose uptake in the pathogenesis of liver inflammatory disease. Its potential as more generalized biomarker or diagnostic approach remains to be established outside of our leptin-receptor-deficient rat model.

Current and emerging drug targets in heart failure treatment.

After initial strategies targeting inotropism and congestion, the neurohormonal interpretative model of heart failure (HF) pathophysiology has set the basis for current pharmacological management of HF, as most of guideline recommended drug classes, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, blunt the activation of detrimental neurohormonal axes, namely sympathetic and renin-angiotensin-aldosterone (RAAS) systems. More recently, sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, combining inhibition of RAAS and potentiation of the counter-regulatory natriuretic peptide system, has been consistently demonstrated to reduce mortality and HF-related hospitalization. A number of novel pharmacological approaches have been tested during the latest years, leading to mixed results. Among them, drugs acting directly at a second messenger level, such as the soluble guanylate cyclase stimulator vericiguat, or other addressing myocardial energetics and mitochondrial function, such as elamipretide or omecamtiv-mecarbil, will likely change the therapeutic management of patients with HF. Sodium glucose cotransporter 2 inhibitors, initially designed for the management of type 2 diabetes mellitus, have been recently demonstrated to improve outcome in HF, although mechanisms of their action on cardiovascular system are yet to be elucidated. Most of these emerging approaches have shifted the therapeutic target from neurohormonal systems to the heart, by improving cardiac contractility, metabolism, fibrosis, inflammation, and remodeling. In the present paper, we review from a pathophysiological perspective current and novel therapeutic strategies in chronic HF.

Post-mortem CMR in a model of sudden death due to myocardial ischemia: validation with connexin-43.

OBJECTIVES: We sought to evaluate the effectiveness of post-mortem cardiac magnetic resonance (PM-CMR) for the identification of myocardial ischemia as cause of sudden cardiac death (SCD) when the time interval between the onset of ischemia and SCD is ≤ 90 min. METHODS: PM-CMR was performed in 8 hearts explanted from pigs with spontaneous death caused by occlusion of the left anterior descending coronary artery: 4 with SCD after ≤ 40 min of coronary occlusion and 4 between 40 and 90 min. PM-CMR included conventional T1 and T2-weighted image and T1, T2, and T2* mapping techniques. Imaging data were compared and validated with immunohistochemical evaluation of the altered proportion and redistribution of phosphorylated versus non-phosphorylated connexin 43 (CX43 and npCX43, respectively), an established molecular marker of myocardial ischemia. RESULTS: At T2-weighted images, the ischemic core was hypointense (core/remote ratio 0.67 ± 0.11) and surrounded by and hyperintense border zone. Compared to remote myocardium, the ischemic core had higher T1 (p = 0.0008), and lower T2 (p = 0.007) and T2* (p = 0.002). Cytoplasmatic npX43 and the npCX43/CX43 ratio were significantly higher in animals deceased > 40 min than in others. CONCLUSION: PM-CMR can reliably detect early signs of myocardial damage induced by ischemia, based on conventional pulse sequences complemented by a novel ad hoc application of quantitative mapping techniques. KEY POINTS: • Post-mortem MRI may help to understand cause of sudden cardiac death. • Post-mortem MRI allows detection of signs of myocardial ischemia as cause of sudden cardiac death within 90 and 40 min following coronary occlusion as demonstrated in a pig model of myocardial ischemia. • Signs of myocardial ischemia using conventional and mapping MRI technique are associated with the immunohistochemical changes of phosphorylated and dephosphorylated connexin-43 which is an established molecular marker of myocardial ischemia.

Selective perfusion of coronary vasculature in preterm sheep: a methodological innovation undermined by unfavourable operation of the foramen ovale.

Antenatal cardiac intervention affords new prospects for hypoplastic left heart syndrome. Its success, however, may come not only from absence of impediments to blood flow but also from a sufficiently developed cardiac wall. Here, we examined the feasibility to perfuse selectively the fetal coronary circulation for treatment with growth promoting agents. Pregnant sheep (94-114 days gestation, term 145 days) were used. An aortic stop-flow procedure was developed for intracoronary access in the nonexposed fetus and human mesenchymal stem cells and their exosomes served as test agents. We found that aortic stop-flow ensures preferential distribution of fluorescent microspheres to the heart. However, intracoronary administration of stem cells or exosomes was detrimental, with fetal demise occurring around surgery or at variable intervals afterwards. Coincidentally, stop-flow caused by itself a marked rise of intraluminal pressure within the occluded aorta along with histological signs of coronary obstruction. We conclude that it is feasible to perfuse selectively the coronary circulation of the preterm fetus, but treatments are not compatible with survival of the animals. The cause for failure is found in the absence of hemodynamic compensation to stop-flow via a left-to-right shunt. This unexpected event is attributed to a largely membranous foramen ovale, characteristic of sheep, that collapses under pressure.

New cardiac expression of two adenosine-2A receptor isoforms in dysfunctioning minipigs.

PURPOSE: Eight A2AR variants are reported in humans while no A2AR isoforms in pigs. The aim of this study was to evaluate potential isoforms presence in cardiac pig tissue to better define possible involvement of A2AR in the cardiovascular pathophysiology. MATERIALS AND METHODS: In adult male minipigs (n = 4) left ventricular dysfunction (LVD) was induced by pacing at 200 bpm in the right ventricular (RV) apex. In these animals and in sham operated pigs (C-SHAM, n = 4) cardiac tissue was collected from LV-septal wall (LV-SW)-close to pacing site-and from lateral (opposite) site (LV-OSW). A2AR specific primers, derived from Sus scrofa AY772412 sequence, were used for Real-Time PCR. The DNA was sequenced using the Sanger method. Histological analysis was also performed. RESULTS: In LV-SW of LVD minipigs the A2AR melting curves were characterized by a sharp peak between 87 and 91 °C (short isoform, 1-94 bp) on the right of the principal peak corresponding to a long A2AR isoform (GenBank: JQ229674.1) 1-213 bp. As for C-SHAM only one peak was observed in LV-OSW region of LVD animals. The short isoform had an alternative promoter region and a specific translated protein. Histology showed in LVD-LV-SW prominent Purkinje cells compared to LV-OSW and C-SHAM. No difference in A2AR expression was observed between LVD animals and C-SHAM although a slight decrease was observed in LVD-LV-OSW. CONCLUSIONS: The presence of two different isoforms in the myocardium close to the insertion of pacing is suggestive of a differential state-specific expression of A2AR in cardiac tissue.

Maternal high-fat feeding leads to alterations of brain glucose metabolism in the offspring: positron emission tomography study in a porcine model.

AIMS/HYPOTHESIS: Maternal obesity negatively affects fetal development. Abnormalities in brain glucose metabolism are predictive of metabolic-cognitive disorders. METHODS: We studied the offspring (aged 0, 1, 6, 12 months) of minipigs fed a normal vs high-fat diet (HFD), by positron emission tomography (PET) to measure brain glucose metabolism, and ex vivo assessments of brain insulin receptors (IRß) and GLUT4. RESULTS: At birth, brain glucose metabolism and IRß were twice as high in the offspring of HFD-fed than control mothers. During infancy and youth, brain glucose uptake, GLUT4 and IRß increased in the offspring of control mothers and decreased in those of HFD-fed mothers, leading to a 40-85% difference (p < 0.05), and severe glycogen depletion, lasting until adulthood. CONCLUSIONS/INTERPRETATION: Maternal high-fat feeding leads to brain glucose overexposure during fetal development, followed by long-lasting depression in brain glucose metabolism in minipigs. These features may predispose the offspring to develop metabolic-neurodegenerative diseases.

Altered expression of connexin 43 and related molecular partners in a pig model of left ventricular dysfunction with and without dipyrydamole therapy.

Gap junctions (GJ) mediate electrical coupling between cardiac myocytes, allowing the spreading of the electrical wave responsible for synchronized contraction. GJ function can be regulated by modulation of connexon densities on membranes, connexin (Cx) phosphorylation, trafficking and degradation. Recent studies have shown that adenosine (A) involves Cx43 turnover in A1 receptor-dependent manner, and dipyridamole increases GJ coupling and amount of Cx43 in endothelial cells. As the abnormalities in GJ organization and regulation have been described in diseased myocardium, the aim of the present study was to assess the regional expression of molecules involved in GJ regulation in a model of left ventricular dysfunction (LVD). For this purpose the distribution and quantitative expression of Cx43, its phosphorylated form pS368-Cx43, PKC phosphorylated substrates, RhoA and A receptors, were investigated in experimental models of right ventricular-pacing induced LVD, undergoing concomitant dipyridamole therapy or placebo, and compared with those obtained in the myocardium from sham-operated minipigs. Results demonstrate that an altered pattern of factors involved in Cx43-made GJ regulation is present in myocardium of a dysfunctioning left ventricle. Furthermore, dipyridamole treatment, which shows a mild protective role on left ventricular function, seems to act through modulating the expression and activation of these factors as confirmed by in vitro experiments on cardiomyoblastic cell line H9c2 cells.

Design, synthesis and preliminary evaluation of (18)F-labelled 1,8-naphthyridin- and quinolin-2-one-3-carboxamide derivatives for PET imaging of CB2 cannabinoid receptor.

In the present work, we report the synthesis of new aryliodonium salts used as precursors of single-stage nucleophilic (18)F radiofluorination. The corresponding unlabelled fluorinated derivatives showed to be CB2 cannabinoid receptor specific ligands, with Ki values in the low nanomolar range and high CB2/CB1 selectivity. The radiolabelled compound [(18)F]CB91, was successfully formulated for in vivo administration, and its preliminary biodistribution was assessed with microPET/CT. This tracer presented a reasonable in vivo stability and a preferential extraction in the tissues that constitutionally express CB2 cannabinoid receptor. The results obtained indicate [(18)F]CB91 as a possible candidate marker of CB2 cannabinoid receptor distribution. This study would open the way to further validation of this tracer for assessing pathologies for which the expression of this receptor is modified.

Independent effects of circulating glucose, insulin and NEFA on cardiac triacylglycerol accumulation and myocardial insulin resistance in a swine model.

AIMS/HYPOTHESIS: Cardiac steatosis and myocardial insulin resistance elevate the risk of cardiac complications in obesity and diabetes. We aimed to disentangle the effects of circulating glucose, insulin and NEFA on myocardial triacylglycerol (TG) content and myocardial glucose uptake. METHODS: Twenty-two pigs were stratified according to four protocols: low NEFA + low insulin (nicotinic acid), high NEFA + low insulin (fasting) and high insulin + low NEFA ± high glucose (hyperinsulinaemia-hyperglycaemia or hyperinsulinaemia-euglycaemia). Positron emission tomography, [U-(13)C]palmitate enrichment techniques and tissue biopsies were used to assess myocardial metabolism. Heart rate and rate-pressure product (RPP) were monitored. RESULTS: Myocardial glucose extraction was increased by NEFA suppression and was similar in the hyperinsulinaemia-hypergylcaemia, hyperinsulinaemia-euglycaemia and nicotinic acid groups. Hyperglycaemia enhanced myocardial glucose uptake due to a mass action. Myocardial TG content was greatest in the fasting group, whereas hyperinsulinaemia had a mild effect. Heart rate and RPP increased in hyperinsulinaemia-euglycaemia, in which cardiac glycogen content was reduced. Heart rate correlated with myocardial TG and glycogen content. CONCLUSIONS/INTERPRETATION: Elevated NEFA levels represent a powerful, self-sufficient promoter of cardiac TG accumulation and are a downregulator of myocardial glucose uptake, indicating that the focus of treatment should be to 'normalise' adipose tissue function to lower the risk of cardiac TG accumulation and myocardial insulin resistance. The observation that hyperinsulinaemia and nicotinic acid led to myocardial fuel deprivation provides a potential explanation for the cardiovascular outcomes reported in recent intensive glucose-lowering and NEFA-lowering clinical trials.

Prevention of excessive endothelin-1 release in sclerotherapy: in vitro and in vivo studies.

BACKGROUND: The foam sclerotherapy technique has become one of the most commonly used treatments for superficial venous insufficiency. Despite excellent results, few visual/neurologic disturbances have been recently reported; their pathogenesis is still debated but a correlation with endothelin-1 (ET-1) release from the treated vein has been proposed. OBJECTIVE: The purpose of this work was to evaluate the ET-1 release after sclerotherapy and to investigate the effects of the anti-endothelin drug aminaphtone. METHODS AND MATERIALS: As in vitro sclerotherapy model, an endothelial cell culture, mimicking vascular endothelium, was pretreated with aminaphtone and exposed to detergents. Cell survival and ET-1 release were measured. In in vivo experiments, 45 rats, fed with different aminaphtone-rich diets, were subjected to sclerotherapy, and the systemic ET-1 was measured. RESULTS: Aminaphtone cell exposure caused a statistically significant reduction in ET-1 release, both before and after in vitro sclerotherapy. Rats fed with aminaphtone showed a trend toward reduced mortality and a significant decrease of ET-1 release after sclerotherapy. CONCLUSION: This is the first study in which an anti-endothelin agent was able to cause a significant reduction of ET-1 release during sclerotherapy. Although clinical studies are required, these findings might advocate the use of anti-endothelin agents in prophylaxis of neurologic or visual disturbances after sclerotherapy.

An autologously generated platelet-rich plasma suturable membrane may enhance peripheral nerve regeneration after neurorraphy in an acute injury model of sciatic nerve neurotmesis.

BACKGROUND: The aim of this study was to investigate the ability of suturable platelet-rich plasma (PRP) membrane to promote peripheral nerve regeneration after neurotmesis and neurorraphy. METHODS: A total of 36 rats were used: 32 animals underwent surgery and were split in two groups. An interim sacrifice was performed at 6 weeks postsurgery and final sacrifice at 12 weeks; four animals did not sustain nerve injury and served as control. Clinical, electromyographic (EMG), gross, and histological changes were assessed. The EMG signal was evaluated for its amplitude and frequency spectrum. Number of regenerating fibers, their diameter, and myelin thickness were histologically analyzed. RESULTS: Both EMG parameters showed a significant (p < 0.05) effect of treatment at 6 and 12 weeks postsurgery. At 6 weeks, the fiber density was statistically different between treated and untreated animals with a higher observed density in treated nerves. No difference in fiber density was observed at 12 weeks postsurgery. The distribution of fiber diameters showed an effect at 12 weeks when only the sections of the nerves sutured with PRP showed fibers with diameters greater than 6 µm. DISCUSSION: Our data show that the application of a PRP fibrin membrane around the neurorraphy improves the nerve regeneration process in a rat sciatic nerve model. The use of PRP as a suturable membrane could perform an action not only as a source of bioactive proteins but also as a nerve guide to hold the scar reaction and thus improve axonal regeneration.

Effects of sacubitril-valsartan on remodelling, fibrosis and mitochondria in a murine model of isoproterenol-induced left ventricular dysfunction.

BACKGROUND: Sacubitril/valsartan has been demonstrated to promote left ventricular (LV) reverse remodelling and improve outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Its molecular and tissue effects have not been fully elucidated yet, due to the paucity of preclinical studies, mostly based on ischaemic models. We aimed to evaluate the effects of sacubitril/valsartan on LV remodelling, myocardial fibrosis and mitochondrial biology in a murine model of non-ischaemic LV dysfunction. METHODS: Adult transgenic male mice with cardiac-specific hyperaldosteronism (AS mice) received subcutaneous isoproterenol injections to induce LV systolic dysfunction. After 7 days, mice were randomized to a 2-week treatment with saline (ISO-AS n = 15), valsartan (ISO + V n = 12) or sacubitril/valsartan (ISO + S/V n = 12). Echocardiography was performed at baseline, at day 7, and after each of the 2 weeks of treatment. After sacrifice at day 21, histological and immunochemical assays were performed. A control group of AS mice was also obtained (Ctrl-AS n = 8). RESULTS: Treatment with sacubitril/valsartan, but not with valsartan, induced a significant improvement in LVEF (p = 0.009 vs ISO-AS) and fractional shortening (p = 0.032 vs ISO-AS) after 2- week treatment. In both ISO + V and ISO + S/V groups, a trend toward reduction of the cardiac collagen 1/3 expression ratio was detected. ISO + V and ISO + S/V groups showed a significant recovery of mitochondrial morphology and inner membrane function meant for oxidative phosphorylation. CONCLUSION: In a murine model of non-ischaemic HF, sacubitril/valsartan proved to have beneficial effects on LV systolic function, and on cardiac energetics, by improving mitochondrial activity.

Effects of pirfenidone on scar size and ventricular remodeling after myocardial infarction: a preclinical study.

BACKGROUND: An intense fibrotic response after myocardial infarction (MI) may lead to scar expansion and left ventricular (LV) remodeling. We investigated the effects of the antifibrotic drug pirfenidone in this setting. METHODS: Male Wistar rats were randomized to: sham procedure (n = 13), reperfused MI-induced by ligating the left anterior descending artery (LAD) for 45 min (n = 17), reperfused MI plus standard therapy (aspirin, angiotensin-converting enzyme inhibitor, beta blocker, and mineralocorticoid receptor antagonist) (n = 17), reperfused MI plus pirfenidone alone (n = 17), or reperfused MI plus standard therapy and pirfenidone (n = 17). Rats surviving MI induction underwent cardiac magnetic resonance scans after 72 h and 30 days from MI, and were sacrificed on day 31. RESULTS: Rats completing the whole protocol numbered 11 in the sham group, 9 in the untreated MI group, 8 in the standard treatment group, 9 in the pirfenidone alone group, and 9 in the standard treatment plus pirfenidone group. No significant differences emerged between LV volumes, ejection fraction or mass at 30 days or the differences from 72 h to 30 days. Small, nonsignificant differences between rats on pirfenidone alone vs. those on standard therapy emerged. The total extent of LV fibrosis, quantified as area and percentage of the tissue sample, did not differ significantly between rats on pirfenidone alone vs. those on standard therapy alone. CONCLUSION: Pirfenidone does not have additional effects on LV remodeling or fibrosis compared with standard therapy, but its effects are similar to standard therapy alone.

Developmental variations of plasma gamma-glutamyltransferase fractions in humans and in laboratory mammalians.

Plasma samples from human cord blood, and fetuses, newborns, and adults of different mammalians species were analyzed by gel-filtration chromatography, to ascertain whether gamma-glutamyltransferase (GGT) fractions reflect liver maturation. Human cord blood plasma showed higher b-, m-, and s-GGT fraction as compared to adult women. In rat and mouse fetuses and in newborns, b-GGT was the most abundant fraction. As in adult humans, in adult rats, mice, rabbits, sheep, and mini pigs, f-GGT was the most abundant fraction. GGT fractions are a common feature of all mammalian species tested. Their pattern changes seem to reflect liver postnatal maturation, function.

Significant endothelin release in patients treated with foam sclerotherapy.

BACKGROUND: Foam sclerotherapy has been proven to be a safe and effective treatment for superficial venous insufficiency, but transient visual and neurologic disturbances continue to be reported. These side effects have been theorized to be related to the presence of air or gases in the sclerosing foam that results in "bubble" migration into the cerebral circulation. We present a differing hypothesis that significant amounts of endothelin are released from the treated veins, amounts capable of causing these complications. MATERIAL AND METHODS: We tested the release of endothelin 1 (ET-1) in 12 rats after sclerotherapy with sodium tetradecyl sulfate (STS) in liquid and foam preparations. In 11 human subjects, we measured ET-1 in systemic circulation and in a draining vein after foam sclerotherapy with polidocanol. RESULTS: Rats treated with STS showed a significant increase in ET-1 levels 1 and 5 minutes after foam sclerotherapy. Patients treated with foam sclerotherapy showed a marked increase in ET-1 levels that correlated significantly with local ET-1 levels. CONCLUSIONS: Evidence of ET-1 release represents a plausible relationship explaining neurologic and visual disturbances reported after sclerotherapy.

The Potential Anti-remodeling Effect of Paroxetine After Myocardial Infarction May Be Blunted by Beta-Blockers.

Background: Left ventricular (LV) remodeling consists in maladaptive changes in cardiac geometry and function following an insult such as ST-segment elevation myocardial infarction (STEMI). Interventions able to prevent LV remodeling after a STEMI are expected to improve the outcome of this condition. Paroxetine has inhibitory effects on GRK2, also known as beta-adrenergic receptor kinase 1 (ADRBK1). This drug does not yield beneficial effects on LV remodeling in patients with STEMI and LV ejection fraction ≤ 45%. Methods: We compared the molecular effects of paroxetine and drugs for neurohormonal antagonism (beta-blockers, angiotensin converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoid receptor antagonists), using a bioinformatic approach integrating transcriptomic data in a swine model of post-MI and available evidence from the literature and massive public databases. Results: Among standard therapies for MI, beta-blockers are the only ones acting directly upon GKR2, but the mechanism of action overlaps with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers with respect to the AT2R-mediated anti-hypertensive response. Moreover, beta-blockers could have anti-fibrotic and anti-inflammatory effects through the regulation of myocyte-specific enhancer factors, endothelins and chemokines. Conclusion: The additive benefit of paroxetine on the background of the standard therapy for STEMI, which includes beta-blockers, is expected to be limited. Nonetheless, paroxetine becomes particularly interesting when a beta-blocker is contraindicated (for example, in hypotensive individuals) or poorly tolerated.

Cardiac protection by pirfenidone after myocardial infarction: a bioinformatic analysis.

Left ventricular (LV) remodeling after myocardial infarction (MI) is promoted by an intense fibrotic response, which could be targeted by the anti-fibrotic drug pirfenidone. We explored the relationship between protein modulation by pirfenidone and post-MI remodeling, based on molecular information and transcriptomic data from a swine model of MI. We identified 6 causative motives of post-MI remodeling (cardiomyocyte cell death, impaired myocyte contractility, extracellular matrix remodeling and fibrosis, hypertrophy, renin-angiotensin-aldosterone system activation, and inflammation), 4 pirfenidone targets and 21 bioflags (indirect effectors). Pirfenidone had a more widespread action than gold-standard drugs, encompassing all 6 motives, with prominent effects on p38γ-MAPK12, the TGFß1-SMAD2/3 pathway and other effector proteins such as matrix metalloproteases 2 and 14, PDGFA/B, and IGF1. A bioinformatic approach allowed to identify several possible mechanisms of action of pirfenidone with beneficial effects in the post-MI LV remodeling, and suggests additional effects over guideline-recommended therapies.

In Vivo Murine Models of Cardiotoxicity Due to Anticancer Drugs: Challenges and Opportunities for Clinical Translation.

Modern therapeutic approaches have led to an improvement in the chances of surviving a diagnosis of cancer. However, this may come with side effects, with patients experiencing adverse cardiovascular events or exacerbation of underlying cardiovascular disease related to their cancer treatment. Rodent models of chemotherapy-induced cardiotoxicity are useful to define pathophysiological mechanisms of cardiac damage and to identify potential therapeutic targets. The key mechanisms involved in cardiotoxicity induced by specific different antineoplastic agents are summarized in this state-of-the-art review, as well as the rodent models of cardiotoxicity by different classes of anticancer drugs, along with the strategies tested for primary and secondary cardioprotection. Current approaches for early detection of cardiotoxicity in preclinical studies with a focus on the application of advanced imaging modalities and biomarker strategies are also discussed. Potential applications of cardiotoxicity modelling in rodents are illustrated in relation to the advancements of promising research topics of cardiotoxicity. Created with BioRender.com.