A review of therapeutic approaches for post-infarction left ventricular remodeling.

Left ventricular remodeling is an adaptive process initially developed in response to acute myocardial infarction (AMI), but it ends up with negative adverse outcomes such as infarcted wall thinning, ventricular dilation, and cardiac dysfunction. A prolonged excessive inflammatory reaction to cardiomyocytes death and necrosis plays the crucial role in the pathophysiological mechanisms. The pharmacological treatment includes nitroglycerine, ß-blockers, ACEi/ARBs, SGLT2i, mineralocorticoid receptor antagonists, and some miscellaneous aspects. Stem cells therapy, CD34+ cells transplantation and gene therapy constitute the promissing therapeutic approaches for post AMI cardiac remodeling, thereby enhancing angiogenesis, cardiomyocytes differenciation and left ventricular function on top of inhibiting apoptosis, inflammation, and collagen deposition. All these lead to reduce infarct size, scar formation and myocardial fibrosis.

Mortality rate after coronary revascularization in heart failure patients with coronary artery disease.

AIMS: Coronary artery disease (CAD) is a common cause of heart failure (HF). It remains unclear who, when and why to direct towards coronary revascularization. The outcomes of coronary revascularization in HF patients are still a matter of debate nowadays. This study aims to evaluate the effect of revascularization strategy on all-cause of death in the context of ischaemic HF. METHODS AND RESULTS: An observational cohort was conducted on 692 consecutive patients who underwent coronary angiography at the University Hospital of Toulouse between January 2018 and December 2021 for either a recent diagnosis of HF or a decompensated chronic HF, and in whom coronary angiograms showed at least 50% obstructive coronary lesion. The study population was divided into two groups according to the performance or not of a coronary revascularization procedure. The living status (alive or dead) of each of the study's participants was observed by April 2022. Seventy-three per cent of the study population underwent coronary revascularization either by percutaneous coronary intervention (66.6%) or coronary artery bypass grafting (6.2%). Baseline characteristics including age, sex and cardiovascular risk factors did not differ between the invasive and conservative groups, respectively. Death occurred in 162 study participants resulting in an all-cause mortality rate of 23.5%; 26.7% of observed deaths have occurred in the conservative group versus 22.2% in the invasive group (P = 0.208). No difference in survival outcomes has been observed over a mean follow-up period of 2.5 years (P = 0.140) even after stratification by HF categories (P = 0.132) or revascularization modalities (P = 0.366). CONCLUSIONS: Findings from the present study showed comparable all-cause mortality rates between groups. Coronary revascularization does not modify short-term survival outcomes in HF patients compared with optimal medical therapy alone outside the setting of acute coronary syndrome.

Spontaneous Coronary Artery Dissection: A Review of Epidemiology, Pathophysiology and Principles of Management.

Spontaneous coronary artery dissection (SCAD) is a sudden rupture of coronary artery wall leading to false lumen and intramural hematoma formation. It commonly occurs in young and middle-aged women lacking typical cardiovascular risk factors. Fibromuscular dysplasia and pregnancy are strongly associated with SCAD. To date, the "inside-out" and "outside-in" are the 2 proposed hypothesis for the pathogenesis of SCAD. Coronary angiography is the gold standard and first line diagnostic test. Three types of SCAD have been described according to coronary angiogram. Intracoronary imaging modalities are reserved for patients with ambiguous diagnosis or to guide percutaneous coronary intervention view the increased risk of secondary iatrogenic dissection. The management of SCAD includes conservative approach, coronary revascularization strategies accounting for percutaneous coronary intervention and coronary artery bypass graft, and long-term follow-up. The overall prognosis of patients with SCAD is favorable marked by a spontaneous healing in a large proportion of cases.

Microvascular obstruction identifies a subgroup of patients who benefit from stem cell therapy following ST-elevation myocardial infarction.

BACKGROUND: Microvascular obstruction (MVO) is associated with greater infarct size, adverse left-ventricular (LV) remodeling and reduced ejection fraction following ST-elevation myocardial infarction (STEMI). We hypothesized that patients with MVO may constitute a subgroup of patients that would benefit from intracoronary stem cell delivery with bone marrow mononuclear cells (BMCs) given previous findings that BMCs tended to improve LV function only in patients with significant LV dysfunction. METHODS AND RESULTS: We analyzed the cardiac MRIs of 356 patients (303 M, 53 F) with anterior STEMIs who received autologous BMCs or placebo / control as part of 4 randomized clinical trials that included the Cardiovascular Cell Therapy Research Network (CCTRN) TIME trial and its pilot, the multicenter French BONAMI trial and SWISS-AMI trials. A total of 327 patients had paired imaging data at 1 year. All patients received 100 to 150 million intracoronary autologous BMCs or placebo / control 3 to 7 days following primary PCI and stenting. LV function, volumes, infarct size and MVO were assessed prior to infusion of BMCs and 1 year later. Patients with MVO (n = 210) had reduced LVEF and much greater infarct size and LV volumes compared to patients without MVO (n = 146) (P < .01). At 12 months, patients with MVO who received BMCs had significantly greater recovery of LVEF compared to those patients with MVO who received placebo (absolute difference = 2.7%; P < .05). Similarly, left-ventricular end-diastolic (LVEDVI) and end-systolic volume indices (LVESVI) demonstrated significantly less adverse remodeling in patients with MVO who received BMCs compared to placebo. In contrast, no improvement in LVEF or LV volumes was observed in those patients without MVO who received BMCs compared to placebo. CONCLUSIONS: The presence of MVO on cardiac MRI following STEMI identifies a subgroup of patients who benefit from intracoronary stem cell therapy.

Pre-Conditioning Methods and Novel Approaches with Mesenchymal Stem Cells Therapy in Cardiovascular Disease.

Transplantation of mesenchymal stem cells (MSCs) in the setting of cardiovascular disease, such as heart failure, cardiomyopathy and ischemic heart disease, has been associated with good clinical outcomes in several trials. A reduction in left ventricular remodeling, myocardial fibrosis and scar size, an improvement in endothelial dysfunction and prolonged cardiomyocytes survival were reported. The regenerative capacity, in addition to the pro-angiogenic, anti-apoptotic and anti-inflammatory effects represent the main target properties of these cells. Herein, we review the different preconditioning methods of MSCs (hypoxia, chemical and pharmacological agents) and the novel approaches (genetically modified MSCs, MSC-derived exosomes and engineered cardiac patches) suggested to optimize the efficacy of MSC therapy.

Coronary artery aneurysm: A review.

Coronary artery aneurysm (CAA) is a clinical entity defined by a focal enlargement of the coronary artery exceeding the 1.5-fold diameter of the adjacent normal segment. Atherosclerosis is the main cause in adults and Kawasaki disease in children. CAA is a silent progressive disorder incidentally detected by coronary angiography, but it may end with fatal complications such as rupture, compression of adjacent cardiopulmonary structures, thrombus formation and distal embolization. The pathophysiological mechanisms are not well understood. Atherosclerosis, proteolytic imbalance and inflammatory reaction are involved in aneurysmal formation. Data from previously published studies are scarce and controversial, thereby the management of CAA is individualized depending on clinical presentation, CAA characteristics, patient profile and physician experience. Multiple therapeutic approaches including medical treatment, covered stent angioplasty, coil insertion and surgery were described. Herein, we provide an up-to-date systematic review on the pathophysiology, complications and management of CAA.

Cardiac macrophage subsets differentially regulate lymphatic network remodeling during pressure overload.

The lymphatic network of mammalian heart is an important regulator of interstitial fluid compartment and immune cell trafficking. We observed a remodeling of the cardiac lymphatic vessels and a reduced lymphatic efficiency during heart hypertrophy and failure induced by transverse aortic constriction. The lymphatic endothelial cell number of the failing hearts was positively correlated with cardiac function and with a subset of cardiac macrophages. This macrophage population distinguished by LYVE-1 (Lymphatic vessel endothelial hyaluronic acid receptor-1) and by resident macrophage gene expression signature, appeared not replenished by CCR2 mediated monocyte infiltration during pressure overload. Isolation of macrophage subpopulations showed that the LYVE-1 positive subset sustained in vitro and in vivo lymphangiogenesis through the expression of pro-lymphangiogenic factors. In contrast, the LYVE-1 negative macrophage subset strongly expressed MMP12 and decreased the endothelial LYVE-1 receptors in lymphatic endothelial cells, a feature of cardiac lymphatic remodeling in failing hearts. The treatment of mice with a CCR2 antagonist during pressure overload modified the proportion of macrophage subsets within the pathological heart and preserved lymphatic network from remodeling. This study reports unknown and differential functions of macrophage subpopulations in the regulation of cardiac lymphatic during pathological hypertrophy and may constitute a key mechanism underlying the progression of heart failure.

Surfing the clinical trials of mesenchymal stem cell therapy in ischemic cardiomyopathy.

While existing remedies failed to fully address the consequences of heart failure, stem cell therapy has been introduced as a promising approach. The present review is a comprehensive appraisal of the impacts of using mesenchymal stem cells (MSCs) in clinical trials mainly conducted on ischemic cardiomyopathy. The benefits of MSC therapy for dysfunctional myocardium are likely attributed to numerous secreted paracrine factors and immunomodulatory effects. The positive outcomes associated with MSC therapy are scar size reduction, reverse remodeling, and angiogenesis. Also, a decreasing in the level of chronic inflammatory markers of heart failure progression like TNF-α is observed. The intense inflammatory reaction in the injured myocardial micro-environment predicts a poor response of scar tissue to MSC therapy. Subsequently, the interval delay between myocardial injury and MSC therapy is not yet determined. The optimal requested dose of cells ranges between 100 to 150 million cells. Allogenic MSCs have different advantages compared to autogenic cells and intra-myocardial injection is the preferred delivery route. The safety and efficacy of MSCs-based therapy have been confirmed in numerous studies, however several undefined parameters like route of administration, optimal timing, source of stem cells, and necessary dose are limiting the routine use of MSCs therapeutic approach in clinical practice. Lastly, pre-conditioning of MSCs and using of exosomes mediated MSCs or genetically modified MSCs may improve the overall therapeutic effect. Future prospective studies establishing a constant procedure for MSCs transplantation are required in order to apply MSC therapy in our daily clinical practice and subsequently improving the overall prognosis of ischemic heart failure patients.

Transplantation of CD34+ cells for myocardial ischemia.

CD34+ cells are multipotent hematopoietic stem cells also known as endothelial progenitor cells and are useful in regenerative medicine. Naturally, these cells are mobilized from the bone marrow into peripheral circulation in response to ischemic tissue injury. CD34+ cells are known for their high proliferative and differentiation capacities that play a crucial role in the repair process of myocardial damage. They have an important paracrine activity in secreting factors to stimulate vasculogenesis, reduce endothelial cells and cardiomyocytes apoptosis, remodel extracellular matrix and activate additional progenitor cells. Once they migrate to the target site, they enhance angiogenesis, neovascularization and tissue regeneration. Several trials have demonstrated the safety and efficacy of CD34+ cell therapy in different settings, such as peripheral limb ischemia, stroke and cardiovascular disease. Herein, we review the potential utility of CD34+ cell transplantation in acute myocardial infarction, refractory angina and ischemic heart failure.

Evaluation of Mitral and Aortic Valvular Disease and Left Ventricular Dysfunction in a Lebanese Population: Retrospective Single-Center Experience.

BACKGROUND Recently, new therapeutic approaches have revolutionized the management of left ventricular dysfunction (LVD) and valvular heart disease (VHD), which are a growing public health problem. In parallel, there are no available epidemiological data about LVD and VHD in developing countries, especially in the Mediterranean area. This retrospective study was conducted at a single center and aimed to evaluate the associations between mitral and aortic valvular disease and left ventricle systolic and diastolic dysfunction in the Lebanese population. MATERIAL AND METHODS A retrospective study was conducted of 4520 consecutive patients aged >18 years who were referred to the Cardiovascular Department of Notre Dame de Secours-University Hospital in Jbeil-Lebanon for transthoracic echocardiography between December 2016 and December 2019. The study population was divided into different groups based on types of LVD and VHD. Left ventricle systolic dysfunction was defined as a left ventricle ejection fraction (EF) ≤40%. Statistical analysis was carried out using SPSS software version 20. RESULTS VHD and systolic dysfunction were more common in men, whereas diastolic dysfunction was more common in women. Being older than age 65 years and smoking were significantly associated with heart failure with preserved EF, whereas female sex was a significant preventive factor against heart failure with reduced EF. Systemic hypertension was correlated with mitral stenosis and tricuspid regurgitation, whereas diabetes mellitus was associated with tricuspid regurgitation (TR). Smoking and older age also appeared to be associated with aortic stenosis. CONCLUSIONS Mitral valve disease (regurgitation and stenosis) was significantly correlated with systolic dysfunction, whereas aortic and mitral regurgitation were associated with diastolic dysfunction. Better monitoring of cardiovascular disease risk factors may lead to a reduced burden of LVD and VHD.

Can myocardial work indices contribute to the exploration of patients with cardiac amyloidosis?

BACKGROUND: Cardiac amyloidosis (CA) is a life-threatening restrictive cardiomyopathy. Identifying patients with a poor prognosis is essential to ensure appropriate care. The aim of this study was to compare myocardial work (MW) indices with standard echocardiographic parameters in predicting mortality among patients with CA. METHODS: Clinical, biological and transthoracic echocardiographic parameters were retrospectively compared among 118 patients with CA. Global work index (GWI) was calculated as the area of left ventricular pressure-strain loop. Global work efficiency (GWE) was defined as percentage ratio of constructive work to sum of constructive and wasted works. Sixty-one (52%) patients performed a cardiopulmonary exercise. RESULTS: GWI, GWE, global longitudinal strain (GLS), left ventricular ejection fraction (LVEF) and myocardial contraction fraction (MCF) were correlated with N-terminal prohormone brain natriuretic peptide (R=-0.518, R=-0.383, R=-0.553, R=-0.382 and R=-0.336, respectively; p<0.001). GWI and GLS were correlated with peak oxygen consumption (R=0.359 and R=0.313, respectively; p<0.05). Twenty-eight (24%) patients died during a median follow-up of 11 (4-19) months. The best cut-off values to predict all-cause mortality for GWI, GWE, GLS, LVEF and MCF were 937 mm Hg/%, 89%, 10%, 52% and 15%, respectively. The area under the receiver operator characteristic curve of GWE, GLS, GWI, LVEF and MCF were 0.689, 0.631, 0.626, 0.511 and 0.504, respectively. CONCLUSION: In CA population, MW indices are well correlated with known prognosis markers and are better than LVEF and MCF in predicting mortality. However, MW does not perform better than GLS.

Incidental discovery of right ventricular lipoma in a young female associated with ventricular hyperexcitability: An imaging multimodality approach.

BACKGROUND: Cardiac lipomas are rare benign tumors commonly found in the right atrium or left ventricle. Patients are usually asymptomatic, and clinical presentation depends on location and adjacent structures impairment. Right ventricle lipomas are scarce in the literature. Moreover, the previous published cases were reported in over 18-year-old patients. CASE SUMMARY: We report a giant right ventricle lipoma discovered incidentally in a 17-year-old female while performing preoperative work-up. The diagnosis was confirmed by histopathological examination, and a conservative approach was performed. CONCLUSION: Multimodal cardiac imaging and histopathological examination are required for a definitive diagnosis. The therapeutic approach depends on clinical presentation.

Coronary angiography in the setting of acute infective endocarditis requiring surgical treatment.

BACKGROUND: International guidelines recommend that preoperative coronary angiography is performed on patients at risk of coronary disease who have infective endocarditis requiring surgical treatment. However, the risks of contrast-induced nephropathy or vegetation embolization in case of aortic endocarditis should be considered. AIMS: To assess the safety, therapeutic implications and prognostic impact of coronary angiography in patients requiring surgical treatment for active infective endocarditis. METHODS: This retrospective monocentric study was conducted in patients referred to a tertiary care centre for active endocarditis management with a theoretical indication for surgery between January 2013 and February 2017. RESULTS: One hundred and ninety-three patients were included; 73.1% were men, the mean age was 61.9±16.3 years and the median EuroSCORE II was 5.8%. One hundred and nineteen patients (61.7%) had aortic endocarditis, which was associated with aortic vegetation in 74 cases (38.3%). Invasive coronary angiography was performed in 142 patients (73.6%) - 130 (91.6%) by radial approach - and 14 patients were evaluated by coronary multislice computed tomography (one patient had exploration with both techniques). Acute renal failure after coronary angiography was observed in 15 patients (10.6%), two patients (1.4%) presented a stroke within 24h after coronary angiography, but none had aortic endocarditis. Among the 178 patients (92.2%) who underwent surgery, 35 (19.7%) had significant coronary lesion(s) and 25 (14.0%) underwent an associated coronary artery bypass graft. CONCLUSIONS: Preoperative coronary angiography in patients affected by infective endocarditis provides relevant information in a significant proportion of patients and can be performed safely.

Aging induces cardiac mesenchymal stromal cell senescence and promotes endothelial cell fate of the CD90 + subset.

Aging is a major risk factor in the development of chronic diseases, especially cardiovascular diseases. Age-related organ dysfunction is strongly associated with the accumulation of senescent cells. Cardiac mesenchymal stromal cells (cMSCs), deemed part of the microenvironment, modulate cardiac homeostasis through their vascular differentiation potential and paracrine activity. Transcriptomic analysis of cMSCs identified age-dependent biological pathways regulating immune responses and angiogenesis. Aged cMSCs displayed a senescence program characterized by Cdkn2a expression, decreased proliferation and clonogenicity, and acquisition of a senescence-associated secretory phenotype (SASP). Increased CCR2-dependent monocyte recruitment by aged cMSCs was associated with increased IL-1ß production by inflammatory macrophages in the aging heart. In turn, IL-1ß induced senescence in cMSCs and mimicked age-related phenotypic changes such as decreased CD90 expression. The CD90+ and CD90- cMSC subsets had biased vascular differentiation potentials, and CD90+ cMSCs were more prone to acquire markers of the endothelial lineage with aging. These features were related to the emergence of a new cMSC subset in the aging heart, expressing CD31 and endothelial genes. These results demonstrate that cMSC senescence and SASP production are supported by the installation of an inflammatory amplification loop, which could sustain cMSC senescence and interfere with their vascular differentiation potentials.

Re-endothelialisation after Synergy stent and Absorb bioresorbable vascular scaffold implantation in acute myocardial infarction: COVER-AMI study.

BACKGROUND/AIMS: Drug eluting stent (DES) decrease the risk of restenosis by reducing the neointimal response. However, DES may impair strut coverage, and this has been associated with late stent/scaffold thrombosis. Bioresorbable vascular scaffold (BVS) may overcome the risk of stent/scaffold thrombosis when completely resorbed. The purpose of this randomised trial was to compare the arterial healing response in the short term, as a surrogate for safety and efficacy, between the metallic everolimus-eluting stent (Synergy; Boston Scientific, Marlborough, MA, USA) and the everolimus BVS (Absorb; Abbott Vascular, Santa Clara, CA, USA) in the particular setting of acute myocardial infarction (AMI). This pilot study sought to compare the neointimal response of metallic everolimus DES (Synergy) with polymeric everolimus BVS (Absorb) by optical coherence tomography (OCT) 3 months after an AMI. METHODS: COVER-AMI was a single-centre, single-blind, non-inferiority, randomised controlled trial. Patients with ST segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention were randomly allocated (1:1) to treatment with the Synergy DES or Absorb BVS. The primary endpoint was the 3-month neointimal response assessed as the percentage of uncovered struts, neointimal thickness, in-stent/scaffold area obstruction, and pattern of neointima. The main secondary endpoint included the device-oriented composite endpoint according to the Academic Research Consortium definition. RESULTS: Twenty patients without clinical and/or angiographic complications (Synergy (n = 10) or BVS (n = 10); mean age 59.0 years; 20% female) were enrolled in our centre. The stent diameter was higher in the Synergy group (3.7 ± 0.4 mm vs 3.4 ± 0.4 mm in the BVS group, p = 0.01). At 3 months, no significant differences in angiographic lumen loss were observed between the everolimus DES and everolimus BVS (0.04 mm (IQR 0.00-0.07) vs 0.11 mm (IQR 0.04-0.31), p = 0.165). OCT analysis of 420 cross-sections showed that the total neointimal area and in-stent obstruction were lower in the Synergy group, while OCT analysis at the strut level (n = 3942 struts) showed that the rate of uncovered struts was lower in the BVS group. CONCLUSIONS: Stenting of culprit lesions in the setting of STEMI resulted in a nearly complete arterial healing for both the Synergy and the BVS devices. Lower neointimal thickness and in-stent obstruction but a higher rate of uncovered struts were observed in the Synergy group. These findings provide the basis for further exploration in clinically oriented outcome trials.

Paclitaxel Drug-Coated Balloon After Bare-Metal Stent Implantation, an Alternative Treatment to Drug-Eluting Stent in High Bleeding Risk Patients (The Panelux Trial).

BACKGROUND: Prolonged dual-antiplatelet therapy (DAPT) in high bleeding risk (HBR) patients undergoing percutaneous coronary intervention can be challenging. We assessed the clinical safety of bare-metal stent (BMS) implantation followed by drug-coated balloon (DCB) treatment in HBR patients for whom drug-eluting stent implantation could be problematic in maintaining low ischemic event rate without increasing hemorrhagic events. METHODS: The study included patients with at least 1 de novo lesion who were either under long-term anticoagulant treatment or required semi-urgent non-coronary intervention. The strategy consisted of PRO-Kinetic Energy BMS stent (Biotronik AG) implantation followed by Pantera Lux DCB (Biotronik AG) and patients were followed for up to 12 months in 37 French centers. RESULTS: Between October 2013 and April 2015, a total of 432 patients with 623 de novo lesions who were either under long-term anticoagulant treatment (n = 300) or required semi-urgent non-cardiac surgery (n = 132) were treated by BMS plus DCB. Mean patient age was 74.1 ± 9.1 years, 76.4% were men, and 38% were diabetic. The composite primary endpoint rate (defined as target-lesion failure at 12 months) was 5.6% (95% confidence interval, 3.3-7.9). Median duration for DAPT treatment was 33 days. Hemorrhagic events, as defined by the Bleeding Academic Research Consortium, occurred in 31 patients (7.2%) and definite stent thrombosis occurred in 5 patients (1.3%). CONCLUSIONS: The combination of BMS plus DCB intervention is safe even with a short duration of DAPT. This strategy might be an alternative to DES implantation in HBR patients if future randomized trials support this approach.

New therapies for acute myocardial infarction: current state of research and future promise.

Progress has been made into research on new therapies, mechanical and pharmacological approaches and repair/regenerative cellular therapy to treat irreversible cardiovascular pathologies, such as acute myocardial infarction. Research into cellular therapies is exploring the use of new cellular types. Although the therapeutic effects of cell therapy remain modest, results from clinical trials are encouraging. To expand this improvement, advances are being made that involve the paracrine function of stem cells, the use of growth factors, miRNA and new biomaterials. In the near future, these therapies should become part of routine clinical practice.

Long-term outcomes of rotational atherectomy of underexpanded stents. A single center experience.

OBJECTIVES: To analyze the procedural and long-term outcomes of the use of rotational atherectomy (RA) in underexpanded stents in our cohort and to provide an overview of currently available data on this technique. BACKGROUND: Stent underexpansion (SU) has been related to stent thrombosis and restenosis. RA has been used to treat undilatable SU as a bail-out strategy with encouraging results. METHODS: This is an observational, single-center study. We included patients who underwent stentablation between 2013 and 2017. Baseline demographics, procedural results, in-hospital major adverse cardiac events (MACE), and long-term follow-up MACE were retrospectively collected. RESULTS: A total of 11 patients (90.9% males, mean age 65.4 ± 18.6) were included in this study. Median left ventricle ejection fraction was 53.5% [46.2-55]. Median calculated Syntax score was 16 [9-31] and 45.5% of patients were admitted for acute coronary syndrome. Radial approach was used in 63.6% of cases. Most patients only required one burr (45% used a 1.5 mm diameter burr) during the intervention. Procedural success was achieved in 90.9% of the cases. Acute lumen gain was 42.7% [30.7-61.49]. There were no in-hospital deaths or MACE. At a median follow-up of 26 months, only one patient (9.1%) suffered MACE in the context of acute coronary syndrome, and two patients (18.2%) required non-target lesion revascularization. No deaths were reported. CONCLUSIONS: RA of under expanded stents is a feasible option with a high rate of procedural success. At long-term follow-up, all of them were alive and 90.9% of patients remained free from MACE.

Therapeutic Benefit and Gene Network Regulation by Combined Gene Transfer of Apelin, FGF2, and SERCA2a into Ischemic Heart.

Despite considerable advances in cardiovascular disease treatment, heart failure remains a public health challenge. In this context, gene therapy appears as an attractive approach, but clinical trials using single therapeutic molecules result in moderate benefit. With the objective of improving ischemic heart failure therapy, we designed a combined treatment, aimed to simultaneously stimulate angiogenesis, prevent cardiac remodeling, and restore contractile function. We have previously validated IRES-based vectors as powerful tools to co-express genes of interest. Mono- and multicistronic lentivectors expressing fibroblast growth factor 2 (angiogenesis), apelin (cardioprotection), and/or SERCA2a (contractile function) were produced and administrated by intramyocardial injection into a mouse model of myocardial infarction. Data reveal that combined treatment simultaneously improves vessel number, heart function parameters, and fibrosis prevention, due to FGF2, SERCA2a, and apelin, respectively. Furthermore, addition of SERCA2a in the combination decreases cardiomyocyte hypertrophy. Large-scale transcriptome analysis reveals that the triple treatment is the most efficient in restoring angiogenic balance as well as expression of genes involved in cardiac function and remodeling. Our study validates the concept of combined treatment of ischemic heart disease with apelin, FGF2, and SERCA2a and shows that such therapeutic benefit is mediated by a more effective recovery of gene network regulation.

Local production of tenascin-C acts as a trigger for monocyte/macrophage recruitment that provokes cardiac dysfunction.

Aims: Tenascin-C (TNC) is an endogenous danger signal molecule strongly associated with inflammatory diseases and with poor outcome in patients with cardiomyopathies. Its function within pathological cardiac tissue during pressure overload remains poorly understood. Methods and results: We showed that TNC accumulates after 1 week of transverse aortic constriction (TAC) in the heart of 12-week-old male mice. By cross bone marrow transplantation experiments, we determined that TNC deposition relied on cardiac cells and not on haematopoietic cells. The expression of TNC induced by TAC, or by administration of a recombinant lentivector coding for TNC, triggered a pro-inflammatory cardiac microenvironment, monocyte/macrophage (MO/MΦ) accumulation, and systolic dysfunction. TNC modified macrophage polarization towards the pro-inflammatory phenotype and stimulated RhoA/Rho-associated protein kinase (ROCK) pathways to promote mesenchymal to amoeboid transition that enhanced macrophage migration into fibrillar collagen matrices. The amplification of inflammation and MO/MΦ recruitment by TNC was abrogated by genetic invalidation of TNC in knockout mice. These mice showed less ventricular remodelling and an improved cardiac function after TAC as compared with wild-type mice. Conclusions: By promoting a pro-inflammatory microenvironment and macrophage migration, TNC appears to be a key factor to enable the MO/MΦ accumulation within fibrotic hearts leading to cardiac dysfunction. As TNC is highly expressed during inflammation and sparsely during the steady state, its inhibition could be a promising therapeutic strategy to control inflammation and immune cell infiltration in heart disease.