Papers by Massimiliano Gnecchi
Circulation, Dec 11, 2012
Finland, became interested in gene therapy for the treatment of cardiovascular diseases and cance... more Finland, became interested in gene therapy for the treatment of cardiovascular diseases and cancer. In 1995, he and his team became the first to report the successful transfer of genes to human arteries with adenoviral vectors in peripheral 1 and coronary arteries. 2 Later, in 2005, to increase his experience and expertise in the field, Professor Ylä-Herttuala took a 1-year sabbatical at the Salk Institute for Biological Studies, La Jolla, CA, in the Lab of Genetics with Professor Inder M. Verma, PhD, currently the American Cancer Society Professor of Molecular Biology and a leading authority on the use of lentiviruses as vehicles for gene therapy. Notable articles by Professor Ylä-Herttuala and his team since include one on the elucidation of the receptor targets of induction of angiogenesis and arteriogenesis in the myocardium by vascular endothelial growth factor B 3 and another on a novel example of epigenetherapy involving regulation of vascular endothelial growth factor expression. 4 Speaking in July 2012, shortly after approval by the European Medicines Agency of the first gene therapy product in the Western world for the treatment of inherited
European Heart Journal, Oct 1, 2019
Arteriosclerosis, Thrombosis, and Vascular Biology, Oct 1, 2004
Most common cardiovascular diseases are accompanied by endothelial dysfunction. Because of its pr... more Most common cardiovascular diseases are accompanied by endothelial dysfunction. Because of its predominant role in the pathogenesis of cardiovascular disease, the vascular endothelium is an attractive therapeutic target. The identification of promoter sequences capable of rendering endothelial-specific transgene expression together with the recent development of vectors with enhanced tropism for endothelium may offer opportunities for the design of new strategies for modulation of endothelial function. Such strategies may be useful in the treatment of chronic diseases such as hypertension, atherosclerosis, and ischemic artery disease, as well as in acute myocardial infarction and during open heart surgery for prevention of ischemia and reperfusion (I/R)-induced injury. The recent identification of putative endothelial progenitor cells in peripheral blood may allow the design of autologous cell-based strategies for neovascularization of ischemic tissues and for the repair of injured blood vessels and bioengineering of vascular prosthesis. "Proof-of-concept" for some of these strategies has been established in animal models of cardiovascular disease. However the successful translation of these novel strategies into clinical application will require further developments in vector and delivery technologies. Further characterization of the processes involved in mobilization, migration, homing, and incorporation of endothelial progenitor cells into the target tissues is necessary, and the optimal conditions for therapeutic application of these cells need to be defined and standardized.
Cardiovascular Research
Here, we review the highlights of cardiovascular basic science published in 2021 and early 2022 o... more Here, we review the highlights of cardiovascular basic science published in 2021 and early 2022 on behalf of the European Society of Cardiology Council for Basic Cardiovascular Science. We begin with non-coding RNAs which have emerged as central regulators cardiovascular biology, and then discuss how technological developments in single-cell ‘omics are providing new insights into cardiovascular development, inflammation, and disease. We also review recent discoveries on the biology of extracellular vesicles in driving either protective or pathogenic responses. The Nobel Prize in Physiology or Medicine 2021 recognized the importance of the molecular basis of mechanosensing and here we review breakthroughs in cardiovascular sensing of mechanical force. We also summarize discoveries in the field of atherosclerosis including the role of clonal haematopoiesis of indeterminate potential, and new mechanisms of crosstalk between hyperglycaemia, lipid mediators, and inflammation. The past 12...
Europace, Jun 1, 2020
Atrial fibrillation (AF) is a common finding in patients with ST elevation myocardial infarction ... more Atrial fibrillation (AF) is a common finding in patients with ST elevation myocardial infarction (STEMI). However, its prognostic influence in MI remains controversial. Almost all previous studies were performed before the era of primary percutaneous coronary intervention (pPCI), and there is a lack of data in patients with STEMI complicated by cardiogenic shock (CS). The aim of our study was to evaluate the prognostic impact of AF in a large real-world population of STEMI undergoing pPCI stratified by the presence of CS. Our registry included 3017 consecutive patients with STEMI undergoing pPCI in our department in 2005-2017. The presence of a persistent (>30 min) systolic blood pressure < 90 mmHg associated with signs of pulmonary congestion/impaired end organ perfusion needing catecholamine infusion or mechanical support devices qualified for CS. Firstly we performed mortality analysis in all patients with AF during hospitalization; secondly, we compared patients with the first episode of AF and patients with AF during hospitalization but known AF in anamnesis. The analysis was stratified for the presence of CS. Univariate (cross-tables and Kaplan-Meier curves with log-rank test) and multivariate mortality analysis (Cox regressions) were performed. In STEMI patients without CS we also performed a propensity-matched analysis including all variables known before STEMI that could influence the occurrence of a first episode of AF. AF was present in 337 (11.3%) patients during hospitalization; in 193 (57.3%) of them was the first episode. CS occurred in 250 patients (8.4%), 27.2% of whom were affected by an AF episode (86.5% as the first episode). Among patients without CS, AF occurred in 269 patients (9.7%) and for the 77.5% was the first episode. In CS patients, AF was not associated with increased mortality, neither at 30 days (43.5% vs 43.7%, p = 0.867) nor at 1 year (47.5% vs 53.1%, p = 0.633). In the population without CS, AF was an independent predictor of mortality both at 30 days (HR 2.25 (1.05; 4.82), p = 0.037) and at 1 year (HR 1.87 (1.094; 3.18), p = 0.022); only new-onset AF was an independent predictor of mortality. We successfully matched 175 pairs of patients with similar propension to experience the first episode of AF. Among them the first episode of AF was confirmed to be an indipendent predictor of mortality (figure). In the present large real-world cohort of unselected patients with STEMI, the presence of an episode of AF during hospitalization was an independent predictor of mortality in patients not complicated by cardiogenic shock. Conversely, AF did not show a significant prognostic impact in patients with STEMI complicated by CS. Furthermore, the presence of a first episode of AF was confirmed to be an independent predictor of mortality, while an AF episode in patients with known AF was not found to have prognostic impact. Abstract Figure
European Heart Journal, Aug 1, 2018
To study gender differences of clinical course and myocardial remodeling in elderly patients with... more To study gender differences of clinical course and myocardial remodeling in elderly patients with idiopathic hypertrophic cardiomyopathy (HCM). The study included 131 patients with idiopathic HCM. Patients underwent standard clinical, laboratory and instrumental diagnostic methods. In the elderly patients with idiopathic HCM, the proportion of females was 63% (n=82), males -37% (n=49). The average age of females was 69±7 years, males -68±7 years. Coronary artery disease (CAD) was more common in males (32%) than in females (22%), but were found no statistically significant differences (p=0.20). Atrial fibrillation was more common in males (49% versus 29%, respectively, p=0.03). Size of left atrium and end-diastolic size of left ventricle in males exceeded those in females (51.2±9.0 mm versus 46.3±4.7 mm, 51.5±7.6 mm versus 45.6±5,7 mm, respectively, p=0.01). In males, a symmetrical myocardial remodeling was established more often (42% versus 25%, p=0.04). Obstructive form of HCM was predominant in females (45% and 14%, p=0.01). Chronic heart failure (CHF) in NYHA FC III was observed in 29% in female group (n=24) and in 12% in male group (n=6), which tends to differ (p=0.06). In females CHF in NYHA FC III was mainly due to left ventricle outflow tract obstruction (n=13) and dilatation phase (n=3). In males, almost all cases of CHF in NYHA FC III-IV (8 from 9 patients) were as a result of a combination of HCM with CAD and previous myocardial infarction. In males, the ejection fraction was significantly lower (55.7±14.8% versus 62.2±10.9%, p=0.01). Conclusions: Proportion of females was higher in elderly patients with idiopathic HCM. Females with HCM were characterized by a more severe course of the disease due to left ventricle outflow tract obstruction and dilatation phase. In males with idiopathic HCM were registered more often atrial fibrillation, bigger size of left atrium and end-diastolic size of left ventricle, symmetrical myocardial remodeling, lower ejection fraction of left ventricle, probably associated with a combination of HCM with CAD and previous myocardial infarction.
European Heart Journal, Aug 1, 2017
Background: Bleeding is associated with increased risk of mortality and morbidity in patients tre... more Background: Bleeding is associated with increased risk of mortality and morbidity in patients treated with percutaneous coronary intervention (PCI). However, whether the bleeding originates from the arterial access site or the non-access organ system, has not been clearly discriminated in previous studies. They differ greatly in terms of their pathogenesis and management. Hence, we evaluated the prevalences of access site and non-access site bleedings in contemporary multicenter PCI registry, and aimed to clarify their clinical determinants and impact on short-term mortality. Methods and results: From 12281 consecutive patients who underwent PCI procedures from January 2010 to December 2013 at 15 Japanese hospitals participating JCD-KiCS Registry, which is an ongoing multicenter PCI database, we abstracted 357 patients who complicated the bleeding related to PCI. (age, 71.0±10.7 years; male, 66.0%; body mass index [BMI], 23.4±4.0 kg/m 2 ). Access site bleeding occurred in 165 patients (1.3%) and non-access site bleeding in 192 (1.6%; gastrointestinal [n=40], urinary system [n=11], intracranial [n=7] and other or unknown location bleeding [n=141]). Multivariate analysis demonstrated that patients present with acute coronary syndrome (ACS) (β=3.05, 95% confidence interval [CI] 1.72-5.39, p<0.001) and cardiogenic shock (β=4.00, 95% CI 1.90-8.43, p<0.001) were independent predictors of non-access site bleeding among the patients with bleeding related to PCI. The prevalence of in-hospital death was higher in patients with non-access site bleeding than those with access site bleeding (26.1% vs 9.1%, p<0.001). Even after adjustment by age, gender, BMI, ACS, cardiogenic shock, and chronic kidney disease (CKD), non-access site bleeding remained as an independent predictor of in-hospital death (β=2.66, 95% CI 1.23-5.75, p=0.013). When the patients were divided into ACS (n=247) and non-ACS groups (n=109), cardiogenic shock was an independent predictor of non-access site bleeding in ACS group (β=3.38, 95% CI 1.56-7.30, p=0.002), and CKD was an independent predictor of non-access site bleeding in non-ACS group (β=5.08, 95% CI 1.17-21.95, p=0.030). The prevalence of in-hospital death was higher in patients with non-access site bleeding in both ACS (25.8% vs 14.8%, p=0.045) and non-ACS groups (28.1% vs 2.6%, p<0.001). The prevalence of non-access site bleeding is more common than that of access site bleeding in Japanese multicenter PCI database. Non-access site bleeding was an independent predictor of in-hospital death, suggesting that physician need to keep attention to the location of bleeding in patients complicated with bleeding related to PCI.
European Heart Journal, Oct 1, 2019
Incomplete ST segment resolution (iSTR) is a well-known marker of poor outcome in patients underg... more Incomplete ST segment resolution (iSTR) is a well-known marker of poor outcome in patients undergoing primary percutaneous coronary intervention (pPCI) for ST elevation myocardial infarction (STEMI). The use of glycoprotein IIbIIIa inhibitors (GPIs) was suggested to be associated with a survival benefit in high-risk patients. A simple score to predict the risk for developing iSTR could help early identification of these patients and could allow a tailored use of pharmacological tools, such as GPIs. The aim of this study was to create and validate a numerical score to predict iSTR occurrence in STEMI patients undergoing pPCI and to assess its association with the potential benefit of GPIs use. We prospectively enrolled all STEMI patients undergoing pPCI in our University Hospital (2005–2017). iSTR was defined as a &amp;amp;lt;70% resolution of initial ST segment shift in the lead with maximal ST deviation 60 min after reperfusion. Our population was randomly divided in two group: a derivation cohort (60%) and a validation cohort (40%). Potential predictors of iSTR were selected at univariate analysis and were then inserted in a multivariate binary stepwise-backward logistic regression. To create a risk score, numerical values were obtained considering the odds ratio of each independent predictor rounding to the nearest unit or half. A ROC curve with its c-statistic was then used to test the discrimination power of the score both in the derivation and in the validation cohort. Out of a total of 2959 patients, 1774 were included in the derivation: 480 (27%) of them presented iSTR. All-cause mortality at 30 days was significantly higher in patients with iSTR (OR 3.2, 95% CI 2.1–4.9, p&amp;amp;lt;0.001). Anterior MI (OR 2.46, 95% CI 1.90–3.14, p&amp;amp;lt;0.001, score 2.5), anemia at admission (OR 1.76, 95% CI 1.29–2.4, p&amp;amp;lt;0.001, score 2), blood glucose &amp;amp;gt;198 mg/dl at admission (OR 1.77, 95% CI 1.29–2.49, p&amp;amp;lt;0.001, score 2), age &amp;amp;gt;75 years (OR 1.54, 95% CI 1.15–2.10, p=0.004, score 1.5), female sex (OR 1.41, 95% CI 1.06–1.88, p=0.02, score 1.5) and Killip class &amp;amp;gt;2 (OR 1.44, 95% CI 1.05–1.98, p=0.024, score 1.5) were identified as independent predictors of iSTR, creating a ISTR-score that ranged from 0 to 11. The validation cohort consisted in 1185 patients, with 31% showing iSTR. The c-statistic was 0.67 and 0.66 in the derivation and validation cohorts. Patients with score ≥4 versus &amp;amp;lt;4 showed present a worst prognosys but a similar GPI use. Notably, GPIs were associated with a significant survival benefit among patients≥4 but not among patients &amp;amp;lt;4 (Figure). The use of GPIs was not associated to any clinically relevant difference, the increase in bleeding risk appeared similar. A simple pre-procedural risk score may predict iSTR following pPPCI, allowing a rapid risk stratification and the identification of patients who show a favorable risk/benefit ratio for the use of more aggressive strategies such as GPIs. These findings deserve a prospective, randomized evaluation.
European Heart Journal, Aug 1, 2018
lower rates of vascular complications (5.3% vs. 15.8%, p=0.034) and accessrelated major bleedings... more lower rates of vascular complications (5.3% vs. 15.8%, p=0.034) and accessrelated major bleedings (1.3% vs. 9.2%, p=0.028). Among TF patients, 15 of them had surgical isolation of the vessel, those showed a higher rate of surgical wound complications, compared with subclavian patients (11.8% vs. 2.6%, p=0.028). TF and TS patients showed similar short-and long-term outcomes, for both fatal and non-fatal events. One-year survival rates were 78.8% for subclavian group and 82% for femoral group (p=0.35), while one-year re-hospitalisation rates were 31.6% and 31.6% (p=1.00) respectively. Conclusions: The trans-subclavian aortic valve implantation is feasible in obese patients, with an excellent efficacy and safety profile. It should be considered as a valid option when obesity could complicate the management of femoral access site.
European Heart Journal, Aug 1, 2018
mortality and heart failure, after discharge, in patients with acute coronary syndrome without pe... more mortality and heart failure, after discharge, in patients with acute coronary syndrome without persistent ST-segment elevation (NSTEMI). Methods: We conducted an observational and retrospective analysis of patients admitted in our cardiology coronary care unit with NSTEMI between 2004 and 2014. Two groups were defined according to time of coronary revascularization from admission, group A (early <24 hours) and group B (delayed >24 hours). We performed a propensity score matched analysis to obtain 2 groups of 938 patients paired according to early or delayed revascularization Results: 2949 patients were admitted with NSTEMI from February 2004 to September 2014. Median age was of 69±13 years and 71.3% were men. During follow-up (median 5.28 years), after propensity score matching, patients who early revascularization had lower rates of mortality 3% group A vs 5.6% group B, p<0.01), less kidney failure (3.3% group A vs 7.3% group B, p<0.01), and fewer infections (3.3% group A vs 7.3% group B, p<0.01). Heart failure was more prevalent in group B. Therefore, the early revascularization was an independent protective factor of mortality after adjusting for confounding variables in the multivariate Cox regression analysis (hazard ratio = 0.74; 95% confidence interval, 0.60-0.92; p=0.0067). Nevertheless, this strategy had protector effect of heart failure no significantly (hazard ratio = 0.84; 95% confidence interval, 0.64-1.09; p=0.09). Conclusions: Early revascularization (<24 hours) of NSTEMI is associated with a significantly lower mortality than delayed revascularization and a rate lower of heart failure.
bioRxiv (Cold Spring Harbor Laboratory), Nov 9, 2020
The release of neutrophil extracellular traps (NETs), a process termed NETosis, avoids pathogen s... more The release of neutrophil extracellular traps (NETs), a process termed NETosis, avoids pathogen spread but may cause tissue injury. NETs have been found in severe COVID-19 patients, but their role in disease development is still unknown. The aim of this study is to assess the capacity of NETs to drive epithelial-mesenchymal transition (EMT) of lung epithelial cells and to analyze the involvement of NETs in COVID-19. Neutrophils activated with PMA (PMA-Neu), a stimulus known to induce NETs formation, induce both EMT and cell death in the lung epithelial cell line, A549. Notably, NETs isolated from PMA-Neu induce EMT without cell damage. Bronchoalveolar lavage fluid of severe COVID-19 patients showed high concentration of NETs. Thus, we tested in an in vitro alveolar model the hypothesis that virus-induced NET may drive EMT. Co-culturing A549 at air-liquid interface with alveolar macrophages, neutrophils and SARS-CoV2, we demonstrated a significant induction of the EMT in A549 together with high concentration of NETs, IL8 and IL1β, best-known inducers of NETosis. Lung tissues of COVID-19 deceased patients showed that epithelial cells are characterized by increased mesenchymal markers. These results show for the first time that NETosis plays a major role in triggering lung fibrosis in COVID-19 patients.
bioRxiv (Cold Spring Harbor Laboratory), Jun 25, 2021
In the early phases of the COVID-19 pandemic, drug repurposing was widely used to identify compou... more In the early phases of the COVID-19 pandemic, drug repurposing was widely used to identify compounds that could improve the prognosis of symptomatic patients infected by SARS-CoV-2. Hydroxychloroquine (HCQ) was one of the first drugs used to treat COVID-19 patients due to its supposed capacity of inhibiting SARS-CoV-2 infection and replication in vitro. While its efficacy is debated, HCQ has been associated with QT interval prolongation and potentially Torsades de Pointes, especially in patients predisposed to developing drug-induced Long QT Syndrome (LQTS) as silent carriers of variants associated with congenital LQTS. If confirmed, these effects represent a limitation to the at-home use of HCQ for COVID-19 infection as adequate ECG monitoring may be challenging. We investigated the proarrhythmic profile of HCQ with Multi-Electrode Arrays after subchronic exposure of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from two healthy donors, one asymptomatic and two symptomatic LQTS patients. We demonstrate that: I) HCQ induced a concentration-dependent Field Potential Duration (FPD) prolongation in vitro and triggered arrhythmias that halted the beating at high concentration. II) hiPSC-CMs from healthy or asymptomatic carriers tolerated higher concentrations of HCQ and showed lower susceptibility to HCQ-induced electrical abnormalities regardless of baseline FPD values. These findings agree with the clinical safety records of HCQ and demonstrated that hiPSC-CMs potentially discriminates symptomatic vs asymptomatic mutation carriers through pharmacological interventions. Disease-specific cohorts of hiPSC-CMs may be a valid preliminary addition to quickly assess drug safety in vulnerable populations, offering rapid preclinical results with valuable translational relevance for precision medicine.
European Heart Journal, Aug 2, 2013
of circulating proBNP1-108 with our immunodepletion process, we are now able to assess the remain... more of circulating proBNP1-108 with our immunodepletion process, we are now able to assess the remaining "true" BNP and NT-proBNP molecules and evaluate their clinical relevance.
European Heart Journal Supplements
Background SARS–CoV–2 primarily affects the respiratory system, but cardiac complications also oc... more Background SARS–CoV–2 primarily affects the respiratory system, but cardiac complications also occur very often. The entry of SARS–CoV–2 into host cells is mediated by the interaction between the viral glycoprotein Spike (S) and the host angiotensin–converting enzyme 2 (ACE2) protein. The use of ACE inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) might influence both ACE2 expression and viral infection, but our knowledge about these possible interactions is limited. Aim. To evaluate the effects of ACEIs and ARBs during active viraemia. Methods We tested the effects of exposure to the ACEI Lisinopril (100nM and 500nM) and the ARB Valsartan (10µM and 50µM) on three different cell types: green monkey–derived epithelial cells (VERO E6) which are used to replicate SARS–CoV–2, cardiomyocytes derived from hiPSC (iPSC–CMs) as heart model and a lung epithelial cancer cell line (16HBE) as pulmonary model. The SARS–CoV–2 wild strain was inoculated on cell lines for 1 hour...
Journal of Cardiovascular Medicine
43° Congresso dell'Associazione NAzionale Medici Cardiologi (ANMCO), 2012
Giornale italiano di nefrologia : organo ufficiale della Società italiana di nefrologia, 2013
Circulation: Genomic and Precision Medicine, 2021
Background: The proliferation of genetic profiling has revealed many associations between genetic... more Background: The proliferation of genetic profiling has revealed many associations between genetic variations and disease. However, large-scale phenotyping efforts in largely healthy populations, coupled with DNA sequencing, suggest variants currently annotated as pathogenic are more common in healthy populations than previously thought. In addition, novel and rare variants are frequently observed in genes associated with disease both in healthy individuals and those under suspicion of disease. This raises the question of whether these variants can be useful predictors of disease. To answer this question, we assessed the degree to which the presence of a variant in the cardiac potassium channel gene KCNH2 was diagnostically predictive for the autosomal dominant long QT syndrome. Methods: We estimated the probability of a long QT diagnosis given the presence of each KCNH2 variant using Bayesian methods that incorporated variant features such as changes in variant function, protein str...
Circulation, 2020
Background: Angiotensin-converting enzyme 2 (ACE2) expression in the lung has a protective role a... more Background: Angiotensin-converting enzyme 2 (ACE2) expression in the lung has a protective role against injury. However, ACE2 is the main host cell receptor for the Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) entry. Human mesenchymal stem cells (hMSCs) are currently under investigation for the treatment of pulmonary and cardiac complications of the SARS-CoV-2 disease (COVID-19). However, it is unclear if hMSCs express ACE2 and if they possibly can secrete ACE2. Also, their predisposition to be infected by SARS-CoV-2 is unknown. Aim: To assess if hMSCs of fetal and adult origin constitutively express and secrete ACE2 and if they can be infected by SARS-CoV-2. Methods: We studied 8 hMSC lines: 4 of fetal origin isolated from human placentas (hA-MSC) and 4 of adult origin isolated from bone marrow aspirates (hBM-MSCs). The lung epithelial cancer cell line CALU-3, which expresses high levels of ACE2, was used as positive control. ACE2 expression was evaluated in both st...
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Papers by Massimiliano Gnecchi