Growth Differentiation Factor 11 and Myostatin: Mechanism and Therapeutic Role in Cardiovascular Diseases

During life, cardiac muscle is capable of remodeling in response to an increased hemodynamic demand through cardiac hypertrophy. However, in most cases, if the stress stimuli become chronic the initially compensatory hypertrophic response evolves towards a pathological condition and heart failure. In this scenario, a therapeutic approach capable of reducing pathological cardiac hypertrophy could be beneficial. Growth differentiation factor 11 (GDF11) is circulating factor able to reduce cardiac hypertrophy in mice. It is a member of TGF-β family, and it shares a high level of homology with myostatin (MSTN) a well-studied protein that regulates skeletal muscle mass and apparently minimal activity on cardiac mass. Our data showed different protein levels between cardiac and skeletal muscle tissues revealed a higher abundancy of type I TGF-β receptors (ALK4/5/7) in the heart samples. Moreover, ALK7 receptor knockout induced a significant reduction in SMAD3/4 signaling only after GDF11 treatment. These results showed a differential quantity and use of ALKs receptors, possibly explaining the higher GDF11 sensitivity of cardiomyocytes compared to skeletal myocytes. Using a model of pressure overload-induced cardiac hypertrophy it was possible to further confirm the anti-hypertrophic activity of GDF11. Interestingly, even if with lower potency, this effect was recapitulated also by MSTN, demonstrating that both peptides have overlapping effects on cardiac tissue. Furthermore, aiming to reduce controversies regarding GDF11 and MSTN serum quantifications, we contributed to develop a novel assay based on mass spectrometry that can discriminate and quantify reliably both proteins. Using this method, it was also possible to identify an age-dependent reduction of both GDF11 and MSTN ligand in mice. In conclusion, GDF11 and MSTN share a common cardiac anti-hypertrophic activity that was not previously expected. Modulation of GDF11/MSTN signaling pathway can be considered for development of novel therapeutic strategies and new biotherapeutics

Characteristics and progression of cognitive deficits in progressive supranuclear palsy vs. multiple system atrophy and Parkinson's disease

Cognitive impairment is frequent in progressive supranuclear palsy (PSP) and less common in multiple system atrophy (MSA), but characteristics and progression compared with Parkinson's disease (PD) need to be properly defined. We evaluated 35 PSP with Richardson's syndrome (PSP-RS), 30 MSA as well as 65 age-, sex-, and education-matched PD with an extensive clinical and neuropsychological assessment, allowing Level II cognitive diagnosis. Eighteen PSP, 12 MSA and 30 PD had a second evaluation between 12 and 18 months (mean 15 months) after the first assessment. PSP performance at Montreal Cognitive Assessment (MoCA), verbal fluencies (phonemic and semantic tasks), Stroop test (Error and Time), Digit Span Sequencing (DSS), incomplete letters of Visual Object and Space Perception (VOSP) and Benton's Judgment of Line Orientation (JLO) performance were significantly poorer at baseline compared to PD and MSA. Executive, language and visuospatial abilities declined longitudinally in PSP, but not in PD and MSA. After 1.5 year, 16% of PSP converted to dementia. Our study provides evidence that cognitive progression is more severe and rapid in PSP-RS than PD and MSA. Further, we observed that MoCA, verbal fluency (particularly semantic), DSS and Benton's JLO are valuable tests to detect cognitive progression in PSP-RS and may be proposed as possible biomarker to assess efficacy of disease modification strategies

Pathways for salvage and protection of the heart under stress: novel routes for cardiac rejuvenation

The world population is aging, and by 2017, there will be more people over the age of 65 than under age 5, and by 2050, two billion of the estimated nine billion people on Earth will be older than 60. Aging itself is a major cardiovascular risk factor, affecting morbidity and mortality of the aging population. At the same time, aging increases the likelihood of the presence of other risk factors. The aged myocardium is characterized by several structural and functional progressive changes that impair its ability to respond appropriately to stressful conditions. Although some progress to understand the complex mechanisms that underlie these phenotypic changes, the molecular pathways that determine the balance between aging and rejuvenation in the aged myocardium still remain elusive. In this article, we review molecular mechanisms responsible for the phenotypic changes observed with aging in the heart, providing insight into molecular pathways and pharmacological interventions that may rejuvenate the aged myocardium. A better understanding of these pathways is essential for determining their therapeutic potential in humans, improving the possibility that the increase in life expectancy that we are observing will be accompanied by a parallel increase in healthspan

iTalian RegIstry of doUble inner branch stent graft for arch PatHology (the TRIUmPH Registry)

The objective of this study was to assess early and midterm results after endovascular aortic arch repair using a double inner branch stent graft (DIBSG) in patients with aortic arch aneurysm or dissection unfit for open surgery

Role of circulating factors in cardiac aging

Worldwide increase in life expectancy is a major contributor to the epidemic of chronic degenerative diseases. Aging, indeed, simultaneously affects multiple organ systems, and it has been hypothesized that systemic alterations in regulators of tissue physiology may regulate this process. Cardiac aging itself is a major risk factor for cardiovascular diseases and, because of the intimate relationship with the brain, may contribute to increase the risk of neurodegenerative disorders. Blood-borne factors may play a major role in this complex and still elusive process. A number of studies, mainly based on the revival of parabiosis, a surgical technique very popular during the 70s of the 20th century to study the effect of a shared circulation in two animals, have indeed shown the potential that humoral factors can control the aging process in different tissues. In this article we review the role of circulating factors in cardiovascular aging. A better understanding of these mechanisms may provide new insights in the aging process and provide novel therapeutic opportunities for chronic age-related disorders

Cardiovascular aging: the unveiled enigma from bench to bedside

9The rapid increase in the median age of the world's population requires particular attention towards older and more fragile people. Cardiovascular risk factors, time and comorbidities play a vicious role in the development of heart failure, both with reduced and preserved ejection fraction, in the elderly. Understanding the mechanisms underlying the pathophysiological processes observed with aging is pivotal to target those patients and their therapeutic needs properly. This review aims to investigate and to dissect the main pathways leading to the aging cardiomyopathy, helping to understand the relationship from bench to bedside of the clinical phenotype.reservedmixedCannata' A, Merlo M, Artico J, Gentile P, Camparini L, Cristallini J, Porcari A, Loffredo F, Sinagra GCannata', A; Merlo, M; Artico, J; Gentile, P; Camparini, L; Cristallini, J; Porcari, A; Loffredo, F; Sinagra,

Echocardiographic Evaluation of Centenarians in Trieste

Background: Population aging has increased together with the need for cardiovascular care. Understanding the relevance of cardiovascular conditions in the very old is crucial to developing a specific and rationale therapeutic approach. Centenarians can be considered a model of successful aging, although the impact of cardiovascular disease in this population is still unclear. Aim: To evaluate the cardiovascular health status of a subset of centenarians enrolled in the Centenari a Trieste study and living in the province of Trieste to describe the prevalence of cardiovascular conditions among them. Methods: The current study included 20 individuals born before 1919 and living in the province of Trieste as of 1 May 2019. All centenarians were able to give consent and were subjected to an in-home complete clinical assessment focused on cardiovascular conditions, ECG and echocardiography. Results: The majority of centenarians were women (85%) and were not taking any chronic cardiovascular medication (55%). No centenarians had a history of ischemic heart disease while about one-third had signs suggestive of heart failure at examination (20%). Atrial fibrillation was present in 20% of individuals and conduction disorders were uncommon. Although the majority of individuals had a preserved left ventricular function, diastolic function was abnormal in 80% of enrolled centenarians that, however, was mild in 73% of cases. Conclusion: This is the second study to perform in-home echocardiography in centenarians and the first to characterize the cardiovascular status of centenarians living in Trieste. The majority of centenarians had asymptomatic diastolic dysfunction and were na\uefve from cardiovascular therapy. The recruitment of new individuals from the Trieste area is continuing to perform analyses on clinical, genetic and environmental factors that may predict greater longevity in this geographical context and unveil mechanisms that regulate cardiac aging associated with increased lifespan

iTalian RegIstry of doUble inner branch stent graft for arch PatHology (the TRIUmPH Registry)

Objective: The objective of this study was to assess early and midterm results after endovascular aortic arch repair using a double inner branch stent graft (DIBSG) in patients with aortic arch aneurysm or dissection unfit for open surgery. Methods: Between 2012 and 2018, there were 24 patients with aortic arch disease who were treated with a single model of a DIBSG (Terumo Aortic, Glasgow, United Kingdom) in nine Italian cardiovascular centers. We investigated technical success, mortality, occurrence of major complications, and need for reintervention in a multicenter, nonrandomized, retrospective fashion. Results: The in-hospital mortality rate was 16.7%. Cerebrovascular events occurred in 25% of patients and major strokes in 12.5%. Two patients experienced a retrograde dissection (8.3%), whereas none reported any type I or type III endoleak. During a mean follow-up of 18 months (range, 1-60 months), one patient died of a nonaortic cause and one reported a nonarch-related major stroke. No late secondary intervention was needed during the follow-up. Excluding from the analysis the first six patients treated until 2014 as part of the learning curve, in-hospital mortality, major stroke, and retrograde dissection rates were 11.1%, 11.1%, and 5.6%, respectively. Conclusions: Endovascular aortic arch repair using this model of DIBSG is feasible, and results are acceptable for a new technique in a high-risk subset of patients. Operative mortality suffers the effect of a learning curve, whereas midterm aorta-related survival is promising. Endovascular repair of aortic arch disease with a DIBSG should always be considered to give high-risk patients a chance of repair. Large-scale studies are needed to assess the long-term durability of this technique

A technical review of bail-out procedures to place Najuta stent-graft into the ascending aorta

BackgroundThe Najuta stent-graft (Kawasumi Laboratories Inc., Tokyo, Japan) is usually easily advanced to the correct deployment position in the ascending aorta thanks to the pre-curved delivery J-sheath with all fenestrations automatically oriented towards the supra-aortic vessels. Aortic arch anatomy and delivery system stiffness could however represent limitations for proper endograft advancement, especially when the aortic arch bends sharply. The aim of this technical note is to report a series of bail-out procedures that could be useful to overcome the difficulties encountered during the Najuta stent-graft advancement up to the ascending aorta.Main bodyThe insertion, positioning and deployment of a Najuta stent-graft requires a through-and-through guidewire technique using a .035 '' 400 cm hydrophilic nitinol guidewire (Radifocus (TM) Guidewire M Non-Vascular, Terumo Corporation, Tokyo, Japan) with right brachial and both femoral accesses. When standard maneuver to put the endograft tip into the aortic arch, some bail-out procedures can be applied to obtain proper positioning. Five techniques are described into the text: positioning of a coaxial extra-stiff guidewire; positioning of a long introducer sheath down to the aortic root from the right brachial access; inflation of a balloon inside the ostia of the supra-aortic vessels; inflation of a balloon inside the aortic arch (coaxial to the device); and transapical access technique. This is a troubleshooting guide for allowing physicians to overcome various difficulties with the Najuta endograft as well as for other similar devices.Short conclusionTechnical issues in advancing the delivery system of Najuta stent-graft could occur. Therefore, the rescue procedures described in this technical note could be useful to guarantee the correct positioning and deployment of the stent-graft