Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy.

The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-ß superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.

Mitophagy modulation for the treatment of cardiovascular diseases.

BACKGROUND: Defects of mitophagy, the selective form of autophagy for mitochondria, are commonly observed in several cardiovascular diseases and represent the main cause of mitochondrial dysfunction. For this reason, mitophagy has emerged as a novel and potential therapeutic target. METHODS: In this review, we discuss current evidence about the biological significance of mitophagy in relevant preclinical models of cardiac and vascular diseases, such as heart failure, ischemia/reperfusion injury, metabolic cardiomyopathy and atherosclerosis. RESULTS: Multiple studies have shown that cardiac and vascular mitophagy is an adaptive mechanism in response to stress, contributing to cardiovascular homeostasis. Mitophagy defects lead to cell death, ultimately impairing cardiac and vascular function, whereas restoration of mitophagy by specific compounds delays disease progression. CONCLUSIONS: Despite previous efforts, the molecular mechanisms underlying mitophagy activation in response to stress are not fully characterized. A comprehensive understanding of different forms of mitophagy active in the cardiovascular system is extremely important for the development of new drugs targeting this process. Human studies evaluating mitophagy abnormalities in patients at high cardiovascular risk also represent a future challenge.

Colchicine in Athero-Thrombosis: Molecular Mechanisms and Clinical Evidence.

Several lines of evidence have clearly indicated that inflammation plays a pivotal role in the development of atherosclerosis and of its thrombotic complications such as acute coronary syndromes or ischemic stroke. Thus, it has been postulated that the use of anti-inflammatory agents might be extremely useful to improve cardiovascular outcome. Recently, increasing attention has been reserved to one of the oldest plant-derived drugs still in use in clinical practice, colchicine that has been used as drug to treat inflammatory diseases such gout or Mediterranean fever. To date, current guidelines of the European Society of Cardiology have included colchicine as first line choice for treatment of acute and recurrent pericarditis. Moreover, several studies have investigated its role in the clinical scenarios of cardiovascular disease including chronic and acute coronary syndromes with promising results. In this review, starting from a description of the mechanism(s) involved behind its anti-inflammatory effects, we give an overview on its potential effects in atherothrombosis and finally present an updated overview of clinical evidence on the role of this drug in cardiovascular disease.

Peripheral Artery Disease and Abdominal Aortic Aneurysm: The Forgotten Diseases in COVID-19 Pandemic. Results from an Observational Study on Real-World Management.

Background and Objectives: It is well established that patients with peripheral artery disease (PAD) as well abdominal aortic aneurysm (AAA) have an increased cardiovascular (CV) mortality. Despite this higher risk, PAD and AAA patients are often suboptimality treated. This study assessed the CV profile of PAD and AAA patients, quantifying the survival benefits of target-based risk-factors modification even in light of the COVID-19 pandemic. Materials and Methods: PAD and AAA patients admitted for any reason to the Vascular Unit from January 2019 to February 2020 were retrospectively analyzed. Biochemical and CV profiles as well as ongoing medical therapies were recorded. Benefits of CV risk-factors control were estimated using the SMART-REACH model. A follow-up visit during the year 2020 was scheduled. Results: A total of 669 patients were included. Of these, 190 showed AAA and 479 PAD at any stage. Only 54% of PAD and 41% of AAA patients were on lipid-lowering drugs with non-optimal low-density lipoprotein (LDL) levels for most of them. A better control of all modifiable CV risk-factors based on the current guidelines would offer an absolute risk reduction of the mean 10-year CV risk by 9% in PAD and 14% in AAA. Unfortunately, the follow-up visit was lost because of COVID-19 limitations. Conclusions: Lipid profiles of PAD and AAA patients were far from guideline-based targets, and medical management was suboptimal. In our center, the COVID-19 pandemic impacted on the strict surveillance required in these very high-risk patients. The achievement of guideline-based therapeutic targets would definitively confer additional significant benefits in reducing the CV risk in these patients.

Percutaneous Left Atrial Appendage Occlusion: An Emerging Option in Patients with Atrial Fibrillation at High Risk of Bleeding.

Atrial fibrillation (AF) is a common cardiac arrhythmia with an estimated prevalence of 1% in the general population. It is associated with an increased risk of ischemic stroke, silent cerebral ischemia, and cognitive impairment. Due to the blood flow stasis and morphology, thrombus formation occurs mainly in the left atrial appendage (LAA), particularly in the setting of nonvalvular AF (NVAF). Previous studies have shown that >90% of emboli related to NVAF originate from the LAA, thus prevention of systemic cardioembolism is indicated. According to the current guidelines, anticoagulant therapy with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs), represents the standard of care in AF patients, in order to prevent ischemic stroke and peripheral embolization. Although these drugs are widely used and DOACs have shown, compared to VKAs, non-inferiority for stroke prevention with significantly fewer bleeding complications, some issues remain a matter of debate, including contraindications, side effects, and adherence. An increasing number of patients, indeed, because of high bleeding risk or after experiencing life-threatening bleedings, must take anticoagulants with extreme caution if not contraindicated. While surgical closure or exclusion of LAA has been historically used in patients with AF with contradictory results, in the recent years, a novel procedure has emerged to prevent the cardioembolic stroke in these patients: The percutaneous left atrial appendage occlusion (LAAO). Different devices have been developed in recent years, though not all of them are approved in Europe and some are still under clinical investigation. Currently available devices have shown a significant decrease in bleeding risk while maintaining efficacy in preventing thromboembolism. The procedure can be performed percutaneously through the femoral vein access, under general anesthesia. A transseptal puncture is required to access left atrium and is guided by transesophageal echocardiography (TEE). Evidence from the current literature indicates that percutaneous LAAO represents a safe alternative for those patients with contraindications for long-term oral anticoagulation. This review summarizes scientific evidences regarding LAAO for stroke prevention including clinical indications and an adequate patient selection.

Targeted Approach to Distinguish and Determine Absolute Levels of GDF8 and GDF11 in Mouse Serum.

Growth differentiation factor 11 (GDF11) is a TGF-ß superfamily circulating factor that regulates cardiomyocyte size in rodents, sharing 90% amino acid sequence identity in the active domains with myostatin (GDF8)-the major determinant of skeletal muscle mass. Conflicting data on age-related changes in circulating levels have been reported mainly due to the lack of specific detection methods. More recently, liquid chromatography tandem mass spectrometry (LC-MS/MS) based assay showed that the circulating levels of GDF11 do not change significantly throughout human lifespan, but GDF8 levels decrease with aging in men. Here a novel detection method is demonstrated based on parallel reaction monitoring LC-MS/MS assay combined with immunoprecipitation to reliably distinguish GDF11 and GDF8 as well as determine their endogenous levels in mouse serum. The data indicate that both GDF11 and GDF8 circulating levels significantly decline with aging in female mice.

Circulating Growth Differentiation Factor 11/8 Levels Decline With Age.

RATIONALE: Growth differentiation factor 11 (GDF11) and GDF8 are members of the transforming growth factor-ß superfamily sharing 89% protein sequence homology. We have previously shown that circulating GDF11 levels decrease with age in mice. However, a recent study by Egerman et al reported that GDF11/8 levels increase with age in mouse serum. OBJECTIVE: Here, we clarify the direction of change of circulating GDF11/8 levels with age and investigate the effects of GDF11 administration on the murine heart. METHODS AND RESULTS: We validated our previous finding that circulating levels of GDF11/8 decline with age in mice, rats, horses, and sheep. Furthermore, we showed by Western analysis that the apparent age-dependent increase in GDF11 levels, as reported by Egerman et al, is attributable to cross-reactivity of the anti-GDF11 antibody with immunoglobulin, which is known to increase with age. GDF11 administration in mice rapidly activated SMAD2 and SMAD3 signaling in myocardium in vivo and decreased cardiac mass in both young (2-month-old) and old (22-month-old) mice in a dose-dependent manner after only 9 days. CONCLUSIONS: Our study confirms an age-dependent decline in serum GDF11/8 levels in multiple mammalian species and that exogenous GDF11 rapidly activates SMAD signaling and reduces cardiomyocyte size. Unraveling the molecular basis for the age-dependent decline in GDF11/8 could yield insight into age-dependent cardiac pathologies.

Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium.

Age-related diastolic dysfunction is a major factor in the epidemic of heart failure. In patients hospitalized with heart failure, HFpEF is now as common as heart failure with reduced ejection fraction. We now have many successful treatments for heart failure with reduced ejection fraction, while specific treatment options for HFpEF patients remain elusive. The lack of treatments for HFpEF reflects our very incomplete understanding of this constellation of diseases. There are many pathophysiological factors in HFpEF, but aging appears to play an important role. Here, we propose that aging of the myocardium is itself a specific pathophysiological process. New insights into the aging heart, including hormonal controls and specific molecular pathways, such as microRNAs, are pointing to myocardial aging as a potentially reversible process. While the overall process of aging remains mysterious, understanding the molecular pathways of myocardial aging has never been more important. Unraveling these pathways could lead to new therapies for the enormous and growing problem of HFpEF.

Keep PNUTS in your heart.

Aging is a major factor in many cardiovascular diseases. The molecular factors that regulate age-related changes in cardiac physiology and contribute to the increased cardiovascular risk in the elderly are not fully understood. A study recently published in Nature suggests a specific role for microRNAs (miRNAs) in regulating cardiac aging and function, challenging the concept that aging is an inevitable process in the heart.

Arrhythmogenic Left Ventricular Cardiomyopathy: From Diagnosis to Risk Management.

PURPOSE OF REVIEW: Left ventricular arrhythmogenic cardiomyopathy (ALVC) is a rare and poorly characterized cardiomyopathy that has recently been reclassified in the group of non-dilated left ventricular cardiomyopathies. This review aims to summarize the background, diagnosis, and sudden cardiac death risk in patients presenting this cardiomyopathy. RECENT FINDINGS: Although there is currently a lack of data on this condition, arrhythmogenic left ventricular dysplasia can be considered a specific disease of the left ventricle (LV). We have collected the latest evidence about the management and the risks associated with this cardiomyopathy. SUMMARY: Left ventricular arrhythmogenic cardiomyopathy is still poorly characterized. ALVC is characterized by fibrofatty replacement in the left ventricular myocardium, with variable phenotypic expression. Diagnosis is based on a multiparametric approach, including cardiac magnetic resonance (CMR) and genetic testing, and is important for sudden cardiac death (SCD) risk stratification and management. Recent guidelines have improved the management of left ventricular arrhythmogenic cardiomyopathy. Further studies are necessary to improve knowledge of this cardiomyopathy.

Evolving Concepts of the SCORE System: Subtracting Cholesterol from Risk Estimation: A Way for a Healthy Longevity?

The role of cholesterol, mainly low-density lipoproteins (LDL-C), as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) is now established and accepted by the international scientific community. Based on this evidence, the European and American guidelines recommend early risk stratification and "rapid" achievement of the suggested target according to the risk estimation to reduce the number of major cardiovascular events. Prolonged exposure over the years to high levels of LDL-C is one of the determining factors in the development and progression of atherosclerotic plaque, on which the action of conventional risk factors (cigarette smoking, excess weight, sedentary lifestyle, arterial hypertension, diabetes mellitus) as well as non-conventional risk factors (gut microbiota, hyperuricemia, inflammation), alone or in combination, favors the destabilization of the atherosclerotic lesion with rupture/fissuration/ulceration and consequent formation of intravascular thrombosis, which leads to the acute clinical manifestations of acute coronary syndromes. In the current clinical practice, there is a growing number of cases that, although extremely common, are emblematic of the concept of long-term exposure to the risk factor (LDL hypercholesterolemia), which, not adequately controlled and in combination with other risk factors, has favored the onset of major cardiovascular events. The triple concept of "go lower, start earlier and keep longer!" should be applied in current clinical practice at any level of prevention. In the present manuscript, we will review the current evidence and documents supporting the causal role of LDL-C in determining ASCVD and whether it is time to remove it from any score.

The Desmoplakin Phenotype Spectrum: Is the Inflammation the "Fil Rouge" Linking Myocarditis, Arrhythmogenic Cardiomyopathy, and Uncommon Autoinflammatory Systemic Disease?

Myocarditis is an inflammatory condition of cardiac tissue presenting significant variability in clinical manifestations and outcomes. Its etiology is diverse, encompassing infectious agents (primarily viruses, but also bacteria, protozoa, and helminths) and non-infectious factors (autoimmune responses, toxins, and drugs), though often the specific cause remains unidentified. Recent research has highlighted the potential role of genetic susceptibility in the development of myocarditis (and in some cases the development of inflammatory dilated cardiomyopathy, i.e., the condition in which there is chronic inflammation (>3 months) and left ventricular dysfunction\dilatation), with several studies indicating a correlation between myocarditis and genetic backgrounds. Notably, pathogenic genetic variants linked to dilated or arrhythmic cardiomyopathy are found in 8-16% of myocarditis patients. Genetic predispositions can lead to recurrent myocarditis and a higher incidence of ventricular arrhythmias and heart failure. Moreover, the presence of DSP mutations has been associated with distinct pathological patterns and clinical outcomes in arrhythmogenic cardiomyopathy (hot phases). The interplay between genetic factors and environmental triggers, such as viral infections and physical stress, is crucial in understanding the pathogenesis of myocarditis. Identifying these genetic markers can improve the diagnosis, risk stratification, and management of patients with myocarditis, potentially guiding tailored therapeutic interventions. This review aims to synthesize current knowledge on the genetic underpinnings of myocarditis, with an emphasis on desmoplakin-related arrhythmogenic cardiomyopathy, to enhance clinical understanding and inform future research directions.

Engineered heart tissue maturation inhibits cardiomyocyte proliferative response to cryoinjury.

The cellular and molecular mechanisms that are responsible for the poor regenerative capacity of the adult heart after myocardial infarction (MI) are still unclear and their understanding is crucial to develop novel regenerative therapies. Considering the lack of reliable in vitro tissue-like models to evaluate the molecular mechanisms of cardiac regeneration, we used cryoinjury on rat Engineered Heart Tissues (rEHTs) as a new model which recapitulates in part the in vivo response after myocardial injury of neonatal and adult heart. When we subjected to cryoinjury immature and mature rEHTs, we observed a significant increase in cardiomyocyte (CM) DNA synthesis when compared to the controls. As expected, the number of mitotic CMs significantly increases in immature rEHTs when compared to mature rEHTs, suggesting that the extent of CM maturation plays a crucial role in their proliferative response after cryoinjury. Moreover, we show that cryoinjury induces a temporary activation of fibroblast response in mature EHTs, similar to the early response after MI, that is however incomplete in immature EHTs. Our results support the hypothesis that the endogenous maturation program in cardiac myocytes plays a major role in determining the proliferative response to injury. Therefore, we propose rEHTs as a robust, novel tool to in vitro investigate critical aspects of cardiac regeneration in a tissue-like asset free from confounding factors in response to injury, such as the immune system response or circulating inflammatory cytokines.

Catch the Cath or Not? A Hamletic Dilemma after 10 Years.

In the last few years, a tremendous advancement has been made in the therapeutical management of several diseases with an increasing need for parental drug administration. To avoid repeated venous insertions and the patient's anxiety related to these procedures, it is now common practice to insert a catheter to leave it in place for a longer time. However, these procedures may generate some complications, such as failure of insertion, embolization, and infection. Different noninvasive techniques have been proposed and used for the retrieval of lost or misplaced foreign objects. Here, we presented a case of the lost fragmented catheter in a young female who underwent a central venous catheter insertion 10 years ago, incidentally detected during an echocardiographic examination. Here, we presented a case of a lost fragmented catheter in a young female who underwent a central venous catheter insertion 10 years before.

Non-Conventional Risk Factors: "Fact" or "Fake" in Cardiovascular Disease Prevention?

Cardiovascular diseases (CVDs), such as arterial hypertension, myocardial infarction, stroke, heart failure, atrial fibrillation, etc., still represent the main cause of morbidity and mortality worldwide. They significantly modify the patients' quality of life with a tremendous economic impact. It is well established that cardiovascular risk factors increase the probability of fatal and non-fatal cardiac events. These risk factors are classified into modifiable (smoking, arterial hypertension, hypercholesterolemia, low HDL cholesterol, diabetes, excessive alcohol consumption, high-fat and high-calorie diet, reduced physical activity) and non-modifiable (sex, age, family history, of previous cardiovascular disease). Hence, CVD prevention is based on early identification and management of modifiable risk factors whose impact on the CV outcome is now performed by the use of CV risk assessment models, such as the Framingham Risk Score, Pooled Cohort Equations, or the SCORE2. However, in recent years, emerging, non-traditional factors (metabolic and non-metabolic) seem to significantly affect this assessment. In this article, we aim at defining these emerging factors and describe the potential mechanisms by which they might contribute to the development of CVD.

Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation.

Therapies halting the progression of fibrosis are ineffective and limited. Activated myofibroblasts are emerging as important targets in the progression of fibrotic diseases. Previously, we performed a high-throughput screen on lung fibroblasts and subsequently demonstrated that the inhibition of myofibroblast activation is able to prevent lung fibrosis in bleomycin-treated mice. High-throughput screens are an ideal method of repurposing drugs, yet they contain an intrinsic limitation, which is the size of the library itself. Here, we exploited the data from our "wet" screen and used "dry" machine learning analysis to virtually screen millions of compounds, identifying novel anti-fibrotic hits which target myofibroblast differentiation, many of which were structurally related to dopamine. We synthesized and validated several compounds ex vivo ("wet") and confirmed that both dopamine and its derivative TS1 are powerful inhibitors of myofibroblast activation. We further used RNAi-mediated knock-down and demonstrated that both molecules act through the dopamine receptor 3 and exert their anti-fibrotic effect by inhibiting the canonical transforming growth factor ß pathway. Furthermore, molecular modelling confirmed the capability of TS1 to bind both human and mouse dopamine receptor 3. The anti-fibrotic effect on human cells was confirmed using primary fibroblasts from idiopathic pulmonary fibrosis patients. Finally, TS1 prevented and reversed disease progression in a murine model of lung fibrosis. Both our interdisciplinary approach and our novel compound TS1 are promising tools for understanding and combating lung fibrosis.

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 naïve 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.

Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice.

Insulin resistance is associated with aging in mice and humans. We have previously shown that administration of recombinant GDF11 (rGDF11) to aged mice alters aging phenotypes in the brain, skeletal muscle, and heart. While the closely related protein GDF8 has a role in metabolism, limited data are available on the potential metabolic effects of GDF11 or GDF8 in aging. To determine the metabolic effects of these two ligands, we administered rGDF11 or rGDF8 protein to young or aged mice fed a standard chow diet, short-term high-fat diet (HFD), or long-term HFD. Under nearly all of these diet conditions, administration of exogenous rGDF11 reduced body weight by 3-17% and significantly improved glucose tolerance in aged mice fed a chow (~30% vs. saline) or HF (~50% vs. saline) diet and young mice fed a HFD (~30%). On the other hand, exogenous rGDF8 showed signifcantly lesser effect or no effect at all on glucose tolerance compared to rGDF11, consistent with data demonstrating that GFD11 is a more potent signaling ligand than GDF8. Collectively, our results show that administration of exogenous rGDF11, but not rGDF8, can reduce diet-induced weight gain and improve metabolic homeostasis.

Colchicine reduces platelet aggregation by modulating cytoskeleton rearrangement via inhibition of cofilin and LIM domain kinase 1.

INTRODUCTION: Platelets activation/aggregation with subsequent thrombus formation is the main event in the pathophysiology of acute coronary syndrome. Once activated, platelets show an extensive cytoskeleton rearrangement that leads to recruitment of additional platelets to finally cause haemostatic plug formation. Thus, the cytoskeleton plays a pivotal role in this phenomenon. Colchicine (COLC) is an anti-inflammatory drug proven to reduce major cardiovascular events in patients with coronary artery disease. The molecular mechanisms by which COLC exerts these protective effects remain partially still unknown. Since COLC causes disruption of tubulin, a component of cell cytoskeleton, we investigated whether this drug might interfere with platelet aggregation by acting on cytoskeleton rearrangement. METHODS AND RESULTS: Platelets isolated from healthy volunteers were activated with Adenosine Diphosphate (ADP, 20 µM) Collagen (COLL, 60 µg/ml) and Thrombin Activating Receptor Peptide (TRAP 25 µM) with/without COLC 10 µM pretreatment. After stimulus, aggregation was measured by light aggregometry overtime. Microtubules structure was assessed by immunohistochemistry and key proteins involved in regulation of actin-filament assembly and contractility such as Myosin Phosphatase Targeting subunit (MYPT), LIM domain kinase 1(LIMK1) and cofilin were evaluated by Western Blot analysis. Colchicine pretreatment significantly blunted ADP/COLL/TRAP-induced platelet aggregation (up to 40%). COLC effects appeared mediated by microtubules depolymerization and cytoskeleton disarrangement associated to inactivation of MYPT and LIMK1 that finally interfered with cofilin activity. CONCLUSIONS: Our data indicate that colchicine exerts anti-platelet effects in vitro via inhibition of key proteins involved in cytoskeleton rearrangement, suggesting that its beneficial cardiovascular properties may be due, at least in part, to an inhibitory effect of platelet activity.