Constantinos H. Davos

Regulation of adverse remodelling by osteopontin in a genetic heart failure model

AIMSnDesmin, the muscle-specific intermediate filament protein, is a major target in dilated cardiomyopathy and heart failure in humans and mice. The hallmarks of desmin-deficient (des(-/-)) mice pathology include pronounced myocardial degeneration, extended fibrosis, and osteopontin (OPN) overexpression. We sought to identify the molecular and cellular events regulating adverse cardiac remodelling in des(-/-) mice and their potential link to OPN.nnnMETHODS AND RESULTSnIn situ hybridization, histology, and immunostaining demonstrated that inflammatory cells and not cardiomyocytes were the source of OPN. RNA profile comparison revealed that activation of inflammatory pathways, sustained by innate immunity mechanisms, predominated among all changes occurring in degenerating des(-/-) myocardium. The expression of the most highly up-regulated genes (OPN: 226×, galectin-3: 26×, osteoactivin/Gpnmb/DC-HIL: 160× and metalloprotease-12: 98×) was associated with heart infiltrating macrophages. To evaluate the role of OPN, we generated des(-/-)OPN(-/-) mice and compared their cardiac function and remodelling indices with those of des(-/-). Osteopontin promoted cardiac dysfunction in this model since des(-/-)OPN(-/-) mice showed 53% improvement of left ventricular function, paralleled to an up to 44% reduction in fibrosis. The diminished fibrotic response in the absence of OPN could be partly mediated by a dramatic reduction in myocardial galectin-3 levels, associated with an impaired galectin-3 secretion by OPN-deficient infiltrating macrophages.nnnCONCLUSIONnCardiomyocyte death due to desmin deficiency leads to inflammation and subsequent overexpression of a series of remodelling modulators. Among them, OPN seems to be a major regulator of des(-/-) adverse myocardial remodelling and it functions at least by potentiating galectin-3 up-regulation and secretion.

The prognostic effect of cardiac rehabilitation in the era of acute revascularisation and statin therapy: A systematic review and meta-analysis of randomized and non-randomized studies – The Cardiac Rehabilitation Outcome Study (CROS)

Background The prognostic effect of multi-component cardiac rehabilitation (CR) in the modern era of statins and acute revascularisation remains controversial. Focusing on actual clinical practice, the aim was to evaluate the effect of CR on total mortality and other clinical endpoints after an acute coronary event. Design Structured review and meta-analysis. Methods Randomised controlled trials (RCTs), retrospective controlled cohort studies (rCCSs) and prospective controlled cohort studies (pCCSs) evaluating patients after acute coronary syndrome (ACS), coronary artery bypass grafting (CABG) or mixed populations with coronary artery disease (CAD) were included, provided the index event was in 1995 or later. Results Out of nu2009=u200918,534 abstracts, 25 studies were identified for final evaluation (RCT: nu2009=u20091; pCCS: nu2009=u20097; rCCS: nu2009=u200917), including nu2009=u2009219,702 patients (after ACS: nu2009=u200946,338; after CABG: nu2009=u200914,583; mixed populations: nu2009=u2009158,781; mean follow-up: 40 months). Heterogeneity in design, biometrical assessment of results and potential confounders was evident. CCSs evaluating ACS patients showed a significantly reduced mortality for CR participants (pCCS: hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.20–0.69; rCCS: HR 0.64, 95% CI 0.49–0.84; odds ratio 0.20, 95% CI 0.08–0.48), but the single RCT fulfilling Cardiac Rehabilitation Outcome Study (CROS) inclusion criteria showed neutral results. CR participation was also associated with reduced mortality after CABG (rCCS: HR 0.62, 95% CI 0.54–0.70) and in mixed CAD populations. Conclusions CR participation after ACS and CABG is associated with reduced mortality even in the modern era of CAD treatment. However, the heterogeneity of study designs and CR programmes highlights the need for defining internationally accepted standards in CR delivery and scientific evaluation.

Psychological consequences among adults following the 1999 earthquake in Athens, Greece

One year after the 7 September 1999 earthquake in Athens, Greece, we investigated the psychological consequences among 305 individuals (71 per cent female) residing in the settlements of Ano Liosia Municipality. Adaptability was difficult (63 per cent) due to limited space (50 per cent). Insecurity feelings were predictive of difficult adaptability (chi2= 29.8, p<0.0001) and were common (63 per cent) among married subjects, independent of age (chi2= 5.0, odds ratio (OR): 0.49, 95 per cent confidence interval (CI): 0.26-0.90). Eighty per cent expressed stress feelings, mainly nervousness/tension (60 per cent). Adaptability (chi2= 5.3, OR: 0.5, 95 per cent CI: 0.27-0.9), age (chi2= 6.5, OR: 1.03, 95 per cent CI: 1.01-1.06), and female gender (chi2= 4.7, OR: 0.48, 95 per cent CI: 0.25-0.90) were independent predictors of stress feelings. The majority (55 percent) developed sleep disorders, chiefly insomnia (60 percent). Adaptability problems were the only predictor of sleep disorders (chi2= 6.4, OR: 0.5, 95 per cent CI: 0.33-0.87). Psychiatric medication use increased after the earthquake.

Local Hemodynamics and Intimal Hyperplasia at the Venous Side of a Porcine Arteriovenous Shunt

Venous anastomotic intimal hyperplasia (IH) observed in the arteriovenous shunt (AVS) has been associated with disturbed hemodynamics. This study aims to correlate hemodynamics with wall histology and wall mechanics by examining the flow field in AVS with computational fluid dynamics using experimental data taken from in vivo experiments. Input data to the computational model were obtained in vivo one month after AVS creation; adjacent vessels were submitted to histological and mechanical examination. The 3-D shunt geometry was determined using biplane angiography. Ultrasound measurements of flow rates were performed with perivascular flow probes and pressures were recorded through intravascular catheters. These data were considered as boundary conditions for calculation of the unsteady flow field. Numerical findings are suggestive of strong Dean vortices toward both vein flow exits, verified by color Doppler. The high wall shear stresses (WSSs) and their gradients appear to be related to areas of IH and vessel wall stiffening, as evidenced in preliminary histological and mechanical studies of the venous wall. Additionally, suture line hyperplasia seems to be aggravated by the high WSS gradients noted at the transition line from graft to vein.

Frailty and cardiac rehabilitation: A call to action from the EAPC Cardiac Rehabilitation Section

Frailty is a geriatric syndrome characterised by a vulnerability status associated with declining function of multiple physiological systems and loss of physiological reserves. Two main models of frailty have been advanced: the phenotypic model (primary frailty) or deficits accumulation model (secondary frailty), and different instruments have been proposed and validated to measure frailty. However measured, frailty correlates to medical outcomes in the elderly, and has been shown to have prognostic value for patients in different clinical settings, such as in patients with coronary artery disease, after cardiac surgery or transvalvular aortic valve replacement, in patients with chronic heart failure or after left ventricular assist device implantation. The prevalence, clinical and prognostic relevance of frailty in a cardiac rehabilitation setting has not yet been well characterised, despite the increasing frequency of elderly patients in cardiac rehabilitation, where frailty is likely to influence the onset, type and intensity of the exercise training programme and the design of tailored rehabilitative interventions for these patients. Therefore, we need to start looking for frailty in elderly patients entering cardiac rehabilitation programmes and become more familiar with some of the tools to recognise and evaluate the severity of this condition. Furthermore, we need to better understand whether exercise-based cardiac rehabilitation may change the course and the prognosis of frailty in cardiovascular patients.

The European Association of Preventive Cardiology Exercise Prescription in Everyday Practice and Rehabilitative Training (EXPERT) tool: A digital training and decision support system for optimized exercise prescription in cardiovascular disease. Concept, definitions and construction methodology

Background Exercise rehabilitation is highly recommended by current guidelines on prevention of cardiovascular disease, but its implementation is still poor. Many clinicians experience difficulties in prescribing exercise in the presence of different concomitant cardiovascular diseases and risk factors within the same patient. It was aimed to develop a digital training and decision support system for exercise prescription in cardiovascular disease patients in clinical practice: the European Association of Preventive Cardiology Exercise Prescription in Everyday Practice and Rehabilitative Training (EXPERT) tool. Methods EXPERT working group members were requested to define (a) diagnostic criteria for specific cardiovascular diseases, cardiovascular disease risk factors, and other chronic non-cardiovascular conditions, (b) primary goals of exercise intervention, (c) disease-specific prescription of exercise training (intensity, frequency, volume, type, session and programme duration), and (d) exercise training safety advices. The impact of exercise tolerance, common cardiovascular medications and adverse events during exercise testing were further taken into account for optimized exercise prescription. Results Exercise training recommendations and safety advices were formulated for 10 cardiovascular diseases, five cardiovascular disease risk factors (type 1 and 2 diabetes, obesity, hypertension, hypercholesterolaemia), and three common chronic non-cardiovascular conditions (lung and renal failure and sarcopaenia), but also accounted for baseline exercise tolerance, common cardiovascular medications and occurrence of adverse events during exercise testing. An algorithm, supported by an interactive tool, was constructed based on these data. This training and decision support system automatically provides an exercise prescription according to the variables provided. Conclusion This digital training and decision support system may contribute in overcoming barriers in exercise implementation in common cardiovascular diseases.

Desmin and αB-crystallin interplay in the maintenance of mitochondrial homeostasis and cardiomyocyte survival

ABSTRACT The association of desmin with the α-crystallin Β-chain (αΒ-crystallin; encoded by CRYAB), and the fact that mutations in either one of them leads to heart failure in humans and mice, suggests a potential compensatory interplay between the two in cardioprotection. To address this hypothesis, we investigated the consequences of αΒ-crystallin overexpression in the desmin-deficient (Des−/−) mouse model, which possesses a combination of the pathologies found in most cardiomyopathies, with mitochondrial defects as a hallmark. We demonstrated that cardiac-specific αΒ-crystallin overexpression ameliorates all these defects and improves cardiac function to almost wild-type levels. Protection by αΒ-crystallin overexpression is linked to maintenance of proper mitochondrial protein levels, inhibition of abnormal mitochondrial permeability transition pore activation and maintenance of mitochondrial membrane potential (Δψm). Furthermore, we found that both desmin and αΒ-crystallin are localized at sarcoplasmic reticulum (SR)–mitochondria-associated membranes (MAMs), where they interact with VDAC, Mic60 – the core component of mitochondrial contact site and cristae organizing system (MICOS) complex – and ATP synthase, suggesting that these associations could be crucial in mitoprotection at different levels. Highlighted Article: Both desmin and its partner chaperone αB-crystallin associate with mitochondria–sarcoplasmic-reticulum contact sites (MAMs), stabilizing MICOS super-complexes, and thus contributing to proper mitochondrial cristae structure–function.

Complement system modulation as a target for treatment of arrhythmogenic cardiomyopathy

AbstractInflammation may contribute to ndisease progression in arrhythmogenic cardiomyopathy (ACM). However, its role in this process is unresolved. Our goal was to delineate the pathogenic role of the complement system in a new animal model of ACM and in human disease. Using cardiac histology, echocardiography, and electrocardiography, we have demonstrated that the desmin-null mouse (Des−/−) recapitulates most of the pathognomonic features of human ACM. Massive complement activation was observed in the Des−/− myocardium in areas of necrotic cells debris and inflammatory infiltrate. Analysis of C5aR−/−Des−/− double-null animals and a pharmaceutical approach using a C5a inhibitor were used to delineate the pathogenic role of the complement system in the disease progression. Our findings indicate that inhibiting C5aR (CD88) signaling improves cardiac function, histopathology, arrhythmias, and survival after endurance. Containment of the inflammatory reaction at the initiation of cardiac tissue injury (2–3xa0weeks of age), with consequently reduced myocardial remodeling and the absence of a direct long-lasting detrimental effect of C5a–C5aR signaling on cardiomyocytes, could explain the beneficial action of C5aR ablation in Des−/− cardiomyopathy. We extend the relevance of these findings to human pathophysiology by showing for the first time significant complement activation in the cardiac tissues of patients with ACM, thus suggesting that complement modulation could be a new therapeutic target for ACM.

Neurohormonal activity and vascular properties late after aortic coarctation repair

BACKGROUNDnCoarctation of aorta (CoA) patients present cardiovascular complications late after repair the causes of which are not fully understood. Our study investigates the neurohormonal and immune activation and the elastic properties of the aorta and peripheral vessels in adult patients with coarctation of aorta (CoA), late after repair.nnnMETHODSnNineteen adult patients with repaired CoA and 29 matched healthy controls underwent aortic distensibility, stiffness index, a study of the elastic properties of peripheral vessels proximal to the coarctation site and measurement of plasma cytokine and neurohormone levels.nnnRESULTSnDistensibility index was reduced (p=0.02) and stiffness index was increased (p=0.005) in CoA patients compared to control. Augmentation index (p=0.0007) and augmented pressure (p=0.001) were higher in CoA patients and Forearm Blood Flow (FBF) index was reduced (p=0.009). Plasma levels of sICAM-1 (p=0.01), sVCAM-1 (p=0.05), E-selectin (p=0.01), sFas-ligand (p=0.02) and IL-10 (p=0.01) were also elevated in CoA patients vs control. TNF-a, IL-6, Endothelin-1 and NT-pro-BNP levels were not.nnnCONCLUSIONSnAdults with repaired CoA seem to develop a late inflammatory reaction, which reflects a functional problem in all vessels, regardless of the initial lesion. This may explain the late complications of the disease despite early repair and improved surgical procedures.

Exercise-based cardiac rehabilitation in twelve European countries results of the European cardiac rehabilitation registry

AIMnResults from EuroCaReD study should serve as a benchmark to improve guideline adherence and treatment quality of cardiac rehabilitation (CR) in Europe.nnnMETHODS AND RESULTSnData from 2.054 CR patients in 12 European countries were derived from 69 centres. 76% were male. Indication for CR differed between countries being predominantly ACS in Switzerland (79%), Portugal (62%) and Germany (61%), elective PCI in Greece (37%), Austria (36%) and Spain (32%), and CABG in Croatia and Russia (36%). A minority of patients presented with chronic heart failure (4%). At CR start, most patients already were under medication according to current guidelines for the treatment of CV risk factors. A wide range of CR programme designs was found (duration 3 to 24weeks; total number of sessions 30 to 196). Patient programme adherence after admission was high (85%). With reservations that eCRF follow-up data exchange remained incomplete, patient CV risk profiles experienced only small improvements. CR success as defined by an increase of exercise capacity >25W was significantly higher in young patients and those who were employed. Results differed by countries. After CR only 9% of patients were admitted to a structured post-CR programme.nnnCONCLUSIONSnClinical characteristics of CR patients, indications and programmes in Europe are different. Guideline adherence is poor. Thus, patient selection and CR programme designs should become more evidence-based. Routine eCRF documentation of CR results throughout European countries was not sufficient in its first application because of incomplete data exchange. Therefore better adherence of CR centres to minimal routine clinical standards is requested.