Luigi Yuri Di Marco

Vascular dysfunction in the pathogenesis of Alzheimer's disease - A review of endothelium-mediated mechanisms and ensuing vicious circles.

Late-onset dementia is a major health concern in the ageing population. Alzheimers disease (AD) accounts for the largest proportion (65-70%) of dementia cases in the older population. Despite considerable research effort, the pathogenesis of late-onset AD remains unclear. Substantial evidence suggests that the neurodegenerative process is initiated by chronic cerebral hypoperfusion (CCH) caused by ageing and cardiovascular conditions. CCH causes reduced oxygen, glucose and other nutrient supply to the brain, with direct damage not only to the parenchymal cells, but also to the blood-brain barrier (BBB), a key mediator of cerebral homeostasis. BBB dysfunction mediates the indirect neurotoxic effects of CCH by promoting oxidative stress, inflammation, paracellular permeability, and dysregulation of nitric oxide, a key regulator of regional blood flow. As such, BBB dysfunction mediates a vicious circle in which cerebral perfusion is reduced further and the neurodegenerative process is accelerated. Endothelial interaction with pericytes and astrocytes could also play a role in the process. Reciprocal interactions between vascular dysfunction and neurodegeneration could further contribute to the development of the disease. A comprehensive overview of the complex scenario of interacting endothelium-mediated processes is currently lacking, and could prospectively contribute to the identification of adequate therapeutic interventions. This study reviews the current literature of in vitro and ex vivo studies on endothelium-mediated mechanisms underlying vascular dysfunction in AD pathogenesis, with the aim of presenting a comprehensive overview of the complex network of causative relationships. Particular emphasis is given to vicious circles which can accelerate the process of neurovascular degeneration.

Modifiable Lifestyle Factors in Dementia: A Systematic Review of Longitudinal Observational Cohort Studies

BACKGROUND Numerous population-based longitudinal studies suggest an association between modifiable lifestyle factors and late-life dementia. A comprehensive description of these factors and their quantification criteria is an important preliminary step toward the elucidation of causes and mechanisms underlying the onset and progression of dementia. OBJECTIVE To present a systematic review of modifiable lifestyle factors associated with dementia risk in longitudinal observational cohort-studies. METHODS A systematic review of original articles, published in English until December 2013, listed in four electronic databases (including PubMed, MEDLINE, PsycINFO) was conducted. RESULTS 75 papers from 33 epidemiologic studies met the inclusion criteria. Included papers focused on dietary habits (n = 26), leisure activities (social, physical, mental) (n = 23), beverages (juice, tea, coffee, alcohol) (n = 15), smoking (n = 13), social network (n = 6), and combined lifestyle factors (n = 2). CONCLUSIONS Broad consensus emerged on the protective role against dementia of leisure activities. Conflicting results were found for the association between dementia and putative risk factors (smoking) and protective factors (mild-to-moderate alcohol consumption, dietary antioxidants, Mediterranean diet, and living with others). However, studies varied largely in the quantification of lifestyle factors in terms of intensity, frequency and duration of exposure, and in the choice of confounders in statistical analyses. The need for standardized quantification criteria emerges, together with the current limitation in reliably tracking the past history of each patient, from childhood and young adulthood to midlife.

A wavelet-based ECG delineation algorithm for 32-bit integer online processing

BackgroundSince the first well-known electrocardiogram (ECG) delineator based on Wavelet Transform (WT) presented by Li et al. in 1995, a significant research effort has been devoted to the exploitation of this promising method. Its ability to reliably delineate the major waveform components (mono- or bi-phasic P wave, QRS, and mono- or bi-phasic T wave) would make it a suitable candidate for efficient online processing of ambulatory ECG signals. Unfortunately, previous implementations of this method adopt non-linear operators such as root mean square (RMS) or floating point algebra, which are computationally demanding.MethodsThis paper presents a 32-bit integer, linear algebra advanced approach to online QRS detection and P-QRS-T waves delineation of a single lead ECG signal, based on WT.ResultsThe QRS detector performance was validated on the MIT-BIH Arrhythmia Database (sensitivity Se = 99.77%, positive predictive value P+ = 99.86%, on 109010 annotated beats) and on the European ST-T Database (Se = 99.81%, P+ = 99.56%, on 788050 annotated beats). The ECG delineator was validated on the QT Database, showing a mean error between manual and automatic annotation below 1.5 samples for all fiducial points: P-onset, P-peak, P-offset, QRS-onset, QRS-offset, T-peak, T-offset, and a mean standard deviation comparable to other established methods.ConclusionsThe proposed algorithm exhibits reliable QRS detection as well as accurate ECG delineation, in spite of a simple structure built on integer linear algebra.

Is Vasomotion in Cerebral Arteries Impaired in Alzheimer’s Disease?

Abstract A substantial body of evidence supports the hypothesis of a vascular component in the pathogenesis of Alzheimer’s disease (AD). Cerebral hypoperfusion and blood-brain barrier dysfunction have been indicated as key elements of this pathway. Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder, frequent in AD, characterized by the accumulation of amyloid-β (Aβ) peptide in cerebral blood vessel walls. CAA is associated with loss of vascular integrity, resulting in impaired regulation of cerebral circulation, and increased susceptibility to cerebral ischemia, microhemorrhages, and white matter damage. Vasomotion— the spontaneous rhythmic modulation of arterial diameter, typically observed in arteries/arterioles in various vascular beds including the brain— is thought to participate in tissue perfusion and oxygen delivery regulation. Vasomotion is impaired in adverse conditions such as hypoperfusion and hypoxia. The perivascular and glymphatic pathways of Aβ clearance are thought to be driven by the systolic pulse. Vasomotion produces diameter changes of comparable amplitude, however at lower rates, and could contribute to these mechanisms of Aβ clearance. In spite of potential clinical interest, studies addressing cerebral vasomotion in the context of AD/CAA are limited. This study reviews the current literature on vasomotion, and hypothesizes potential paths implicating impaired cerebral vasomotion in AD/CAA. Aβ and oxidative stress cause vascular tone dysregulation through direct effects on vascular cells, and indirect effects mediated by impaired neurovascular coupling. Vascular tone dysregulation is further aggravated by cholinergic deficit and results in depressed cerebrovascular reactivity and (possibly) impaired vasomotion, aggravating regional hypoperfusion and promoting further Aβ and oxidative stress accumulation.

Characteristics of atrial fibrillation cycle length predict restoration of sinus rhythm by catheter ablation

BACKGROUND Successful termination of atrial fibrillation (AF) during catheter ablation (CA) is associated with arrhythmia-free follow-up. Preablation factors such as mean atrial fibrillation cycle length (AFCL) predict the likelihood of AF termination during ablation but recurring patterns and AFCL stability have not been evaluated. OBJECTIVE To investigate novel predictors of acute and postoperative ablation outcomes from intracardiac electrograms: (1) recurring AFCL patterns and (2) localization index (LI) of the instantaneous fibrillatory rate distribution. METHODS Sixty-two patients with AF (32 paroxysmal AF; 45 men; age 57 ± 10 years) referred for CA were enrolled. One-minute electrogram was recorded from coronary sinus (CS; 5 bipoles) and right atrial appendage (HRA; 2 bipoles). Atrial activations were detected automatically to derive the AFCL and instantaneous fibrillatory rate (inverse of AFCL) time series. Recurring AFCL patterns were quantified by using recurrence plot indices (RPIs): percentage determinism, entropy of determinism, and maximum diagonal length. AFCL stability was determined by using the LI. The CA outcome predictivity of individual indices was assessed. RESULTS Patients with terminated atrial fibrillation (T-AF) had higher RPI (P < .05 in CS7-8) and LI than did those with nonterminated atrial fibrillation (P < .005 in CS3-4; P < .05 in CS5-6, CS7-8, and HRA). Patients free of arrhythmia after 3-month follow-up had higher RPI and LI (all P < .05 in CS7-8). All indices except percentage determinism predicted T-AF in CS7-8 (area under the curve [AUC] ≥ 0.71; odds ratio [OR] ≥ 4.50; P < .05). The median AFCL and LI predicted T-AF in HRAD (AUC ≥ 0.75; OR ≥ 7.76; P < .05). The RPI and LI predicted 3-month follow-up in CS7-8 (AUC ≥ 0.68; OR ≥ 4.17; P < .05). CONCLUSIONS AFCL recurrence and stability indices could be used in selecting patients more likely to benefit from CA.

Systematic comparison of non-invasive measures for the assessment of atrial fibrillation complexity: a step forward towards standardization of atrial fibrillation electrogram analysis

AIMS To present a comparison of electrocardiogram-based non-invasive measures of atrial fibrillation (AF) substrate complexity computed on invasive animal recordings to discriminate between short-term and long-term AF. The final objective is the selection of an optimal sub-set of measures for AF complexity assessment. METHODS AND RESULTS High-density epicardial direct contact mapping recordings (234 leads) were acquired from the right and the left atria of 17 goats in which AF was induced for 3 weeks (short-term AF group, N = 10) and 6 months (long-term AF group, N = 7). Several non-invasive measures of AF organization proposed in the literature in the last decade were investigated to assess their power in discriminating between the short-term and long-term group. The best performing measures were identified, which when combined attained a correct classification rate of 100%. Their ability to predict standard invasive AF complexity measures was also tested, showing an average R(2) of 0.73 ± 0.04. CONCLUSION An optimal set of measures of the AF substrate complexity was identified out of the set of non-invasive measures analysed in this study. These measures may contribute to improve patient-tailored diagnosis and therapy of sustained AF.

Recurring patterns of atrial fibrillation in surface ECG predict restoration of sinus rhythm by catheter ablation

BACKGROUND Non-invasive tools to help identify patients likely to benefit from catheter ablation (CA) of atrial fibrillation (AF) would facilitate personalised treatment planning. AIM To investigate atrial waveform organisation through recurrence plot indices (RPI) and their ability to predict CA outcome. METHODS One minute 12-lead ECG was recorded before CA from 62 patients with AF (32 paroxysmal AF; 45 men; age 57±10 years). Organisation of atrial waveforms from i) TQ intervals in V1 and ii) QRST suppressed continuous AF waveforms (CAFW), were quantified using RPI: percentage recurrence (PR), percentage determinism (PD), entropy of recurrence (ER). Ability to predict acute (terminating vs. non-terminating AF), 3-month and 6-month postoperative outcome (AF vs. AF free) were assessed. RESULTS RPI either by TQ or CAFW analysis did not change significantly with acute outcome. Patients arrhythmia-free at 6-month follow-up had higher organisation in TQ intervals by PD (p<0.05) and ER (p<0.005) and both were significant predictors of 6-month outcome (PD (AUC=0.67, p<0.05) and ER (AUC=0.72, p<0.005)). For paroxysmal AF cases, all RPI predicted 3-month (AUC(ER)=0.78, p<0.05; AUC(PD)=0.79, p<0.05; AUC(PR)=0.80, p<0.01) and 6-month (AUC(ER)=0.81, p<0.005; AUC(PD)=0.75, p<0.05; AUC(PR)=0.71, p<0.05) outcome. CAFW-derived RPIs did not predict acute or postoperative outcomes. Higher values of any RPI from TQ (values greater than 25th percentile of preoperative distribution) were associated with decreased risk of AF relapse at follow-up (hazard ratio ≤0.52, all p<0.05). CONCLUSIONS Recurring patterns from preprocedural 1-minute recordings of ECG TQ intervals were significant predictors of CA 6-month outcome.

Electrocardiographic Reference Values for a Population of Older Adults in Sub‐Saharan Africa

Older adults in sub‐Saharan Africa (SSA) are at greatest risk of an impending noncommunicable diseases epidemic, of which cardiac disease is the most prevalent contributor. Thus, it is essential to establish electrocardiographic reference values for a population that is likely to differ genetically and environmentally from others where reference values are established.

Protective Role of False Tendon in Subjects with Left Bundle Branch Block: A Virtual Population Study

False tendons (FTs) are fibrous or fibromuscular bands that can be found in both the normal and abnormal human heart in various anatomical forms depending on their attachment points, tissue types, and geometrical properties. While FTs are widely considered to affect the function of the heart, their specific roles remain largely unclear and unexplored. In this paper, we present an in silico study of the ventricular activation time of the human heart in the presence of FTs. This study presents the first computational model of the human heart that includes a FT, Purkinje network, and papillary muscles. Based on this model, we perform simulations to investigate the effect of different types of FTs on hearts with the electrical conduction abnormality of a left bundle branch block (LBBB). We employ a virtual population of 70 human hearts derived from a statistical atlas, and run a total of 560 simulations to assess ventricular activation time with different FT configurations. The obtained results indicate that, in the presence of a LBBB, the FT reduces the total activation time that is abnormally augmented due to a branch block, to such an extent that surgical implant of cardiac resynchronisation devices might not be recommended by international guidelines. Specifically, the simulation results show that FTs reduce the QRS duration at least 10 ms in 80% of hearts, and up to 45 ms for FTs connecting to the ventricular free wall, suggesting a significant reduction of cardiovascular mortality risk. In further simulation studies we show the reduction in the QRS duration is more sensitive to the shape of the heart then the size of the heart or the exact location of the FT. Finally, the model suggests that FTs may contribute to reducing the activation time difference between the left and right ventricles from 12 ms to 4 ms. We conclude that FTs may provide an alternative conduction pathway that compensates for the propagation delay caused by the LBBB. Further investigation is needed to quantify the clinical impact of FTs on cardiovascular mortality risk.

Screening for Cognitive Impairment by Model-Assisted Cerebral Blood Flow Estimation

Objective: Alzheimers disease (AD) is a progressive and debilitating neurodegenerative disease; a major health concern in the ageing population with an estimated prevalence of 46 million dementia cases worldwide. Early diagnosis is therefore crucial so mitigating treatments can be initiated at an early stage. Cerebral hypoperfusion has been linked with blood-brain barrier dysfunction in the early stages of AD, and screening for chronic cerebral hypoperfusion in individuals has been proposed for improving the early diagnosis of AD. However, ambulatory measurements of cerebral blood flow are not routinely carried out in the clinical setting. In this study, we combine physiological modeling with Holter blood pressure monitoring and carotid ultrasound imaging to predict 24-h cerebral blood flow (CBF) profiles in individuals. One hundred and three participants [53 with mild cognitive impairment (MCI) and 50 healthy controls] underwent model-assisted prediction of 24-h CBF. Model-predicted CBF and neuropsychological tests were features in lasso regression models for MCI diagnosis. Results: A CBF-enhanced classifier for diagnosing MCI performed better, area-under-the-curve (AUC) = 0.889 (95%-CI: 0.800 to 0.978), than a classifier based only on the neuropsychological test scores, AUC = 0.818 (95%-CI: 0.643 to 0.992). An additional cohort of 25 participants (11 MCI and 14 healthy) was recruited to perform model validation by arterial spin-labeling magnetic resonance imaging, and to establish a link between measured CBF that predicted by the model. Conclusion: Ultrasound imaging and ambulatory blood pressure measurements enhanced with physiological modeling can improve MCI diagnosis accuracy.