Initial investigation of athletes’ electrocardiograms acquired by wearable sensors during the pre-exercise phase

Aim: The aim of this study is to support large-scale prevention programs fighting sport-related sudden cardiac death by providing a set of electrocardiographic features representing a starting point in the development of normal reference values for the pre-exercise phase. Background: In people with underlying, often unknown, cardiovascular abnormalities, increased cardiovascular load during exercise can trigger sport-related sudden cardiac death. Prevention remains the only weapon to contrast sport-related sudden cardiac death. So far, no reference values have been proposed for electrocardiograms of athletes acquired with wearable sensors in the pre-exercise phase, consisting of the few minutes immediately before the beginning of the training session. Objective: To perform an initial investigation of athletes’ electrocardiograms acquired by wearable sensors during the pre-exercise phase. Methods: The analyzed electrocardiograms, acquired through BioHarness 3.0 by Zephyr, belong to 51 athletes (Sport Database and Cycling Database of the Cardiovascular Bioengineering Lab of the Università Politecnica delle Marche, Italy). Preliminary values consist of interquartile ranges of six electrocardiographic features which are heart rate, heart-rate variability, QRS duration, ST level, QT interval, and corrected QT interval. Results: For athletes 35 years old or younger, preliminary values were [72;91]bpm, [26;47]ms, [85;104]ms, [-0.08;0.08]mm, [326;364]ms and [378;422]ms, respectively. For athletes older than 35 years old, preliminary values were [71;94]bpm, [16;65]ms, [85;100]ms, [-0.11;0.07]mm, [330;368]ms and [394;414]ms, respectively. Conclusion: Availability of preliminary reference values could help identify those athletes who, due to electrocardiographic features out of normal ranges, are more likely to develop cardiac complications that may lead to sport-related sudden cardiac death

Enhanced adaptive matched filter for automated identification and measurement of electrocardiographic alternans

Electrocardiographic alternans, consisting of P-wave alternans (PWA), QRS-complex alternans (QRSA) and Twave alternans (TWA), is an index of cardiac risk. However, only automated TWA measurement methods have been proposed so far. Here, we presented the enhanced adaptive matched filter (EAMF) method and tested its reliability in both simulated and experimental conditions. Our methodological novelty consists in the introduction of a signal enhancement procedure according to which all sections of the electrocardiogram (ECG) but the wave of interest are set to baseline, and in the extraction of the alternans area (AAr) in addition to the standard alternans amplitude (AAm). Simulated data consisted of 27 simulated ECGs representing all combinations of PWA, QRSA and TWA of low (10 mu V) and high (100 mu V) amplitude. Experimental data consisted of exercise 12-lead ECGs from 266 heart failure patients with an implanted cardioverter defibrillator for primary prevention. EAMF was able to accurately identify and measure all kinds of simulated alternans (absolute maximum error equal to 2%). Moreover, different alternans kinds were simultaneously present in the experimental data and EAMF was able to identify and measure all of them (AAr: 545 mu V x ms, 762 mu V x ms and 1382 mu V x ms; AAm: 5 mu V, 9 mu V and 7 mu V; for PWA, QRSA and TWA, respectively) and to discriminate TWA as the prevalent one (with the highest AAr). EAMF accurately identifies and measures all kinds of electrocardiographic alternans. EAMF may support determination of incremental clinical utility of PWA and QRSA with respect to TWA only.Cardiolog

Nanodiamond quantum sensors reveal temperature variation associated to hippocampal neurons firing

Temperature is one of the most relevant parameters for the regulation of intracellular processes. Measuring localized subcellular temperature gradients is fundamental for a deeper understanding of cell function, such as the genesis of action potentials, and cell metabolism. Here, we detect for the first time temperature variations (1{\deg}C) associated with potentiation and depletion of neuronal firing, exploiting a nanoscale thermometer based on optically detected magnetic resonance in nanodiamonds. Our results provide a tool for assessing neuronal spiking activity under physiological and pathological conditions and, conjugated with the high sensitivity of this technique (in perspective sensitive to < 0.1{\deg}C variations), pave the way to a systematic study of the generation of localized temperature gradients. Furthermore, they prompt further studies explaining in detail the physiological mechanism originating this effect.Comment: 27 pages, 5 figures, 3 table

Microparticles Carrying Sonic Hedgehog Are Increased in Humans with Peripheral Artery Disease.

Sonic hedgehog (Shh) is a prototypical angiogenic agent with a crucial role in the regulation of angiogenesis. Experimental studies have shown that Shh is upregulated in response to ischemia. Also, Shh may be found on the surface of circulating microparticles (MPs) and MPs bearing Shh (Shh + MPs) have shown the ability to contribute to reparative neovascularization after ischemic injury in mice. The goal of this study was to test the hypothesis that, in humans with peripheral artery disease (PAD), there is increased number of circulating Shh + MPs. This was done by assessing the number of Shh + MPs in plasma of patients with PAD and control subjects without PAD. We found significantly higher number of Shh + MPs in plasma of subjects with PAD, compared to controls, while the global number of MPs\u2014produced either by endothelial cells, platelets, leukocytes, and erythrocytes\u2014was not different between PAD patients and controls. We also found a significant association between the number of Shh + MPs and the number of collateral vessels in the ischemic limbs of PAD patients. Interestingly, the concentration of Shh protein unbound to MPs\u2014which was measured in MP-depleted plasma\u2014was not different between subjects with PAD and the controls, indicating that, in the setting of PAD, the call for Shh recapitulation does not lead to secretion of protein into the blood but to binding of the protein to the membrane of MPs. These findings provide novel information on Shh signaling during ischemia in humans, with potentially important biological and clinical implications

Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channels

Voltage-gated Ca2+ channels couple membrane depolarization to Ca2+-dependent intracellular signaling events. This is achieved by mediating Ca2+ ion influx or by direct conformational coupling to intracellular Ca2+ release channels. The family of Cav1 channels, also termed L-type Ca2+ channels (LTCCs), is uniquely sensitive to organic Ca2+ channel blockers and expressed in many electrically excitable tissues. In this review, we summarize the role of LTCCs for human diseases caused by genetic Ca2+ channel defects (channelopathies). LTCC dysfunction can result from structural aberrations within their pore-forming α1 subunits causing hypokalemic periodic paralysis and malignant hyperthermia sensitivity (Cav1.1 α1), incomplete congenital stationary night blindness (CSNB2; Cav1.4 α1), and Timothy syndrome (Cav1.2 α1; reviewed separately in this issue). Cav1.3 α1 mutations have not been reported yet in humans, but channel loss of function would likely affect sinoatrial node function and hearing. Studies in mice revealed that LTCCs indirectly also contribute to neurological symptoms in Ca2+ channelopathies affecting non-LTCCs, such as Cav2.1 α1 in tottering mice. Ca2+ channelopathies provide exciting disease-related molecular detail that led to important novel insight not only into disease pathophysiology but also to mechanisms of channel function

Dysfunctional autophagy induced by the pro-apoptotic natural compound climacostol in tumour cells

Autophagy occurs at a basal level in all eukaryotic cells and may support cell survival or activate death pathways. Due to its pathophysiologic significance, the autophagic machinery is a promising target for the development of multiple approaches for anti-neoplastic agents. We have recently described the cytotoxic and pro-apoptotic mechanisms, targeting the tumour suppressor p53, of climacostol, a natural product of the ciliated protozoan Climacostomum virens. We report here on how climacostol regulates autophagy and the involvement of p53-dependent mechanisms. Using both in vitro and in vivo techniques, we show that climacostol potently and selectively impairs autophagy in multiple tumour cells that are committed to die by apoptosis. In particular, in B16-F10 mouse melanomas climacostol exerts a marked and sustained accumulation of autophagosomes as the result of dysfunctional autophagic degradation. We also provide mechanistic insights showing that climacostol affects autophagosome turnover via p53-AMPK axis, although the mTOR pathway unrelated to p53 levels plays a role. In particular, climacostol activated p53 inducing the upregulation of p53 protein levels in the nuclei through effects on p53 stability at translational level, as for instance the phosphorylation at Ser15 site. Noteworthy, AMPK\u3b1 activation was the major responsible of climacostol-induced autophagy disruption in the absence of a key role regulating cell death, thus indicating that climacostol effects on autophagy and apoptosis are two separate events, which may act independently on life/death decisions of the cell. Since the activation of p53 system is at the molecular crossroad regulating both the anti-autophagic action of climacostol and its role in the apoptosis induction, it might be important to explore the dual targeting of autophagy and apoptosis with agents acting on p53 for the selective killing of tumours. These findings also suggest the efficacy of ciliate bioactive molecules to identify novel lead compounds in drug discovery and development

Effects of intrauterine food restriction and long-term dietary supplementation with L-arginine on age-related changes in renal function and structure of rats

We have previously demonstrated that restricting intrauterine food by 50% in 3-mo-old rats produced lower nephron numbers and early-onset hypertension, the latter being normalized by L-arginine administration. in 18-mo-old rats, such restriction increased glomerulosclerosis. in this study, we expanded our investigation, evaluating functional, morphologic, and immunohistochemical parameters in intrauterine-food-restricted 18-mo-old rats, either receiving L-arginine (RA18) or not (R18). Age-matched, non-food-restricted controls were assigned to similar groups with L-arginine (CA18) and without (C18). After weaning, L-arginine was given daily for 17 mo. No functional or morphologic changes were observed in C IS rats. the R18 rats developed early-onset hypertension, which persisted throughout the observation period, as well its significant proteinuria from 12 mo on. in RA18 rats, L-arginine decreased both blood pressure levels and proteinuria, and glomerular diameter was si,significantly smaller than in R18 rats (115.63 +/- 2.2 versus 134.8 +/- 1.0 mu m, p < 0.05). However, in RA18 rats, glomerular filtration rate remained depressed. Although L-arginine prevented glomerulosclerosis (R18 = 14%, RA18 = 4%; p < 0.05), glomerular expression of fibronectin and desmin was still greater in RA18 rats than in controls. Our data show that, although L-arginine prevented hypertension and proteinuria, glomerular injury still occurred, suggesting that intrauterine food restriction may be one of the leading causes of impaired renal function in adult life.Universidade Federal de São Paulo, Dept Physiol, EPM, Dept Physiol, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Physiol, EPM, Dept Morphol,Embrol Div, BR-04023900 São Paulo, BrazilUniv São Paulo, Ribeirao Preto Sch Med, Dept Physiol & Biophys, Brookline, MA 02146 USAUniversidade Federal de São Paulo, Dept Physiol, EPM, Dept Physiol, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Physiol, EPM, Dept Morphol,Embrol Div, BR-04023900 São Paulo, BrazilWeb of Scienc

Blood-based omic profiling supports female susceptibility to tobacco smoke-induced cardiovascular diseases

We recently reported that differential gene expression and DNA methylation profiles in blood leukocytes of apparently healthy smokers predicts with remarkable efficiency diseases and conditions known to be causally associated with smoking, suggesting that blood-based omic profiling of human populations may be useful for linking environmental exposures to potential health effects. Here we report on the sex-specific effects of tobacco smoking on transcriptomic and epigenetic features derived from genome-wide profiling in white blood cells, identifying 26 expression probes and 92 CpG sites, almost all of which are affected only in female smokers. Strikingly, these features relate to numerous genes with a key role in the pathogenesis of cardiovascular disease, especially thrombin signaling, including the thrombin receptors on platelets F2R (coagulation factor II (thrombin) receptor; PAR1) and GP5 (glycoprotein 5), as well as HMOX1 (haem oxygenase 1) and BCL2L1 (BCL2-like 1) which are involved in protection against oxidative stress and apoptosis, respectively. These results are in concordance with epidemiological evidence of higher female susceptibility to tobacco-induced cardiovascular disease and underline the potential of blood-based omic profiling in hazard and risk assessment

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk